Ug Notes

Compiled By: Jordiann A.
Samuels
MBBS/DDS 2K16

MDSC 3102- The Genito-Urinary System
(9 credits)
Lecture Notes

Areas Covered
Physiology
Pathology
Pharmacology
Medicine and Surgery
Microbiology
Obstetrics and Gynaecology

Compiled By: Jordiann A. Samuels
MBBS/DDS Class of 2016
UNIVERSITY OF THE WEST INDIES,
MONA
Faculty of Medical Sciences
Undergraduate MBBS/DDS Programme
Year 2, Semester 2
MBBS/DDS 2K16

Gross Anatomy

Physiology

1.Anatomy of Ureter

1.Introduction to Renal Physiology

2.Anatomy of Urinary Bladder

2.Glomerular Filtration

3.Anatomy of the Uterus

3.Tubular Reabsorption and Secretion

4.Anatomy of Bony Pelvis and Sexual Dimorphism

4.Tubular Excretion I

5.Anatomy of Uterine Tubes,Ovaries

5.Regulation of Kidney Function I and II

6.Support of the Uterus and Vagina

6.Normal Water and Electrolyte Metabolism

7.Perineal Region

7.Renal Endocrine function and neonatal Kidney

8.Scrotum, Spermatic Cord (Review of Inguinal
Canal)
8.Sexual Differentiation: Genetic Basis and
Methods of
Determination of gender

9.Testes, Epididymis, Seminal Vesicle

9.Sex Differentiation: Phenotype and Genotype

10.Gross Anatomy of Prostate

10.Abberation of Sexual Differentiation

11.Gross Anatomy and Histology of Penis and
Urethra
11.Puberty in Females: Timing and Body
Changes

Embryology: Anatomy

12.Puberty in Females :Menstrual Cycle

12.Embryology of Urinary System I and II
13.Male Reproduction: Pubertal Hormone
Changes

13.Embryology and Gross Anatomy of the Breast
14.Fertilisation, Implantation and Pregnancy
diagnosis

14.Embryology of the Male Reproductive System
15.Puberty: Hormonal Basis
15.Embryology of Female Reproductive System Pathology
16.Gross Anatomy of Posterior Abdominal Wall and
Kidney
1.Pathology of Kidney: Pathogenesis of
Glomerular Disease

17.Nerves, Blood supply and Lymphatics of the
Pelvis

2.Disorders of Water and Electrolyte Balance

Histology: Anatomy
3.Pathology of Kidney: Tubulointerstitial Disease
18.Histology of Kidney, Ureter and Urinary Bladder
4.Tests for Glomerular Filtration
19.Histology of Kidney, Ureter and Urinary Bladder
5.Renal Cysts and Tumours including Clinical
Aspects

20.Histology of Testes,Epididymis,Seminal
Vesicle,Vasdeferens,Prostate

6.Acid Base Balance

21.Histology of Uterus,Uterine Tube, Vagina and
Ovary

7.Pathology of Male Genitalia: Penis and Testes

22.Histology of Male Reproductive System 8.Pathology of Breast
Medicine
9.Bladder and Prostate Pathology
1.Nephrotic Syndrome
10. Tests of Tubular Function
2.Acute and Chronic Renal Failure Microbiology
3.Acute Pyelonephritis
1.Urinary Tract Infection

4. Clinical Application of Acid- Base Balance
2.Human Immunodeficiency Viral Infection

Surgery

3.Genital Ulcers (Practical Demonstration)

Pharmacology
1. Kidney Function Tests and Acute GN

1.Pharmacology Lab discussion of diuretics

2.Bladder and Prostate Cancer (Clinical Features)

3. Bladder Outflow Obstruction

4. Calculus Disease of the Urinary Tract

5. Urinary Tract Infection in Adults

MDSC 3102 The Genito Urinary System (9 credits) Year 2012/2013 Semester 2 Year 2

MBBS/DDS 2K16

DEFINITION
PROTEINURIA > 3.5 G/ D
HYPOALBUMINEMIA < 30 G/ L
EDEMA
CAUSES- COMMON
DIABETES MELLITUS
GLOMERULAR DISEASES
Minimal change disease
Focal and Segmental Glomerulosclerosis
Membranous Nephropathy
Membranoproliferative
LESS COMMON CAUSES
Sickle Cell Disease
Amyloidosis
Systemic Lupus Erythematosus
Infectious Diseases
Some Cancers
Some Drugs
INFECTIONS
Beta Hemolytic Streptococcus
Lecture 1: Nephrotic Syndrome

Winston Williams MBBS DM FACP FASN
Senior Lecturer in Medicine and Nephrology

MBBS/DDS 2K16
Sub acute bacterial endocarditis
Viral
Hepatitis B and C
Human Immunodeficiency Virus
Quartan Malaria
Treponema Pallidum
DRUGS
Gold
Penicillamine
Non Steroidal Antiinflammatory Drugs
High Dose Captopril
Interferon alpha
CANCERS
Prostate
Bronchus
Large Bowel
Lymphomas
Leukemias

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MECHANISMS OF PROTEINURIA
Proteins in excess of 70 kd do not pass through glomerular basement membrane
2 main processes are
Charge selectivity
Size selectivity > 150 kd

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CELLULAR MECHANISM
Activation of T Cells leads to
Production of non immunoglobulin circulating permeability factor examples
Minimal Change Disease
Focal and Segmental Glomerulosclerosis
HUMORAL MECHANISM
Circulating immune complexes are deposited in the kidneys leading to
Activation of the complement system
Release of Cytokines
Generation of Chemoattractants
Infiltration of inflammatory cells: Neutrophils, Lymphocytes and Macrophages.
Proliferation of Mesangial and Endothelial cells.
CAUSES OF EDEMA
Underfill theory
Overfill theory

MBBS/DDS 2K16
CLINICAL FEATURES
Salt and Water retention
Edema: ankles, periorbital, sacral
3
rd
space: ascites, pleural effusions
COMPLICATIONS
Infections
Thromboembolic
Dyslipidemias
Changes in drug availability
INFECTIONS
Immunosupressed
Reduced levels of immunoglobulins
Reduced levels of alternative complement factor B
Pneumococcal pneumonias
Bacterial peritonitis
HYPERCOAGULABLE
Increase in progoagulatory factors: V, VIII
Increase in Fibrinogen level
Reduction in coagulation inhibitors
antithrombin III
NOT Protein C and S
Increased platelet reacitivity
Altered endothelial function
HYPERLIPIDEMIA
Increased production
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Defective catabolism of apolipoprotein B containing lipoproteins
Increases in VLDL, LDL and Lp(a)
HDL normal
Decrease catabolism of chylomicrons and VLDL
Decrease catabolism of LDL and apolipoprotein
Laboratory Investigations
Full Blood Count
ESR and CRP
PT and PTT
Urea, Electrolytes, Creatinine
Albumin, Immunoglobulins
Complemrnt: C3 and C4
Calcium, Phosphorous, Alkaline Phosphatase
Uric Acid
Hepatitis B and C
HIV, VDRL, FTA
ASOT, Anti nuclear factor
Anti double stranded DNA
Anti Sm, Anti SSA, Anti SSB
Rheumatoid Factor
Anti Neutrophil Cytoplasmic Antibody (ANCA)
Anti Glomerular Basement Antibody
Lupus Anticoagulant
Anti Phospholipid Antibody
Serum and Urine protein electrophoresis
Fasting blood glucose
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Lipid profile
Urinanalysis, Culture
Urine Microscopy
Urinary Protein Excretion
24 Hour Collection
Timed overnight Collection
Urine albumin to Creatinine ratio in random sample
Creatinine Clearance
24 hour urine collection
Calculated
INVESTIGATIONS
Renal Ultrasound
Renal Biopsy
MANAGEMENT
EDEMA
HYPERLIPIDEMIA
HYPERCOAGULABLE STATE
MEASURES TO REDUCE PROTEINURIA
EDEMA
Salt and Water Restriction
Furosemide
Metolozone
Aldosterone antagonist eg Spironolactone
HYPERLIPIDEMIA
Dietary
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Low fat and Cholesterol diet
Soy diet
Fish oil
Lipid lowering drugs
HYPERCOAGUABLE STATE
Prophylactic partial antigcoagulation with Heparin if patient is on bed rest
Full anticoagulation if serum albumin is less than 20G/L
MEASURES TO REDUCE PROTEINURIA
Angiotensin Converting Enzyme Inhibitors ( ACE)
Angiotensin Receptor Blockers (ARB)
? NSAIDS
Management of Glomerulonephritis
Steroids
Cytotoxics
Cyclophosphamide
Azathioprine
Methotrexate
Chlorambucil
Mycophenolate Moffetil
Cyclosporine A

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Lecture 2: ACUTE AND CHRONIC RENAL FAILURE
(CLINICAL ASPECTS)

- Dr. A. Soyibo
- Department of Medicine
- www.caribbeaninstituteofnephrology.com
OBJECTIVES
- Introduction
- Definition
- Pathophysiology
- Staging of AKI and CKD
- Clinical presentation
- Laboratory investigation
- Management strategy
- Follow-up

ECONOMIC MODEL
- AN INDIAN CORPORATION: You have two cows. You worship them.
- A BRITISH CORPORATION: You have two cows. Both are mad.
DEFINITION
Chronic kidney disease is either
kidney damage or
a decreased kidney glomerular filtration rate (GFR) of less than 60 mL/min/1.73
m
2

for 3 or more months
Acute renal failure (ARF) or acute kidney injury (AKI)
is defined as an abrupt or rapid decline in renal filtration function
PATHOPHYSIOLOGY: AKI
This condition is usually marked by a rise in serum creatinine concentration or azotemia.
However, immediately after a kidney injury, BUN or creatinine levels may be normal, and the
only sign of a kidney injury may be decreased urine production.
AKI can be oliguric or non-oliguric

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OLIGURIA
<400ml/24hours
ANURIA
<100ml/24
NON-OLIGURIA
>400ml/24hours
AKI may be classified into 3 general categories, as follows:
Prerenalas an adaptive response to severe volume depletion and hypotension, with
structurally intact nephrons
Intrinsicin response to cytotoxic, ischemic, or inflammatory insults to the kidney,
with structural and functional damage
Postrenalfrom obstruction to the passage of urine.
PATHOPHYSIOLOGY OF CKD
Approximately 1 million nephrons are present in each kidney, each contributing to the total
GFR.
With progressive destruction of nephrons, the kidney has an innate ability to maintain GFR by
hyperfiltration and compensatory hypertrophy of the remaining nephrons.
This nephron adaptability allows for continued normal clearance of plasma solutes so that
substances such as urea and creatinine start to show significant increases in plasma levels only
after total GFR has decreased to 50%,
The plasma creatinine value will approximately double with a 50% reduction in GFR.
The residual nephron hyperfiltration and hypertrophy, although beneficial for the reasons
noted, represent a major cause of progressive renal dysfunction.
This is because of increased glomerular capillary pressure, which damages the capillaries and
leads to
focal and segmental glomerulosclerosis
and eventually to global glomerulosclerosis..
Factors other than the underlying disease process and glomerular hypertension that may cause
progressive renal injury include the following:
Systemic hypertension
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Acute insults from nephrotoxins or decreased perfusion
Proteinuria
Increased renal ammoniagenesis with interstitial injury
Hyperlipidemia
Hyperphosphatemia with calcium phosphate deposition
Decreased levels of nitrous oxide
Smoking
Staging of AKI and CKD
The RIFLE system
AKIN classification
The Kidney Disease Outcomes Quality Initiative (K/DOQI) classification
Staging of AKI
In 2004, the Acute Dialysis Quality Initiative work group set forth a definition and classification
system for acute renal failure, described by the acronym RIFLE
R: Risk of renal dysfunction
I: Injury to the kidney
F: Failure
L: Loss of kidney function, and
E: End-stage kidney disease;
RIFLE CLASSIFICATION OF AKI
Stage GFR Criteria Urine Output
Criteria
Risk
SCreat increased 1.5 UO <0.5 mL/kg/h 6 h
or GFR decreased >25%
Injury
SCreat increased 2 UO <0.5 mL/kg/h 12 h
or GFR decreased >50%
Failure
SCreat increased 3 UO <0.3 mL/kg/h 24 h (oliguria)
or GFR decreased 75%
or SCreat 4 mg/dL anuria 12 h
acute rise 0.5 mg/dL
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Loss
Persistent acute renal failure: complete loss of kidney function >4 wk

ESKD*
Complete loss of kidney function >3 mo

RIFLE System
Patients can be classified by GFR criteria and/or UO criteria.
The criteria that support the most severe classification should be used.
The superimposition of acute on chronic failure is indicated with the designation RIFLE-F C
When the failure classification is achieved by UO criteria, the designation of RIFLE-F O is used to
denote oliguria.
AKIN CLASSIFICATION OF AKI
AKI stage Creatinine criteria Urine output criteria
Stage I Increase of serum creatinine by < 0.5 ml/kg/hour for > 6
hours
26.4 mol/L or increase to
150% 200% from baseline

Stage II
Increase of serum creatinine to < 0.5 ml/kg/hour for > 12 hours
> 200% 300% from baseline
Stage III
Increase of serum creatinine to < 0.3 ml/kg/hour for > 24 hours
or > 300% from baseline
or serum creatinine 354 mol/L anuria for 12 hours
after a rise of at least 44 mol/L
or
treatment with renal replacement
therapy

MBBS/DDS 2K16
CLINICAL CLASSIFICATION OF AKI
Reversible
Reduced effective renal perfusion
Extra renal obstruction to renal flow
Self limited
ATN
AIN
Renal tubular obstruction: drugs, uric acid
AGN
Irreversible
Cortical necrosis
Large vessel occlusion
Certain nephrotoxin: methoxyflourane
STAGING OF CKD
Whatever the underlying etiology, the destruction of renal mass with irreversible sclerosis and
loss of nephrons leads to a progressive decline in GFR.
The different stages of chronic kidney disease form a continuum in time.
Staging of CKD
Stage 1:
Kidney damage with normal or increased GFR (>90 mL/min/1.73 m
2
)
Stage 2:
Mild reduction in GFR (60-89 mL/min/1.73 m
2
)
Stage 3:
Moderate reduction in GFR (30-59 mL/min/1.73 m
2
)
Stage 4:
Severe reduction in GFR (15-29 mL/min/1.73 m
2
)
Stage 5:
Kidney failure (GFR <15 mL/min/1.73 m
2
or dialysis)
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In stage 1 and stage 2 chronic kidney disease, GFR alone does not clinch the diagnosis. Other
markers of kidney damage, including abnormalities in the composition of blood or urine or
abnormalities in imaging tests, should also be present in establishing a diagnosis of stage 1 and
stage 2 chronic kidney disease.
CLINICAL PRESENTATION
Distinguishing AKI from chronic renal failure is important, yet making the distinction can be
difficult.
A history of chronic symptoms fatigue, weight loss, anorexia, nocturia, and pruritus
suggests chronic renal failure.
History
A detailed and accurate history is crucial to aid in diagnosing the type of AKI and in determining
its subsequent treatment.
A detailed history and a physical examination in combination with routine laboratory tests are
useful in making a correct diagnosis.
Urine output history can be useful.
Oliguria generally favors AKI.
Abrupt anuria suggests
acute urinary obstruction
acute and severe glomerulonephritis
embolic renal artery occlusion.
A gradually diminishing urine output may indicate a urethral stricture or bladder outlet
obstruction due to prostate enlargement
People with the following comorbid conditions are at a higher risk for developing AKI
Hypertension
Congestive cardiac failure
Diabetes
Sickle cell disease
SLE
Multiple myeloma
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Chronic infection
Myeloproliferative disorder
Take note of the following findings during the physical examination (AKI)
Hypotension
Volume contraction
Congestive heart failure
Nephrotoxic drug ingestion
History of trauma or unaccustomed exertion
Blood loss or transfusions
Evidence of connective tissue disorders or autoimmune diseases
Exposure to toxic substances, such as ethyl alcohol or ethylene glycol
Exposure to mercury vapors, lead, cadmium, or other heavy metals, which can be
encountered in welders and miners
History: CKD
Patients with CKD stages 1-3 (GFR >30 mL/min) are generally asymptomatic and do not
experience clinically evident disturbances in water or electrolyte balance or
endocrine/metabolic derangements.
Generally, these disturbances clinically manifest with chronic kidney disease stages 4-5 (GFR
<30 mL/min).
Uremic manifestations in patients with chronic kidney disease stage 5 are believed to be
primarily secondary to an accumulation of toxins.
Physical: CKD
The physical examination often is not very helpful but may reveal findings characteristic:
Of the condition underlying chronic kidney disease (eg, lupus, severe arteriosclerosis,
hypertension)
Or complications of chronic kidney disease (eg, anemia, bone disease, bleeding diathesis,
pericarditis,).
Other manifestations of uremia in CKD
Pericarditis - Can be complicated by cardiac tamponade, possibly resulting in death.
MBBS/DDS 2K16
Encephalopathy - Can progress to coma and death
Peripheral neuropathy
Restless leg syndrome
GI symptoms - Anorexia, nausea, vomiting, diarrhea
Skin manifestations - Dry skin, pruritus, ecchymosis
Fatigue, increased somnolence, failure to thrive
Malnutrition
Erectile dysfunction, decreased libido, amenorrhea
Platelet dysfunction with tendency to bleeding
CAUSES
Causes: Prerenal AKI
Volume depletion
Renal losses (diuretics, polyuria)
GI losses (vomiting, diarrhea)
Cutaneous losses (burns, Stevens-Johnson syndrome)
Hemorrhage
Pancreatitis
Decreased cardiac output
Heart failure
Pulmonary embolus
Acute myocardial infarction
Severe valvular disease
Abdominal compartment syndrome (tense ascites)
Systemic vasodilation
Sepsis
Anaphylaxis
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Anesthetics
Drug overdose
Afferent arteriolar vasoconstriction
Hypercalcemia
Drugs (NSAIDs, amphotericin B, calcineurin inhibitors, norepinephrine,
radiocontrast agents)
Hepatorenal syndrome
Efferent arteriolar vasodilation ACEIs or ARBs
Causes: Intrinsic AKI
Vascular (large and small vessel)
Renal artery obstruction (thrombosis, emboli, dissection, vasculitis)
Renal vein obstruction (thrombosis)
Microangiopathy (TTP, hemolytic uremic syndrome [HUS], DIC, preeclampsia)
Malignant hypertension
Scleroderma renal crisis
Transplant rejection
Atheroembolic disease
Glomerular
Antiglomerular basement membrane (GBM) disease (Goodpasture syndrome)
Antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-
associated GN) (Wegener granulomatosis, Churg-Strauss syndrome, microscopic
polyangiitis)
Immune complex GN (lupus, postinfectious, cryoglobulinemia, primary
membranoproliferative glomerulonephritis)
Tubular
Ischemic
Cytotoxic
Heme pigment (rhabdomyolysis, intravascular hemolysis)
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Crystals (tumor lysis syndrome, seizures, ethylene glycol poisoning,
megadose vitamin C, acyclovir, indinavir, methotrexate)
Drugs (aminoglycosides, lithium, amphotericin B, pentamidine, cisplatin,
ifosfamide, radiocontrast agents)
Interstitial
Drugs (penicillins, cephalosporins, NSAIDs, proton-pump inhibitors, allopurinol,
rifampin, indinavir, mesalamine, sulfonamides)
Infection (pyelonephritis, viral nephritides)
Systemic disease (Sj gren syndrome, sarcoid, lupus, lymphoma, leukemia,
tubulonephritis, uveitis)
Causes: Postrenal AKI
Ureteric obstruction (stone disease, tumor, fibrosis, ligation during pelvic surgery)
Bladder neck obstruction (benign prostatic hypertrophy [BPH], cancer of the prostate
[CA prostate or prostatic CA], neurogenic bladder, tricyclic antidepressants, ganglion
blockers, bladder tumor, stone disease, hemorrhage/clot)
Urethral obstruction (strictures, tumor, phimosis)
Causes: CKD
Primary glomerular disease
Membranous nephropathy,
immunoglobulin A (IgA) nephropathy,
focal and segmental glomerulosclerosis (FSGS),
minimal change disease,
membranoproliferative glomerulonephritis,
rapidly progressive (crescentic) glomerulonephritis
Secondary glomerular disease
Diabetes mellitus
hypertension
systemic lupus erythematosus, rheumatoid arthritis,
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mixed connective tissue disease, scleroderma,
mixed cryoglobulinemia,
hepatitis B and C,
human immunodeficiency virus (HIV), parasitic infection,
heroin use,
Drugs: gold, penicillamine,
amyloidosis,
light chain deposition disease,
neoplasia,,
Alport syndrome,
reflux nephropathy
Vascular disease
Renal artery stenosis,
ANCApositive vasculitides,
Atheroemboli
renal vein thrombosis
Tubulointerstitial disease
Drugs (e.g, sulfa, allopurinol),
infection (viral, bacterial, parasitic)
sarcoidosis,
multiple myeloma cast nephropathy,
heavy metals,
radiation nephritis,
polycystic kidneys,
cystinosis
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Urinary tract obstruction - Urolithiasis, benign prostatic hypertrophy, tumors, retroperitoneal
fibrosis, urethral stricture, neurogenic bladder
Laboratory Studies
Several laboratory tests are useful for assessing the etiology of AKI, and the findings can aid in
proper management.
These tests include
complete blood count (CBC),
serum biochemistries,
urine analysis with microscopy,
urine electrolytes.
Serum electrolytes, BUN, and creatinine
The BUN and creatinine levels will be elevated in patients with chronic kidney disease.
Hyperkalemia or low bicarbonate levels may be present in patients with chronic kidney
disease.
Serum calcium, phosphate, vitamin D, and intact parathyroid hormone (PTH) levels are
obtained to look for evidence of renal bone disease
CBC count - Normochromic normocytic anemia is commonly seen in chronic kidney disease.
Other underlying causes of anemia should be ruled out.
Serum albumin - Patients may have hypoalbuminemia due to urinary protein loss or
malnutrition.
Lipid profile - A lipid profile should be performed in all patients with chronic kidney disease
because of their increased risk of cardiovascular disease.
Urinalysis
proteinuria may suggest a glomerular or tubulointerstitial problem.
urine sediment finding of RBCs, RBC casts, suggests proliferative glomerulonephritis.
Pyuria and/or WBC casts are suggestive of interstitial nephritis (particularly if
eosinophiluria is present) or urinary tract infection.
Spot urine collection for total protein-to-creatinine ratio allows reliable approximation
(extrapolation) of total 24-hour urinary protein excretion.
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A value of greater than 2 g is considered to be within the glomerular range, and a value
of greater than 3-3.5 g is within the nephrotic range;
less than 2 is characteristic of tubulointerstitial problems.
Twenty-fourhour urine collection for total protein and CrCl
In certain cases, the following tests may be ordered as part of the evaluation of patients with
chronic kidney disease:
Serum and urine protein electrophoresis to screen for a monoclonal protein possibly
representing multiple myeloma
Antinuclear antibodies (ANA), double-stranded DNA antibody levels to screen for
systemic lupus erythematosus
Serum complement levels - May be depressed with some glomerulonephritides
C-ANCA and P-ANCA levels - Helpful if positive in diagnosis of Wegener granulomatosis
and polyarteritis nodosa or microscopic polyangiitis, respectively
Antiglomerular basement membrane (anti-GBM) antibodies - Highly suggestive of
underlying Goodpasture syndrome
Hepatitis B and C, HIV, Venereal Disease Research Laboratory (VDRL) serology -
Conditions associated with some glomerulonephritides
Histological Studies
Renal biopsy
Percutaneous and open
Light microscopic examination
Immunoflorescence
Electron microscopy
Other tissue site for histology
Fat pad
Skin lession
Imaging Studies
Plain abdominal x-ray
Intravenous pyelogram
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Renal ultrasound -
Renal radionuclide scan
CT scan -
MRI
Voiding cystourethrogram (VCUG) - Criterion standard for diagnosis of vesicoureteral reflux
TREATMENT
THERAPY FOR AKI
IDENTIFY ETIOLOGY AND DISCONTINUE
Fluid balance
Correct acid/base disturbance
Metabolic disturbance: hyperkalemia
hematologic abnormalities (eg, anemia, platelet dysfunction)
The medical care of patients with CKD should focus on the following:
Delaying or halting the progression of chronic kidney disease
Treatment of the underlying condition if possible
Aggressive blood pressure control to target values per current guidelines.
Use of ACE inhibitors or angiotensin receptor blockers as tolerated,
Aggressive glycemic control per the American Diabetes Association (ADA)
recommendations (target HbA1C <7%)
Protein restriction
Treatment of hyperlipidemia to target levels per current guidelines
Avoidance of nephrotoxins - IV radiocontrast, nonsteroidal anti-inflammatory agents,
aminoglycosides
Encourage smoking cessation, as smokers tend to reach ESRD earlier than nonsmokers.
bicarbonate supplementation
Treating the pathologic manifestations of chronic kidney disease, including the following
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Anemia with erythropoietin, with the goal being 11-12 g/dL, as normalization of
hemoglobin in patients with chronic kidney disease stages 4-5 has been associated with
an increased risk of combined outcome. Before starting Epogen, iron stores should be
checked, and the aim is to keep iron saturation at 30-50% and ferritin at 200-500.
Hyperphosphatemia with dietary phosphate binders and dietary phosphate restriction
Hypocalcemia with calcium supplements with or without calcitriol
Hyperparathyroidism with calcitriol or vitamin D analogs
Volume overload with loop diuretics or ultrafiltration
Metabolic acidosis with oral alkali supplementation
Uremic manifestations with chronic renal replacement therapy
Cardiovascular complications
Timely planning for chronic renal replacement therapy
Early education regarding natural disease progression, different dialytic modalities,
renal transplantation, patient option to refuse or discontinue chronic dialysis
Timely placement of permanent vascular access (arrange for surgical creation of
primary arteriovenous fistula, if possible, and preferably at least 6 months in advance of
anticipated date of dialysis)
Timely elective peritoneal dialysis catheter insertion
Timely referral for renal transplantation

MBBS/DDS 2K16
Lecture 3: ACUTE PYELONEPHRITIS

Winston Williams MBBS DM FACP FASN
Senior Lecturer in Medicine and Nephrology
OBJECTIVES
Definition
Causes
Clinical Features
Investigations
Management
Long term Outcome

DEFINITION
Clinical Syndrome consisting of
Flank pain(bilateral or unilateral)
Fever and chills
Renal tenderness
Bacteruria

Bacterial Infection involving
Renal pelvis and calyces
Renal tubules
Interstitum
Blood vessels
Glomeruli rarely if ever
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Uncomplicated:young non pregnant female
Complicated : All other types
Community acquired
Hospital acquired: Nosocomial
COMPLICATED URINARY TRACT INFECTIONS
Diabetes
Pregnancy
History of acute pyelonephritis in the past year
Symptoms for seven or more days before seeking care
Broad-spectrum antimicrobial resistant uropathogen
Hospital acquired infection
Renal failure
Urinary tract obstruction
Presence of an indwelling urethral catheter, stent, nephrostomy tube or urinary diversion
Recent urinary tract instrumentation
Functional or anatomic abnormality of the urinary tract
History of urinary tract infection in childhood
Renal transplantation
Immunosuppression
Community acquired organisms
E. coli: 75-90%
Klebsiella pneumnoniae
Proteus Mirabilis
Staphylococcus Saphrophyticus
Staphylococcus Aureus

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Hospital acquired organisms
E. coli
Pseudomonas Aurigenosa
Serratia Marcesens
PREVALENCE AND INCIDENCE
Annual incidence of 16 per 100000 population
Greater in females than males below age 60 years. M=F in over 60 years.
Uncommon in males between 1 and 20 years.
20% community acquired bacteremias due to invasive urinary tract infections.
7 per 10000 hospitalised persons will get pyelonephritis.
Patients who have had a previous attack are at increased risk.
Average attack in these patients is about 2.5 per patient year.
Ratio of cystitis to pyelonephritis is 18:1
ASYMPTOMATIC UPPER URINARY TRACT INFECTION
Incidence unknown
Certain factors influence the spread of infection to upper urinary tract
Factors influencing spread of bacteria to upper urinary tract.
Duration of bacteruria
Infecting organisms
Associated medical ilnesses
Presence of vesicoureteric reflux
Urinary tract obstruction.
Associated conditions
Pregnancy
Diabetes Mellitus in females but not males
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Increasing age over 65 years.
Nursing home residents
Sexually active females
Pathogenesis of Renal invasion
Organisms
Resistance to the bactericidal activity of
normal human serum
Presence of adhesion molecules that bind
to receptors on epithelial cells.
Host factors
Obstruction at level of kidney or ureters.
Voiding abnormalities: Neurogenic bladder. Prostatic hyperplasia. Urethral strictures
Host Response
Local
Pyuria
Inflammatory mediators: Interlukins 6, 8
Urinary antibodies.
Systemic inflammatory response ranging from none to septic shock.
Interleukin 1 and 6 levels are increased.
C Reactive Protein levels increased.
Serum antibody response.
Clinical Features
Pyrexia usually > 38.5
o
C
Chills and Rigors
Pain tenderness in lumbar flank regions.
Generalised constitutional symptoms
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Headaches, vomiting, diahorrea, myalgia.
15-30% have associated symptoms of lower
urinary tract infection.
50% will have had a cystitis in the previous 6 months.
Differential Diagnosis
Acute bacterial pneumonia
Acute appendicitis
Perforated viscus
Splenic infarction
Acute pancreatitis
Aortic dissection
Acute pelvic inflammatory disease
Renal infarction
Acute glomerulonephritis
Laboratory Diagnosis
MSU( Mid stream specimen of urine)
2 positive cultures with same organism
Colony count of 10
5
/ml.
In males 1 positive culture is sufficient.
Pus cells > 10/cmm in unspun urine
Microscopic hematuria
Blood cultures
INDICATIONS FOR RENAL IMAGING
MALES
DELAYED RESPONSE TO ANTIBIOTICS
DIABETES OR IMMUNOSUPRESSED
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VIRULENT ORGANISM : PSEUDOMONAS
RECURRENT EPISODES OR RELAPSE WITH SAME ORGANISM
UROSEPSIS
SYMPTOMS OF RENAL COLIC
Organ Imaging
Ultrasound abdomen
CAT scan abdomen
Abdominal X Ray
Intravenous Pyelogram(IVP)

Renal ultrasonography in a patient with acute pyelonephritis showing a hypodense mass with
internal echoes (outlined by the arrows).
Courtesy of Alain Meyrier, MD.

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Contrast-enhanced CT scan in bilateral acute pyelonephritis showing triangular hypodense streaks
spreading from the pelvis to the renal cortex (arrows).

Contrast-enhanced CT scan in a patient with acute pyelonephritis showing a large,
hypodense region in the right kidney. There is no discrete abscess formation in this setting.

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Inpatient Management
Supportive
Intravenous fluids
Analgesics
Bed rest
Antibiotics: Intravenous
Cephalosporin
Fluroquinolone
Penicillin and aminoglycoside
Switch to oral antibiotics after 3 days if patient is afebrile.
Total duration of therapy 2 weeks.
Follow up
Urine culture 1 and 4 weeks after therapy.
10-15% women will relapse after 4 weeks
40 % males will relapse after 4 weeks.
50% patients with urinary tract abnormality will relapse in 6 weeks.
COMPLICATIONS OF ACUTE PYELONEPHRITIS
EMPHYSEMATOUS PYELONEPHRITIS
RENAL CORTICOMEDULLARY ABSCESS
PERINEPHRIC ABSCESS
PAPILLARY NECROSIS
Long term Complications
Recurrent pyelonephritis
Significant renal damage
Renal calculi
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Does not contribute to chronic renal failure
Does not cause hypertension

MBBS/DDS 2K16
Lecture 4: Clinical application of Acid-Base balance

- Dr Alan Barnett
- Consultant Anaesthetist
- Lecturer, Anaesthesia & Intensive Care
OBJECTIVES
Describe how to apply previously learned information to a clinical setting and
explain the need for homeostasis
Classify the types of derangement which may occur
Discuss the aetiology of acid-base derangement
Explain how to diagnose specific conditions
Propose a treatment plan for these derangements

Introduction
Maintenance of stable pH in body fluids is necessary for normal enzyme activity, ion
distribution and protein structure
Normal blood pH is maintained at
7.35 7.45
[H
+
] = 35 - 45 nmol l
-1

Normal values
Arterial blood pH : 7.35 7.45
PaCO2: 35 - 45 mmHg
[HCO3
-
] 20 - 28 mmol l
-1

Arterial lactate: 0.5 - 1.6 mmol l
-1

Venous lactate: 0.5 - 2.2 mmol l
-1

Deviations of systemic acidity in either direction can have adverse consequences
When severe, this may be life-threatening
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It is the nature of the condition responsible for the change which largely determines the
patients prognosis
Management of serious acid-base disorders always demands precise diagnosis and
treatment of the underlying disease
Of secondary importance is the direct treatment of the deviation in systemic acidity
(usually)
Remember . . .
Maintenance of pH depends upon
Buffers
Renal regulation of bicarbonate
Pulmonary regulation of carbon dioxide
H2O + CO2 H2CO3 HCO3
-
+ H
+

pH = pKa + log [HCO3
-
] / [CO2]
Classification
Acidosis (acidaemia)
pH < 7.35
Alkalosis (alkalaemia)
pH > 7.45
Metabolic
Respiratory
Compensation
There is always an attempt at compensation by the other process
Compensation results in the pH tending towards normal
Compensation can never overshoot
Consequences of severe acidaemia
Cardiovascular
Impairment of cardiac contractility
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Arteriolar dilatation, venoconstriction
Increased pulmonary vascular resistance
Reduction in CO, ABP, hepatic & renal blood flow
Myocardial sensitization
Attenuation of cardiovascular responsiveness to catecholamines
Respiratory
Hyperventilation
Decreased strength of respiratory muscles
Generalized muscle fatigue
Dyspnoea
Metabolic
Increased metabolic demands
Insulin resistance
Inhibition of anaerobic glycolysis
Reduction in ATP synthesis
Hyperkalaemia
Increased protein degradation
Cerebral
Inhibition of metabolism
Inhibition of cell-volume regulation
Obtundation and coma
Consequences of severe alkalaemia
Cardiovascular
Arteriolar constriction
Reduction in coronary blood flow
Reduction in anginal threshold
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Predisposition to supraventricular and ventricular dysrhythmias
Respiratory
Hypoventilation
Hypercapnoea
Hypoxia
Metabolic
Stimulation of anaerobic glycolysis and organic acid production
Hypokalaemia an almost constant feature, especially with metabolic disorders
Decreased plasma ionized calcium concentration
Hypomagnesaemia & Hypophosphataemia
Cerebral
Reduction in cerebral blood flow
Diagnosis
- HISTORY
- EXAMINATION
- INVESTIGATIONS
Acidosis
Increased production of acids
Loss of alkali
Decreased renal excretion of acids
Specific investigations
Serum bicarbonate
Arterial blood gases
Serum lactate
Look at pH
Identify the respiratory component
Identify the metabolic component
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Apply the information to clinical situation
Treatment
A
B
C
Lactic acidosis
Lactate is a byproduct of anaerobic glycolysis
It may also accumulate if gluconeogenesis is reduced
Lactic acidosis is defined as a metabolic acidosis accompanied by raised plasma lactate
levels
Lactic acidosis type A
Due to overt tissue hypoxia
Severe hypoxaemia
Severe anemia
Shock / haemorrhage / hypotension
Cardiac failure
Severe exercise
Lactic acidosis type B
Without apparent initial tissue hypoxia
Diabetes mellitus
Hepatic failure
Renal failure
Severe infection, leukemia, lymphoma
Drug-induced: biguanides, alcohols, salicylates
Glycogen storage disorders
Lactic acidosis - treatment
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Secure adequate tissue oxygenation
FIO2, ventilation,
Infusion / transfusion
Afterload reduction, avoid vasoconstriction
Identify & treat the underlying cause

Prognosis is often ominous, because the underlying disease cannot be managed effectively
It is best to prevent its occurrence by optimizing patient management
Consider administration of bicarbonate
Diabetic ketoacidosis
Insulin administration is the cornerstone of management
Replace deficits of water, sodium, and potassium
Alkali should not be administered routinely
Management should be aggressive, with close monitoring
Alcoholic ketoacidosis
Mainstay of therapy is provision of nutrients and interruption of alcohol intake
Also administer volume (i.e. saline)
Lifestyle changes needed
Methanol / Ethylene glycol
These may produce severe metabolic acidoses caused by the accumulation of toxic
metabolites
May require large amounts of alkali
Additionally
Gastric lavage, oral charcoal, i.v. ethanol (!)
Haemodialysis, forced diuresis

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Aspirin intoxication
Good exam question!
Variable clinical picture
Respiratory alkalosis, mixed respiratory alkalosis, metabolic acidosis
Administer activated charcoal
Increase alkalinity of blood and urine
Haemodialysis
Other metabolic acidoses
Loss of bicarbonate from digestive tract
Renal failure
Dilutional acidosis
Respiratory acidosis
This occurs whenever CO2 production is greater than CO2 removal by alveolar ventilation
Aetiology
Aetiology is as for respiratory failure
. . . See earlier notes!
Management
A B C
? Mechanical ventilation
Treat underlying cause
Alkali therapy sodium bicarbonate
Sometimes needed to reverse severe acidosis ( pH < 7.1), or to buy time
Dose in mmol = Base deficit x body wt (kg)
3
Half of this dose is given initially, as an infusion

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Risks of bicarbonate therapy
Hypernatraemia
Hyperosmolality
Extracellular-fluid volume overload
Overshoot alkalosis
Increase in CO2 leading to paradoxical intracellular acidosis if ventilation is inadequate
Metabolic alkalosis - aetiology
Acid loss
Vomiting, nasogastric aspiration
Base ingestion
Bicarbonate (usually iatrogenic)
Citrate from blood transfusion
Milk-alkali syndrome
Forced alkaline diuresis
Potassium/chloride depletion acid urine production
Remember that hypokalaemia is an almost constant feature.
There is also usually a marked ECF volume deficit
Metabolic alkalosis - management
Address the factors that have caused the problem
Correction of ECF volume and potassium deficit
Rarely, consider acid therapy
Ammonium chloride, hydrochloric acid
Be cautious when treating patients with cardiac or renal dysfunction
Haemodialysis or haemofiltration may be required
Respiratory alkalosis
This may be the most frequently encountered acid-base disorder
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Occurs in normal pregnancy and with high-altitude residence
Respiratory alkalosis aetiology
Various hypoxaemic conditions
Pulmonary disorders
CNS diseases
Salicylate intoxication
Hepatic failure
Sepsis
Anxiety-hyperventilation syndrome
Respiratory alkalosis - management
Treat the underlying cause
Summary
Maintenance of stable pH in body fluids is necessary for normal enzyme activity, ion
distribution and protein structure
Disorders may be classified as Acidosis or Alkalosis, with each group divided into
Metabolic or Respiratory causes
Management of serious acid-base disorders always demands precise diagnosis and
treatment of the underlying disease:
- Accurate diagnosis is the first step in management
- Treatment is directed at the underlying disorder
Direct manipulation of pH is rare and must be done cautiously

END OF MEDICINE SECTION

MBBS/DDS 2K16
Lecture 5: KIDNEY FUNCTION TEST AND ACUTE
GLOMERULONEPHRITIS

- Dr. A. Soyibo
- Department of Medicine
- www.caribbeaninstituteofnephrology.com

OBJECTIVES
KIDNEY FUNCTION TEST
BLOOD INVESTIGATION
URINE TEST
IMAGING
KIDNEY BIOPSY

SCHEMATIC DIAGRAM OF THE FILTERATION SYSTEM

Measuring Kidney Function
BUN
When elevated reflects an decrease in kidney function.
Pre-renal cause (ratio 10:1)
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While there is a "normal range
"normal" serum urea depends
Blood in the gut
Protein load
Liver cirrhosis
serum creatinine
When elevated reflects an decrease in kidney function.
Acute or chronic
While there is a "normal range"
normal" serum creatinine depends
muscle mass
level of activity
GFR (glomeruli filtration rate)
measures the rate at which the kidneys' two million glomeruli filter plasma.
In chronic kidney disease (CKD), the GFR gradually declines
kidney function can be estimated by measuring or calculating the GFR.
The normal value for GFR in a normal-sized person is 100-150 ml/min.
Methods for determining GFR are
creatinine clearance
Mathematical equation
Creatinine clearance
requires collection of a 24-hour urine;
the patient must save all the urine that they produce for a 24-hour period.
A blood sample is drawn at some point during the 24-hour period, and creatinine clearance.
eGFR (estimated GFR) determined by the Cockcroft-Gault formula
A simpler method for estimating creatinine clearance is based upon a formula that includes
a
age
gender
weight
serum creatinine level
but does not require the collection of a 24-hour urine.
eGFR (estimated GFR) determined by the MDRD equation
developed as part of a study called the Modification of Diet in Renal Disease (MDRD) Study,
can estimate GFR based on a:
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age
gender
ethnicity
serum creatinine level.
eGFR
The "eGFR" when determined by this equation) is the basis for classifying CKD into 5 stages.
Urine Tests
One of the primary functions of the kidneys is to filter blood and remove waste products.
Urine tests measure how well kidney filters.
When functioning normally, glomerular filters are able
to filter out wastes,
but keep protein and red blood cells in the bloodstream.
In many types of kidney disease, the glomerular filters are damaged and become abnormally leaky.
This allows proteins and red blood cells to spill into the urine, where they can then be detected in
several ways.
Urine protein determination
24hr urine protein
This test provides the actual amount of protein in a sample.
Timed-urine collection
Spot protein/creatinine ratio
The test result is reported as a ratio of protein to creatinine.
A urine protein/creatinine ratio greater than 100 mg protein per gram of creatinine is abnormal.
A ratio greater than 3000mg usually indicates serious damage to the glomerular filters of the
kidneys.
Cystatin C
Problem with creatinine (varying muscle mass, recent meat ingestion, etc.) have led to evaluation of
alternative agents for estimation of GFR.
Cystatin C,
a ubiquitous protein secreted by most cells in the body
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it is an inhibitor of cysteine protease
freely filtered at the glomerulus and not reabsorbed.
After filtration, cystatin C is normally catabolized in the renal tubules and none appears in the
urine, so urine collection methods cannot be used.
equations have been developed linking estimated GFR to serum cystatin C levels.
Most recently (2009) some proposed equations have combined creatinine and cystatin.
Urine dipstick

Urine dipstick
- A small flat plastic stick containing a row of several chemically-treated paper squares is
dipped into a urine sample (see photo right).
- The squares then turn different colors.
- By comparing the stick with a color chart, one can tell whether or not the urine contains
various substances, such as
- protein,
- blood,
- glucose (or sugar, suggesting diabetes)
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- white blood cells (suggesting infection)
- Ph
- Specific gravity

Urine sediment examination
Urine is poured into a test tube and spun
sediment can then be examined under a microscope.
The findings in the urine sediment can be very helpful in diagnosing kidney disease, and
have even been referred to as the "poor man's renal biopsy."
Useful findings in the urine sediment may include:
white blood cells (suggesting infection)
red blood cells
bacteria
yeast
crystals (especially useful in people with kidney stones)
renal tubular cells (indicating damage to various parts of the kidney
Urinary electrolyte
Sodium
Potassium
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urea
Glucose
Calcium
Phosphate
Other Kidney Tests
Imaging Tests
Various imaging tests can provide useful information about the kidneys with little or no discomfort
and minimal risk to the patient.
Ultrasound
IVP
Renal scan
CAT scan (computed tomography)
MRI (magnetic resonance imaging)
Ultrasound
uses sound waves to give images
This procedure is good for determining the size of the kidneys and for detecting
cysts (round fluid-filled pockets)
solid masses that may be benign or malignant tumors
kidney stones.
estimate the amount of scarring in a kidney
whether there is a obstruction to urine flow anywhere in the kidney, the ureters, or the bladder.
IVP (intravenous pyelogram)
IVP uses traditional x-rays to produce pictures of the kidneys, ureters, and bladder.
A substance called "contrast dye" is injected into a vein, circulates through the bloodstream, and is
processed and excreted by the kidneys.
This technique produces two-dimensional black-and-white images and can provide fairly-detailed
information about the size and shape of the kidneys, as well as the presence of kidney stones and
sometimes cysts or tumors.
However, if kidney function is reduced, IVPs are not done, for two reasons:
1) the kidneys will not process the dye as well and will not show up well in the pictures
MBBS/DDS 2K16
2) there is some risk of the dye's causing renal failure (temporary) in people who already have
reduced kidney function to begin with.
3)The contrast dye may also produce an allergic reaction in some people.
Renal scan
A renal scan is a nuclear medicine exam in which a small amount of radioactive material
(radioisotope) is used to measure the function of the kidneys.
A renal scan is similar to a renal perfusion scintiscan.
CAT (Computed Axial Tomography) scan
CAT scan uses x-rays to produce pictures in crosswise slices.
CAT scan can detect kidney stones, blockage, cysts, and solid masses.
CAT scans are sometimes done using contrast dye, which (as with IVPs) carries the risk of inducing
an allergic reaction and/or causing renal failure, especially in people who already have reduced
kidney function.
MRI (Magnetic Resonance Imaging) scan
MRI scan exposes the body to a strong magnetic field and creates images based on the molecular
composition of different organs and tissues.
cannot be used in those who have metal devices in their bodies (such as pacemakers or
defibrillators).
The procedure may also be somewhat difficult for patients to undergo, since the patient must lie
still in a dark, enclosed tunnel and must not be upset by banging noises made by the machinery.
MRI scans are sometimes done with a special type of dye (administered by IV) called gadolinium:
this dye is not used in patients with moderately- to severely-reduced renal function because of a
small risk of adverse effects in such patients.
Kidney Biopsy
Performed after informed consent and bleeding parameters performed
Ultrasound or CAT scan to localize the kidney.
Once the spot for the biopsy is located using ultrasound or CAT scan, the area is anesthetized using
xylocaine.
A small incision is made and a spring-loaded needle is used.
The biopsy specimens are frozen, sliced, stained, and studied by a variety of microscopic methods
MBBS/DDS 2K16
Light
Immunoflorescence
electron.
It usually takes one to two weeks for the processing to be completed and for a diagnosis of the
kidney disease to be made.
ACUTE GLOMERULONEPHRITIS
CONTENT
INTRODUCTION
BACKGROUND
DEFINITION
PATHOPHYSIOLOGY
CAUSES
DIFFERENTIAL DIAGNOSIS
LABORATORY WORK-UP
IMAGING
RENAL BIOPSY
TREATMENT
FOLLOW-UP
INTRODUCTION
Hippocrates originally described the manifestation of
back pain and hematuria,
which lead to oliguria or anuria.
With the development of the microscope, Langhans was later able to describe these
pathophysiologic glomerular changes.
Bright initially described acute glomerulonephritis in 1927.
BACKGROUND
Acute post-streptococcal glomerulonephritis (PSGN) is the archetype of acute GN.
Present with
Proteinuria
Nephrotic syndrome
Nephritic syndrome
hematuria
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Acute nephritic syndrome is the most serious and potentially devastating form of various
renal syndromes.
DEFINITION
Acute glomerulonephritis is defined as the sudden onset of
hematuria
proteinuria
red blood cell casts.
This clinical picture is often accompanied by
hypertension
edema
impaired renal function.
PATHOPHYSIOLOGY
Acute GN has 2 components:
structural changes
functional changes
Structural changes
Cellular proliferation (mesangial cell)
Leukocyte proliferation/infiltration
Glomerular basement membrane thickening
Hyalinization or sclerosis
Electron-dense deposits
These structural changes could be focal, diffuse or segmental, and global.
Cellular proliferation
This leads to an increase in the number of cells in the glomerular tuft because of the
proliferation of endothelial, mesangial

and epithelial cells.
The proliferation could be endocapillary (i.e within the confines of the glomerular capillary
tufts) or extracapillary (i.e in the Bowman space involving the epithelial cells).
In extracapillary proliferation, proliferation of parietal epithelial cells leads to the formation
of crescents, a feature characteristic of certain forms of rapidly progressive GN.
Leukocyte proliferation
This is indicated by the presence of neutrophils and monocytes within the glomerular
capillary lumen and often accompanies cellular proliferation.
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Glomerular basement membrane thickening
light microscopy
appears as thickening of capillary walls.
Using electron microscopy,
this may appear as the result of thickening of basement membrane proper (eg,
diabetes)
deposition of electron-dense material, either on the endothelial or epithelial side of
the basement membrane.
Hyalinization or sclerosis:
These conditions indicate irreversible injury.
Electron-dense deposits:
Such deposits could be
Subendothelial
Subepithelial
Intramembranous
mesangial,
and they correspond to an area of immune complex deposition.
Functional changes
Functional changes include
proteinuria
hematuria
reduction in GFR (i.e, oligo-anuria),
active urine sediment with RBCs and RBC casts.
The decreased GFR and avid distal nephron salt and water retention result
in expansion of intravascular volume,
edema
Frequently systemic hypertension
HISTORY
PHYSICAL EXAMINATION
History
Determine onset of disease:
Ask the patient about onset and duration of illness.
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Relation to other symptoms
IgAN
PSGN
Initiation of drug (*OTC)
Identify clinical features:
Gross hematuria is the most common abnormality observed in patients with acute PSGN
and often manifests as
smoky
coffee
cola-coloured urine
Pepsi-coloured
edema
decreased volume and frequency of urination
systemic hypertension
uremic symptoms

Assess the consequences of the disease process (eg, uremic symptoms):
Inquire about loss of appetite
generalized itching
tiredness
listlessness
nausea
easy bruising
nose bleeds
facial swelling
leg edema
shortness of breath.

Identify a possible etiologic agent
streptococcal throat infection [pharyngitis]
skin infection [pyoderma]):
joint pains
Hepatitis/HIV
Travel
valve replacement
intravenous drug use.

Identify systemic disease (eg, malar rash, arthralgia, diabetes).

MBBS/DDS 2K16
Physical Examination
Signs of fluid overload
Periorbital and/or pedal edema
Edema and hypertension due to fluid overload (in 75% of patients)
Crackles (ie, if pulmonary edema)
Elevated jugular venous pressure
Ascites and pleural effusion
Rash
(vasculitis, Henoch-Schnlein purpura)
Pallor
Renal angle (ie, costovertebral) fullness or tenderness,
joint swelling, or tenderness
CAUSES
The causal factors that underlie this syndrome can be broadly divided into infectious and
noninfectious groups.
Nephrotic Syndrome
Glomerular disease associated with heavy albuminuria (> 3-3.5g/day)
Hypoalbuminaemia
Oedema
Hyperlipidaemia
Thrombotic tendency
(associated endocrine abnormalities, anaemia, infection)
Infectious
Streptococcal:
Poststreptococcal GN usually develops 1-3 weeks following acute infection with specific
nephritogenic strains of group A beta-hemolytic streptococcus.
The incidence of GN is approximately 5-10% in persons with pharyngitis and 25% in those with
skin infections.
Nonstreptococcal postinfectious glomerulonephritis
Bacterial - Infective endocarditis, shunt nephritis, sepsis, pneumococcal pneumonia, typhoid,
secondary syphilis, meningococcemia, and infection with methicillin-resistant Staphylococcus
aureus (MRSA)
Viral - Hepatitis B, infectious mononucleosis, mumps, measles, varicella, vaccinia, echovirus,
parvovirus, and coxsackievirus
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Parasitic - Malaria, toxoplasmosis
Non-infectious
Multisystem systemic diseases
Systemic lupus erythematosus
Vasculitis
Henoch-Schnlein purpura,
Goodpasture syndrome,
Wegener granulomatosis
Primary glomerular diseases
Membranoproliferative GN (MPGN),
IgA nephropathy (Berger disease)
"pure" mesangial proliferative GN
3

Miscellaneous - Guillain-Barr syndrome, radiation of Wilms tumor, diphtheria-pertussis-
tetanus vaccine, serum sickness
Other Problems to Be Considered
Lupus nephritis
Gross hematuria is unusual in lupus nephritis
Sickle cell disease
Thrombotic thrombocytopenic purpura
hemolytic-uremic syndrome
atheroembolic renal disease
acute hypersensitivity interstitial nephritis
may present with features of acute nephritic syndrome and should be differentiated.
Laboratory Studies
Urinalysis and sediment examination
These tests are crucial in the evaluation of patients with acute nephritic syndrome.
Look for protein, blood, RBCs and WBCs, dysmorphic red cells, acanthocytes, cellular (ie, RBC, WBC)
casts, granular casts, and oval fat bodies.
Finding RBC casts is an almost pathognomonic sign of GN.
MBBS/DDS 2K16
Urine electrolytes, urine sodium, and fractional excretion of sodium (FENa) assays are needed to
assess salt avidity.
BUN, serum creatinine and electrolytes (potassium level)
Complete blood cell count
ESR and CRP
Complement levels (C3, C4, CH50)
ASTO
Collagen vascular screen
Imaging Studies
Abdominal ultrasound
Assesses renal size
Assesses echogenicity of renal cortex
Excludes obstruction
Procedures
Generally, a renal biopsy is not necessary for a diagnosis of acute PSGN;
it is important because histology guides both prognosis and therapy
Medical Care
Treatment of acute GN is mainly supportive because there is no specific therapy for renal
disease.
Treat the underlying infections when acute GN is associated with chronic infections.
Antimicrobial therapy
Antibiotics (eg, penicillin) are used to control local symptoms and to prevent spread of
infection to close contacts.
Antimicrobial therapy does not appear to prevent the development of GN, except if given
within the first 36 hours.
Loop diuretic therapy
Loop diuretics may be required in patients who are edematous and hypertensive in order to
remove excess fluid and to correct hypertension.
Relieves edema and controls volume, thereby helping to control volume-related elevation in
BP.
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Hypertension
Treat hypertension
ACEI,
ARB,
RI,
CCB
Hydralazine
may be used if severe hypertension or encephalopathy is present.
Diet and Activity
Sodium and fluid restriction
Protein restriction for patients with azotemia - If no evidence of malnutrition
Recommend bed rest until signs of glomerular inflammation and circulatory congestion
subside.
Prolonged inactivity does not benefit in the patient recovery process

MBBS/DDS 2K16
Lecture 6: PROSTATE AND BLADDER CANCER-
CLINICAL FEATURES

Dr. Belinda F Morrison
Urologist
Lecturer
UWI/UHWI

PROSTATE CANCER
Prostate cancer in Jamaica
Leading cancer in Jamaica
78.1 per 100,000
1

304 per 100,000
2

70 per 100,000
3

Leading cause of cancer-related deaths
AETIOLOGY of prostate cancer
Age
Ethnicity
Family history
Genetics
Environmental factors
Diet

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AGE

Risk of diagnosis by age

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ETHNICITY

Hereditary prostate cancer

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Diet and prostate cancer

Asymptomatic- SCREENING
Local symptoms
Distant Disease
SCREENING

Annually
Commencing at age 40 years.
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Male must have a life-expectancy of at least 10 years.
Do not screen if patient has a medical illness that will reduce life expectancy.
PSA

Derivatives of PSA
Age-specific PSA
PSA Velocity
PSA Density
Race-specific PSA
Confirmation of Malignancy
- Transrectal Ultrasound-guided biopsy

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Staging of Prostate cancer

Local Symptoms

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Voiding Symptoms
Poor Stream
Hesitancy
Intermittency
Straining
Sensation of Incomplete Evacuation
Urinary retention
Storage Symptoms
Increased daytime frequency
Nocturia
Urgency
Urge Incontinence
Haematuria- May be MASSIVE
Sclerotic Metastases

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Bone Scan

Spinal Cord Compression-
UROLOGICAL EMERGENCY

MBBS/DDS 2K16
Signs and Symptoms
Bony Pain
Paraesthesia
Lower extremity Weakness
Paralysis
Urinary Incontinence
Fecal Incontinence
Lymph nodes and prostate cancer

Ureteric Obstruction

MBBS/DDS 2K16
Symptoms and Signs
Renal Failure
Lower extremity Oedema
Treatment
According to AGE, STAGE
Early Disease
Surgery- Radical retropubic prostatectomy
Radiation
External Beam
Brachytherapy
Advanced Disease
Hormonal Therapy
BLADDER CANCER
Second most common cancer of the GU tract.
Whites> Blacks
Age- 65 years- average age of diagnosis
Clinical Presentation
Haematuria- 80-95% of patients
Gross or microscopic
Storage LUTS- especially with CIS
Increased frequency
Nocturia
Urgency
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Cystoscopic Appearance

Bladder Cancer

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Urinary Cytology and Bladder Cancer

Staging of Bladder Cancer

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Locally advanced or metastatic disease
Bony Pain
Ureteric Obstruction
Lymphoedema
Hepatomegaly
Transurethral Resection of Bladder Tumor

Treatment
Non Muscle Invasive
TURBT
Intravesical Chemotherapy
Muscle Invasive
Radical Cystectomy

MBBS/DDS 2K16
Lecture 7: Bladder Outlet Obstruction

William D. Aiken DM, FRCSEd, FACS
Objectives
At the end of the lecture students should be able to state and / or explain
clearly:
1. The functional components and organisation of the LUT
2. The function of the lower urinary tract
3. Functional derangements of the LUT
4. Causes of Bladder Outflow Obstruction
5. Effects of BOO on the UT and Renal function
6. Management of most common causes of BOO

Functional Components of the LUT
Lower Urinary Tract
Bladder
Detrusor Dome (mobile)
Detrusor Base (fixed)
Urethra
Sphincters & surrounding muscles

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Male & Female LUT

Functional Bladder
Dome and Base differ embryologically, neurologically and pharmacologically
Dome
Receptive Relaxation during storage depends on normal innervation
Coordinated Detrusor contraction during expulsion depends on innervation and
syncytium via gap junctions.
Dichotomous Function of the LUT
1. The continent storage of urine at low pressure and without reflux
Allows continued antegrade flow of urine from the renal pelvis to the
bladder
2. The complete expulsion of urine in an unimpeded fashion and without reflux when the
person desires

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The Innervation of the LUT

Storage Phase
Relaxed Detrusor Muscle
Contracted Outlet
Bladder neck (Internal sphincter)
Tonic contraction of smooth muscle of BN and prostate
Under control of alpha 1 adrenergic sympathetic fibres from superior
hypogastric plexus originating from T10 L1/2 spinal levels
External sphincter (Distal urethral sphincter)
Tonic contraction of the urethral striated sphincter
Predominantly composed of slow twitch muscle fibres
Dual innervation autonomic and somatomotor
Pelvic plexus (Inferior Hypogastric Plexus)
Pudendal nerve
Evacuation Phase
Contracting Bladder Dome
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Pelvic nerves (S2,3,4) acting via M2 & M3 cholingeric receptors
Relaxed Bladder neck and outlet
Coordination of Detrusor muscle contraction with relaxation of the outlet occurs in the
Pontine Micturition Centre
Failure to Empty
1. Failure of the Detrusor muscle to contract / Weak detrusor contraction
2. Failure of the Bladder neck / Outlet to relax
1. Neurogenic
2. Non neurogenic (dysfunctional voiding)
3. Anatomical obstruction to outlet
1. Intraluminal eg. blood clot, calculus, polyp, FB
2. Intramural urethral stricture, BPH, CaP
3. Extramural faecal impaction, pelvic mass, phimosis
Poor Detrusor Function
Failure of Detrusor to Contract
1. Drugs eg. anticholinergics
2. Overdistension of Bladder
3. Ageing
4. Neurologic disorders
1. Diabetic, alcoholic and lead neuropathies
2. Spinal cord injuries, SACD, Syphillis, HTLV
5. Decompensation of detrusor muscle secondary to outlet obstruction
Functional Outlet Obstruction
Neurogenic
Suprasacral SCI
Detrusor Sphincter Dyssynergia
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Infrsacral SCI
Detrusor failure
Hypertonic sphincter
Non neurogenic
Primary bladder neck obstruction (failure of adequate relaxation of BN during
voiding)
Dysfunctional Voiding
Non neurogenic neurogenic bladder (Hinman Bladder)
Site of Obstruction
Anatomical Bladder Outlet Obstruction
Luminal
Mural
Extramural
Luminal Obstruction
1. Blood Clots from haemorrhage within UT
2. Impacted Urethral calculus
3. Urethral Polyps
4. Foreign bodies within urethra
Mural Obstruction
1. Benign Prostatic Hyperplasia (BPH)
2. Prostate Cancer
3. Urethral Strictures restriction of the urethral lumen due to scarring of the urethra
4. Bladder Neck Stenosis
5. Meatal or Submeatal Stenosis
6. Prostatitis
7. Posterior Urethral Valves
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Extra-Mural Obstruction
1. Pelvic mass eg. Fibroids, ovarian mass
2. Phimosis (tight foreskin of penis)
3. Penile rings
4. Kinking of the urethra eg. in uterine prolapse
5. Faecal Impaction
6. Obstructed Labour
Obstruction
Q = Pv Pu / R
Q = P / R
BOO exists if there has to be a greater pressure gradient than normal to maintain the same urinary
flow rate
Effects of BOO on the Urinary Bladder
A. Morphological Effects
B. Functional Effects
Morphological Effects
1. Detrusor Hypertrophy
1. Bladder wall thickening
2. Trabeculation
3. Cellules and Pulsion Diverticula
4. Varying volumes of post void residual

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Gross Appearance of an Obstructed Bladder

Functional Effects of BOO on the Urinary Bladder
B. Functional Effects
A. Compensatory Phase
A. Bladder continues to empty completely
B. Decompensatory Phase
A. Increasing collagen infiltration of muscle
B. Reduced contractility of detrusor muscle
C. Lack of sustained and coordinated detrusor contraction
D. Increasing volumes of post void residual urine
E. Culminates in chronic retention
Effects of BOO on Renal Function
If Pv > P renal pelvis Reversal of pressure gradient Hydronephrosis (dilation of the
pelvicalyceal system) and hydroureter (dilation of the ureters) and Retention of
Nitrogenous waste products, volume retention and electrolyte and acid/ base imbalance
Bowman capsule pressure Filtration Pressure Glomerular Filtration Rate
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Clinical Features of BOO
LUTS
Acute Urinary Retention
Chronic Urinary Retention
Acute on Chronic Urinary Retention
Renal Impairment and attendant effects
Recurrent Urinary Tract Infections
Bladder Calculi with attendant symptoms
Benign Prostatic Hyperplasia (BPH)
Disorder that affects men of increasing age
Increase in stromal and glandular epithelial tissue due to an increase in the number of
constituent cells
Transition zone of prostate increases in size
Obstruction occurs due to
Static anatomical obstruction from gland size
Dynamic obstruction from smooth muscle tone under influence of norepinephrine
on alpha 1 adrenergic receptors

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Zonal Anatomy of the Prostate

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Enlarged Prostate (EP)
in Relation to LUTS and BPH
Approximately 50% of men over the age of 50 years have an enlarged prostate (EP).
1

At the histological level, BPH refers to an increase in number of epithelial and stromal cells in the
prostate which may or may not be detected at the clinical level as an enlarged prostate (> 30 mL) on
digital rectal examination (DRE).
2

The chief complaint of men with BPH is usually bothersome LUTS. However, not all men with BPH
will develop LUTS. Moreover, not all men with LUTS will have BPH.
3

For the purposes of this presentation, we will be using the term Enlarged Prostate (EP) to refer to
symptomatic men with enlarged prostates.
Prevalence of BPH
The prevalence of BPH increases sharply with age.
Berry et al combined and analyzed data from 10 autopsy studies of more than 1000 prostates. In
this study, 42% of men 51 to 60 years of age had histologic evidence of BPH. As illustrated by this
study, most men (82%) reaching average life expectancy (age 7180 years) are affected by BPH.
1

There are an estimated 37 million men over the age of 50 years in the United States.
2
If half of these
men have BPH (based on the data shown here), then approximately 18 million men in the United
States may have histologic BPH, many of whom will be symptomatic. As the population continues to
age, the prevalence of BPH is likely to rise.
Dihydrotestosterone (DHT)- Drives Prostate Growth
Although the etiology of BPH is multifactorial and not yet definitively established, prostate growth
is regulated by androgens, particularly DHT.
DHT and other androgens bind to androgen receptors in the stromal and epithelial cells of the
prostate. When DHT binds to the androgen receptor, this causes a cascade of intracellular events
that leads to the expression of genes and production of growth factors that regulate cell division
and proliferation in the prostate.
1
DHT has approximately five times greater affinity for the
androgen receptor than testosterone.
2

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Expression of both type 1 and type 2 5-reductases is increased in the prostates of men
with BPH

Components of BPH
Urethral
Dynamic: alpha 1 adrenergic mediated prostatic smooth muscle contraction
Static due to prostatic enlargement (EP) encroaching on urethral lumen / bladder neck
Vesical
Compensation
Decompensation
Overactive bladder (secondary detrusor instability)
Gross Appearance of an Obstructed Bladder

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Complications of BPH
Acute Urinary Retention
Chronic Urinary Retention
Acute on Chronic Urinary Retention
Recurrent Urinary Tract Infections
Bladder Stones
Haematuria
Hydronephrosis
Renal Impairment
Lower Urinary Tract Symptoms (LUTS)
LUTS
Storage Symptoms
Nocturia (small volumes)
Frequency (small volumes)
Urgency
Urge Incontinence
Voiding Symptoms
Hesitancy
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Poor stream
Straining to pass urine
Intermittency
Prolonged voiding
Terminal dribbling
Sensation of incomplete emptying
IPSS
7 Item instrument
Each item scored 0 5
Separate item assessing QoL
Scoring
Mild 0 7
Moderate 8 19
Severe 20 - 35

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International Prostate Symptom Score (IPSS)
0 7 Mild
8 -19 Moderate
20 35 Severe

History
Symptom severity IPSS
Degree of bothersomeness
Symptom differentiation
Predominance of storage symptoms should arouse suspicion of OAB, bladder
tumour, UTI or vesical calculus
Longstanding pelvic pain CPPS / chronic prostatitis
BPH complications haematuria, UTIs, AUR/CUR,
Med. Hx.: DM, neurologic disease, medications
PSH especially prior LUT surgery
History of STI should arouse suspicion of urethral stricture disease
Sexual Dysfunction
Physical Examination
General
GU
Palpate / percuss for urinary bladder
Examine genitalia
DRE: size, consistency, mobility
Focused neurologic examination
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Anal sphincter tone, active anal sphincter contraction, lower extremity
neuromuscular function
Investigations
Mandatory
Dipstick urinalysis / urine microscopy
Blood, Protein, Nitrite, Leucocyte esterase
Serum Creatinine
Optional / Specific Indications
Urine culture
Urine cytology
Urea and creatinine
Prostate specific antigen (PSA)
Uroflowmetry and measurement of PVR
Normal Uroflow Pattern

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Prevalence of BOO varies with Peak Flow Rates (Qmax)
Peak Flow rate
(Qmax)
Prevalence of
Bladder outlet
obstruction
< 10 ml / sec 90%
10 15 ml / sec 70%
> 15 ml / sec 30%

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Investigations
Optional / Specifically Indicated Inx.
Abdominopelvic ultrasound
Objective measure of baseline prostate size
Bladder wall thickness
Measure PVR
Examine upper tracts
BPH related complications, eg bladder stone
Pressure flow studies
Cystoscopy
Treatment Decision

Treatment Objectives
Provide rapid symptom relief
Treat existing BPH related complications
Arrest disease progression
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Prevent BPH complications eg. AUR
Decrease need for BPH related surgery
Medical Treatment of BPH
1 adrenergic antagonists (ABs)
Tamsulosin (Flomax)
Terazosin (Hytrin)
Doxazosin (Cardura)
Alfuzosin (Xatral)
5 reductase Inhibitors
Dutasteride (Avodart): Inhibits both type 1 and type 2 isozymes of 5 reductase
Finasteride (Proscar): only inhibits type 2
Surgical Treatment of BPH
Open Prostatectomy
Trans urethral resection of the prostate (TURP)
Minimally Invasive Techniques
Laser prostatectomy
Thermotherapy
Urethral Stricture Disease
A urethral stricture is a narrowing of the urethral lumen due to scarring of the urethral wall
Aetiology
Congenital
Incomplete canalisation of the urethra
Acquired
Sexually Transmitted Infections Gonococcal infection, Chlamydia infections
Trauma iatrogenic, external eg. MVAs, Straddle injury
Idiopathic
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Balanitis Xerotica Obliterans (BXO)
Affects Younger men
Straining to pass urine
Weak Urinary Stream
Investigations
Retrograde Urethrogram
Cystoscopy
Retrograde Urethrogram
Bulbar urethral
Stricture

Urethroscopic pictures of Urethral Strictures

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Treatment of Urethral Strictures
Urethral Dilation
Optical Internal Urethrotomy
Urethroplasty
Excision and Primary Anastomosis (Anastomotic Urethroplasty)
Substitution Urethroplasty
Grafts
Buccal mucosa
Bladder urothelium
Scrotal and Penile skin
Flaps
Foreskin
Penile skin
Scrotal skin

MBBS/DDS 2K16
Lecture 8: Calculus Disease of the Urinary Tract

Dr. Richard Mayhew
Objectives
Focus on Upper Tract Calculi
Epidemiology
Physicochemistry / Pathogenesis
Diagnosis
History
Metabolic assessment
Imaging
Management
Medical
Surgical

Epidemiology
Global prevalence is estimated at 1 15%
USA prevalence 10 15%
Prevalence has been increasing
Male > Female but gender difference decreasing. May be reversed in Blacks
In USA Caucasians > Hispanics > Asians > African Americans
Peak incidence in 4
th
6
th
decades
Obesity / weight gain, occupational heat exposure, dehydration,? sedentary lifestyle
increase risk

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Stone Formation Complex Cascade

Urinary Inhibitors of Stone Formation
Citrate
Magnesium
Pyrophosphate
Urinary glycoproteins Nephrocalcin, Tamm-Horsfall Protein
Polyanions
Glycosaminoglycans
Mucopolysaccharides
RNA

Supersaturation of urine with respect to stone-forming
salts
Dissolved ions or molecules precipitate out of solution
and form crystals
Crystals become retained at sites which promote
growth and aggregation, resulting in stone formation
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Stone Composition and Relative Occurrence
Composition Occurrence (%)
Calcium oxalate 60
Calcium Phosphate * 22
Uric acid 7
Struvite / Infection / MAP 7
Cystine 1-3
Medications or byproducts (such as
Indinavir, Triamterene, Ephedrine)
<1

Stone composition in Jamaica
Review of calculi seen at UHWI over 25 years
Similar pattern to global prevalence

Constituent % of Stones
Calcium 93.9
Oxalate 60.1
Urate 37
Bicarbonate 16.5
Magnesium 8.6
Cystine 0.6
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Calcium Stone Formation
Hypercalciuria
Absorptive increased intestinal absorption of calcium
Renal primary renal leak of calcium
Resorptive due to increased bone demineralization, associated with
hypercalcaemia
Hyperoxaluria
Inherited enzymatic disorder Primary hyperoxaluria
Intestinal malabsorption
Excess dietary intake
Idiopathic
Hypocitraturia
Idiopathic
Metabolic acidosis
Malabsorption
Uric Acid Stone Formation
Low urine pH solubility decreases below pH 6
Idiopathic
Acidosis
Metabolic
Hyperuricosuria
Dietary
Hereditary
Myeloproliferative disorders
Low urine volume
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Infection / Struvite Stone Formation
Magnesium Ammonium Phosphate with Calcium phosphate ( Triple Phosphate)
Urease producing (urea splitting) organism, most commonly Proteus. Also Klebsiella,
Pseudomonas, Staphylococcus
Ammonia formation increases urine pH ( more alkaline)
Exacerbated by obstruction
Cystine Stone Formation
Cystinuria caused by inherited defect in intestinal and renal tubular transport of dibasic
amino acids
Lysine, ornithine and arginine urinary levels also increased but cystine is the least soluble
Symptoms and Signs
Pain
Colic stretching/spasm of ureter or collecting system
Noncolicky distension of renal capsule
Loin, loin to groin, groin / scrotum/ labia
Severity does not correlate with stone burden
Haematuria
Gross or microscopic
Fever/Recurrent
Infection/Sepsis
Nausea, vomiting
Renal impairment
Flank mass hydronephrotic
kidney

MBBS/DDS 2K16

Why do Metabolic Assessment ?
26 to 50% of first stone formers recur in the first 10 yrs
Limit morbidity, expense
Identify significant underlying disease which requires treatment to prevent extrarenal
complications
Risk Assessment
Recurrent stone formers ( 3 stones in 3 years)
Children and teenagers
Family history of stone disease
Intestinal disease ( eg. chronic diarrhoea)
Bone disease ( eg pathological fractures, osteoporosis)
Gout
Recurrent UTI
Nephrocalcinosis
Large/complex stones
Obesity
Type II Diabetes
Renal insufficiency
Solitary Kidney
Stones composed of cystine, uric acid, struvite
Screening Evaluation
History
Dietary aberrations
Low fluid intake
High oxalate diet
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High salt intake
Low or high Ca intake
High animal protein
Medications
Fluid Loss
Sweating
Diuretics
Urinary Tract Infection
Laboratory
Stone analysis
Serum Ca, Phosphate, Uric acid, Electrolytes, Creatinine, Urea
Urinalysis, microscopy
Urine culture
Screening Evaluation contd.
Imaging studies
Plain radiography
10 % of calculi radiolucent
Ultrasonography
Intravenous Pyelogram (IVP)
Good intrarenal anatomy which guides intervention
Cheaper than CT
CT Urogram (MDCT) gold standard for diagnosing urolithiasis
Standard Metabolic Evaluation
As for screening evaluation
24 hour urine analysis on random diet
Volume
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Oxalate
Citrate
Calcium
Sodium
Uric acid
Measure PTH when serum calcium elevated
Extended Metabolic Evaluation
24hr urine assessment
Random diet
Restricted diet (400 mg calcium and 100 mEq sodium/day)
Fasting and calcium load test
Not commonly done
Intervention
Observation
Calyceal asymptomatic stones < 5 mm can be managed expectantly
Medical management
Adjunct to surgical removal
For patients on expectant management
As definitive therapy for asymptomatic uric acid calculi
Surgical management
Minimally invasive surgery / Endourology
Extracorporeal Shock Wave Lithotripsy (ESWL)
Percutaneous Nephrolithotomy
Ureteroscopy
Open surgery

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Medical Management
General dietary modification
For patients with a single episode and risk factors or those with recurrent episodes
High fluid intake to ensure output > 2L/dy or specific gravity < 1.010
Sodium restriction
Reduce animal protein intake
Increase citrus products (lime/lemon, orange)
Oxalate limitation seems intuitive but no confirmed benefit as a general measure
Thiazide diuretics
Decrease calcium levels in the urine by stimulating calcium resorption in the distal
nephron while promoting excretion of sodium
Long term use can cause volume depletion, hypocitraturia, acidosis, potassium
depletion
Citrate supplement
Increase urinary pH, urinary citrate levels
Treat hypercalcaemia
Allopurinol
Decrease serum uric acid
Weight control
Infection Stones
Complete stone removal
Antibiotics / infection control
Ureteric stones
blocker - preferred
Steroids
Calcium channel blockers no longer recomended

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Surgical Management
Method depends on:
Burden Size and number
Location
Calyceal vs Pelvic vs Ureteric
Upper, Mid, Lower calyx
Composition
Urgent intervention required for:
Renal impairment
Solitary kidney
Associated infection
Complete obstruction
Bladder Calculi
Migrant
Ureteric calculus which enters bladder and does not pass
Secondary
Due to bladder outlet obstruction and stasis, infection or foreign body
Most common - > 75%
Uric acid, Ca oxalate or MAP
Primary idiopathic
Occurs in children in the absence of obstruction, neurologic lesion or infection
Due to dietary deficiencies, especially animal protein, and dehydration
Most commonly composed of ammonium acid urate alone or mixed with calcium
oxalate
Surgical Management
Endoscopic cystolitholopaxy
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Open cystolithotomy
Summary
Nephrolithiasis is increasing in prevalence
Complete metabolic assessment is important
Medical management of nephrolithiasis limits recurrence
Surgery for upper tract calculi depends on stone and patient factors
Bladder calculi mainly due to bladder outlet obstruction

END OF SURGERY SECTION

MBBS/DDS 2K16
Lecture 1: PATHOGENESIS OF GLOMERULAR DISEASES

Objectives
At the end of these two lectures (Pathogenesis of the glomerular diseases and
Pathology of specific glomerular diseases) students should have understanding of:

(1) Ultrastructure and functions of glomerular capillary wall
(2) Pathogenetic mechanisms of glomerular damage
(3) Classification of the glomerular diseases
(4) Clinical expressions of the glomerular diseases
(5) Pathological nomenclature of the glomerular diseases
(6) Some of the common specific glomerular diseases and their outcome

Glomerular disease encompasses a spectrum of morphological changes resulting from a
wide variety of etiological factors. Majority of the glomerular diseases are immune-mediated.

PATHOGENESIS OF GLOMERULAR DISEASE
1
0
Immunopathogenetic mechanism: - Initiator of the disease process by
deposition/formation of immune complexes
(1) Antibody mediated
(2) T-cell-mediated
2
0
immunopathogenetic mechanism: - Actual mediation of the disease
(1) Role of complement
(2) Role of neutrophils
(3) Role of monocytes/macrophages
(4) Role of coagulation systems
1
0
Immunopathogenetic mechanisms:
Antibody mediated:
o Circulating immune complex deposition
(granular immunofluorescent pattern)
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o In-situ immune complex formation
(I) Intrinsic fixed glomerular antigen
(1) Normal component of glomerular basement membrane, linier immunofluorescent
pattern:
Anti-glomerular basement membrane-antibody disease
(2) Podocyte antigen, granular immunofluorescent pattern
Immune complex glomerulonephritis
(II) Intrinsic and/or extrinsic non-glomerular; non-fixed antigen
- Planted antigen, granular immunoflorescent pattern
Intrinsic i.e. endogenous proteins
Extrinsic i.e. products of bacteria, viruses, parasites, foreign proteins etc.
T-cell-mediated:
T-lymphocytes are essential for cell-mediated and antibody-mediated
immune response. Thus it is responsible for both induction and mediation of renal disease
that are caused by immune responses. This may occur through regulation of B-cell
differentiation and antibody production or by local cell-mediated immunity i.e. delayed-
type hypersensitivity reaction. The later is initiated by CD4+ cells by activating
monocytes/macrophages which produces cytokines: IL12, IL2, INF- and TNF-o which are
powerful inflammatory mediators causing injury.
CD8+ cells acts by their cytotoxic ability.
2
0
Immunopathogenetic mechanisms:
(1) Role of complement:
Complement is activated by immune complexes (classic pathway) or by complex
polysaccharides (alternate pathway). C3 & C5 are chemoattractant for leukocytes,
neutrophils in particular which causes damage by releasing proteolytic enzymes and by
generating reactive oxygen metabolites. Terminal complement components C5b-9,
membrane attack complex (MAC) causes injury by basement membrane lysis.
(2) Role of neutrophil:
Neutrophils can cause damage to the membrane and cause proteinuria by
generating reactive oxygen metabolites and by releasing of proteolytic enzymes. They can
also mediate acute changes in glomerular hemodynamics i.e. alter glomerular filtration by
mechanical obstruction of capillary lumens, attaching themselves to the endothelium and in
tern stripping the same from the underlying basement membrane reducing the available
surface areas for filtration.
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(3) Role of monocyte/macrophage:
These groups of cells play major part in acute as well as chronic inflammatory
process by producing various cytokines, reactive oxygen metabolites, plasminogen activator
etc. The resident macrophages may participate in the local presentation of antigen in
delayed-type hypersensitivity reaction. They are also responsible for hypercellularity of the
glomerular tuft particularly in diffuse proliferative glomerulonephritis, crescentic
glomerulonephritis etc.
(4) Role of coagulation system:
Glomerular deposition of fibrin is important factor in causing proliferation of
parietal epithelial cells forming crescent. Intra-glomerular fibrin deposition may lead to
glomerulosclerosis.

COMMONEST IMMUNE-MEDIATED GLOMERULAR DISEASE IS IMMUNE-COMPLEX
GLOMERUONEPHRITIS
Clinical expressions of the glomerular diseases:
Patients can present with any one of the following or combination of more than one:-
(1) Asymptomatic proteinuria
(2) Microscopic hematuria
(3) Acute renal failure
(4) Chronic renal failure
(5) Acute nephritic syndrome
(6) Nephrotic syndrome

Acute nephritic Syndrome comprises of:-
- Hematuria
- Azotemia
- Proteinuria
- Edema
- Hypertension

The Nephrotic Syndrome is characterized by:-

- Proteinuria > 3.5 gms/24 hrs
- Hypoalbuminemia < 25 g/l
- Edema
- Hyperlipidemia
- Lipiduria

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Some of the common causes of nephrotic syndromes are:-
- Minimal change disease (common in children)
- Membranous glomerulonephropathy (common in adults)
- Mesangiocapillary (membranoproliferative) GN
- Focal & Segmental glomerulosclerosis
- Systematic diseases including:
- Diabetes mellitus
- Systematic lupus erythematosus (lupus nephritis)
- Amyloidosis etc.

Terminology used in glomerular diseases

Diffuse - A lesion involving all or nearly all glomeruli (> 80%)
Focal - A lesion involving some but not all glomeruli (< 50%)
Segmental - A lesion involving portion of glomerulus (i.e. some
capillary loops remain uninvolved)
Sclerosis - A lesion of the glomerulus where there is increase in
fibrillary material laid within mesangial areas with
collapse of capillary loops and condensation of basement
membrane.
Crescent:-
Cellular - A lesion consisting of cellular proliferation of parietal epithelial
cells filling part of Bowmans space.
Fibro-cellular - A lesion which is similar to cellular crescent but with
variable amount of fibrillar material.
Fibrous - A lesion within Bowmans space which is predominantly
composed of fibrous tissue i.e. scarred cellular/
fibrocellular crescent.

Classification of Glomerular Disease
- Clinical
- Morphological
- Etiological
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- Immunopathological
Basis of Classification

- Immune complex glomerulonephritis
- Anti-GBM-antibody diseases


- Associated with infection
Post-streptococcal GN
Post-infections GN
- Associated with systemic diseases
Systemic lupus erythematosus i.e. lupus nephritis
- Primary Glomerular diseases
Idiopathic membranous GN
Mesangiocapillary (membranoproliferative) GN

Anti-GBM-antibody disease

Goodpasture syndrome

Disease with immune mechanisms without IC formation or anti-GBM-antibody development
Focal & segmental glomerulosclerosis.

PATHOLOGY OF SPECIFIC GLOMERULAR DISEASES
Acute (diffuse proliferative) glomerulonephritis
It is also described as post-streptococcal / post-infectious glomerulonephritis. It is a form of
immune-complex glomerulonephritis and is characterized histologically by diffuse proliferation of
glomerular cells with or without influx of polymorphs. The disease is more common in children &
young adults and usually presents as acute nephritic syndrome. One can elicit h/o preceding
MBBS/DDS 2K16
infection i.e. sore throat or skin sepsis. The most common organism responsible is group A |-
hemolytic streptococci but other organisms have been identified. Serological investigation shows
rising titers of ASO and low levels of C3. Electron microscopic examination of the glomeruli will
show electron dense subepithelial immune complex deposit classically known as subepithelial
hump. This disease is usually self limiting and only less then 5% of the patients may either
progress to rapidly progressive glomerular disease (crescentic glomerulonephritis) or to chronic
renal disease.
Lupus nephritis
As much as 70% of the patient suffering from Systemic Lupus Erythematosus (SLE) will
show renal involvement. This is an autoimmune disease, also an example of immune-complex
glomerulonephritis where the antigen is an endogenous protein. The presence of antibodies to
nuclear protein i.e. anti-nuclear-antibody (ANA) to double stranded DNA is a hallmark of the
disease. The hallmark of the disease in tissue is hematoxylin bodies.
The disease is more common in women, particularly of African descent, in child bearing age
group with F:M ratio being 9-10:1.The patients can present as significant proteinuria ( 200mg/24
hr.); nephrotic syndrome; acute nephritic syndrome etc. The renal prognosis will depend on
histological features i.e. diffuse proliferative type of histology will carry much worse prognosis then
diffuse mesangial proliferative type of histology.
Idiopathic membranous glomerulonephritis
Most common cause of nephrotic syndrome in adults and is characterized by diffuse
thickening of the capillary walls due to extensive subepithelial immune-complex deposition which
can be identified on light, electron and immunofluorescence microscopic examinations. The disease
is insidious in onset and shows slow progression to reach to chronic state eventually. The
management of this disease remains controversial.
When the disease is associated with other systemic diseases, it is no longer idiopathic but
will be known as secondary type of membranous glomerulonephritis. This occurs commonly in
following conditions:
- Drug therapy, after prolonged gold therapy, penicillamine or NSAIDs etc.
- Systemic Lupus Erythematosus i.e. lupus nephritis
- Infections: Hepatitis-B, or C etc
- Secondary to malignant tumors, especially epithelial tumors
Mesangiocapillary (Membranoproliferative) glomerulonephritis
This disease is also known as hypocomplementemic glomerulonephritis as there is low
levels of C3 in almost all the patients. This is a disease of children in general but can occur at any
age. The classical presentation of this disease is nephrotic syndrome but can also presents as acute
nephritic syndrome and is characterized by enlarged, hypercellular glomeruli with accentuation of
MBBS/DDS 2K16
the lobules, with marked thickening of the capillary wall which shows double contour or tram-
track appearance. There are subendothelial electron-dense deposits seen on electron microscopy.
The course of this disease is one of slow progression and is generally not responding to
corticosteroid or immunosuppressive therapy and eventually ends in chronic renal failure.
Is a commonest cause of nephrotic syndrome in children in whom this disease occur
frequently. Despite massive proteinuria, the renal function remains normal. Over 90% of patients
are corticosteroid sensitive while small numbers of patients are corticosteroid dependent or
resistant. The later can be treated by immunosuppressive agents. The disease is characterized by
normal appearing glomeruli on light and immunofluorescence microscopy and the only
abnormality detected is effacement of epithelial cell foot processes which is identified on electron
microscopy only. No immune-complexes are identified and so the disease is not an immune
complex in origin but several associated features suggests immune mediation. The current
hypothesis is that the cell-mediated immunity seems to play an important role where T-
lymphocytes are said to produce vascular permeability factor which is responsible for massive
proteinuria.
Chronic glomerulonephritis
It is an end stage disease in which there is wide spread (>90%) glomerulosclerosis
associated with extensive tubular atrophy, interstitial fibrosis, mononuclear cell infiltration and
vascular changes of benign hypertension. The pelvis will remain unaffected (unlike chronic
pyelonephritis). This results in marked reduction in glomerular function leading to chronic renal
failure. At this stage no underlying glomerular pathology can be determined.

MBBS/DDS 2K16
Lecture 2: PATHOLOGY OF ACUTE & CHRONIC RENAL
FAILURE AND TUBULOINTERSTITIAL NEPHRITIS

READ TEXT FOR ADDITIONAL INFO ON THIS LECTURE

NOMENCLATURE
TUBULOINTERSTITIAL NEPHRITIS
Primary/Idiopathic Inflammation limited to tubules and interstitium, glomeruli
and blood vessels are not involved.
- Acute - Sudden onset & rapid decline in renal function associated with
edema
- Chronic - Protracted onset and slow decline in renal function associated
with interstitial fibrosis
Secondary Tubulointerstitial inflammation associated with primary
glomerular or vascular diseases
Reactive - Tubulointerstitial inflammation from the effects of systemic
infections
Infectious Tubulointerstitial nephritis associated with presence of live
organisms
Idiopathic Tubulointerstitial nephritis in which etiological agent or cause is not
known

URINARY TRACT INFECTION
Colonization of outflow (excretory) tract by live microorganisms
Pyelonephritis is a form of tubulointerstitial nephritis in which there is
involvement of pelvis and calyceal structures in addition
to renal parenchyma
- Acute Infectious, usually suppurative, often associated with outflow
obstruction. Can also occur from ascending infection through vasicoureteral
reflux of infected urine or by hematogenous spread of infection with
localization of live microorganisms in kidney
- Chronic Is chronic tubulointerstitial inflammation with prominent
scarring. It can be due to obstruction with recurrent infection or non-
obstructive associated with vasicoureteral reflux reflux nephropathy
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Lecture 3: Renal Pathology #3- Renal Cysts & Tumors

Lecturer: Dr. Shah

** Cystic disease of the kidney are a heterogeneous group comprising hereditary, developmental &
acquired disorders
Cystic Disease of the Kidney
- Fluid filled spaces within the kidney
- May involve cortex or medulla of both
- May be unilateral or bilateral
- May be unilocular or multilocular
- May be congenital or acquired
- May be sporadic or genetically determined
- The clinical significance may be trivial or grave

** The classifications of renal cystic disease are:
1- Cystic renal dysplasia
2- Polycystic kidney disease
i- Autosomal-dominant (adult) polycystic disease
ii- Autosomal- recessive (childhood) polycystic disease
3- Medullary cystic disease
i- Medullary sponge kidney
ii- Nephronophthisis
4- Acquired (dialysis-associated) cystic disease
5- Localized (simple) renal cysts
6- Renal cysts- in hereditary malformation syndromes
7- Glomerulocystic disease
8- Extra parenchymal renal cysts- pyelocalyceal cysts, hilar lymphatic cysts

Classification of Renal Cystic Disease
** Polycystic kidney diseases:
i- Autosomal recessive polycystic kidney disease- classic in neonates and infants. With
hepatic fibrosis in older children
ii- Autosomal dominant polycystic kidney disease- classic in adults
** Simple cortical cysts
** Acquired (dialysis-induced) cysts
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Autosomal Recessive PKD
- Rare developmental anomaly that is genetically distinct from adult polycystic kidney
disease
- Abnormal gene (PKHD1) on chromosome 6p21
- The PKHD1 gene encodes a large novel protein called fibrocystin

- Classically presents in antenatal or in the neonatal period. However it can present in
infancy or adulthood
- Perinatal, neonatal, infantile and juvenile subcategories have been defined depending on the
time of presentation and presence of associated hepatic lesions
- Patients who survive infancy may develop a type of hepatic fibrosis
- 30% of patients die of respiratory failure due to pulmonary hypoplasia or sepsis
- Complications includes chronic lung disease, growth retardation, hyponatremia, UTIs,
hypertension

Gross Morphology- The kidneys are enlarged and have a smooth, external appearance
- Cut section shows numerous small cysts in the cortex and medulla
- Therefore the kidney has a sponge like appearance
- Cysts have a uniform lining of cuboidal cells
- Disease is bilateral
- Liver has cysts with portal fibrosis as well as proliferation of portal bile ducts
- Diffuse fusiform dilatation of the collecting ducts
- Normal reniform shape complete with fetal lobation and normal sized ureter

Autosomal Dominant PKD
- Hereditary disorder characterized by multiple expanding cysts of both kidneys
- These cysts eventually destroy the renal parenchyma and cause renal failure
- Most common inherited kidney disease
- Affects 1:1000 individuals and account for 5-10% of patients in dialysis or with renal
transplant
- Abnormal gene on the short arm of chromosome 16
- The cysts initially involve only portions of the nephrons, therefore renal function is
retained until about the 4
th
or 5
th
decade of life

** Many patients remain asymptomatic until indications of renal insufficiency announce the
presence of underlying kidney disease
- Dull loin pain
- Hemorrhage or dilation of cysts may produce pain
- Excretion of blood clots causes renal colic
- Flank masses that are apparent on abdominal palpation
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- Hematuria, proteinuria, polyuria, hypertension
- Progressive renal failure - anemia and decreased GFR, increased urea and creatinine

Note: Progression of the disease is accelerated in blacks, especially in correlation with the sickle
cell train
** Associated cysts in the liver found in the biliary type (75%) and in the pancreas (10%)
- Vascular anomalies including intracranial aneurysms (10%), colonic diverticula and mitral
valve prolapse (25%)

** Bilaterally enlarged kidneys (up to 4000 gms)
- External surface appears to be composed mainly of a mass of cysts with no intervening
parenchyma
- Diffuse cystic change with uninvolved intervening parenchyma
- Varying sized, numerous generally oval-to spherical unilocular cysts
- The cysts are distributed in the cortex and medulla and obscure the normal reniform shape
- Cysts filled with fluid that may range from clear, to turbid, to gelatinous to hemorrhagic fluid
- Distorted pelvi-calyceal system
- Cysts can arise from any part of the excretory nephron
- Neoplastic change is uncommon but can occur

Simple Cortical Cysts
- Extremely common as age advances
- Occur as multiple or single cortical cystic spaces
- Acquired cysts may originate from diverticula of the distal convoluted or collecting tubules
due to weakening of the basement membrane
- The membrane are made up of cuboidal epithelium
- Usually asymptomatic with normal renal function
- However hemorrhage into the cysts may cause sudden distention and pain
- Radiology- Renal cysts have smooth contours unlike renal tumors. Cysts tend to be
avascular and give fluid signals on ultrasonography

Acquired (Dialysis-Associated) Cystic Kidney Disease
** Kidneys from patients with end-stage renal disease who have undergone prolonged dialysis
exhibit numerous cortical + medullary cysts
- Cysts are 0.5 to 2 cm in diameter
- Contain clear fluid and are lined by hyperplastic/flattened tubular epithelium
- Usually contain calcium oxalate crystals

** These cysts may form as a result of obstruction of tubules by interstitial fibrosis
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- Most are asymptomatic
- Complication: Neoplastic changes are common. Development of renal carcinoma in the
walls of these cysts in 7% of dialyzed patients

Renal Tumors
In infants & children:
- Nephroblastoma (Wilms tumor)

In adults:
- Renal cell carcinoma
- Renal cell adenoma
- Renal oncocytoma

Nephroblastoma (Wilms Tumor)
** Wilms tumor is the most common genitourinary malignant embryonal tumor derived from
nephrogenic blastemal cells
- Can differentiate into several cell lines: blastemal, epithelial, stromal
- May replicate developing kidneys

** Common in young children and uncommon in neonates + infants
- 90% in < 6year olds
- Peak: 3yrs in boys and 3.5 years in girls

** 5-10% of Wilms Tumors involve both kidneys:
i- Synchronous- simultaneously
ii- Metachronous- affecting one kidney after the other

** The pathogenesis and etiology is widely unknown. However has a worldwide incidence,
therefore no associated environmental factors
- Variable incidence in racial groups
- Blacks > Caucasian > Asians

** The risk of Wilms tumor is increased in association with at least 3 recognizable groups of
congenital malformations associated with distinct chromosomal loci
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- Familial tendencies- 1% autosomal dominant with variable penetrance and expressivity
- Genetic predispositions= WT-1 gene, WT-2 gene

** Most children present with a large abdominal mass that may be unilateral
- If large they may extend across the midline and down into the pelvis
- Hematuria, abdominal pain, intestinal obstruction and the appearance of hypertension are
other patterns of presentation

Gross Morphology- Present as a large, solitary well-circumscribed mass
- Tumor has a peritumoral fibrous capsule
- Variable size and weight
- 10% are bilateral or multicentric
- Tumor is soft and homogenous.
- Tan to gray with occasional foci of hemorrhage, cyst formation or necrosis

Microscopy: Demonstrates a classic triphasic combination of cell types
- Blastemal, stromal and epithelial
- The tumor appears as sheets of small blue cells
- May contain other heterologous elements such as squamous/mucinous epithelium, smooth
muscle, adipose tissue, cartilage, neurogenic tissue

** The histology may be favorable or unfavorable depending on the state of nuclear anaplasia
- Marked nuclear enlargement
- Abnormal mitoses
- Pleomorphic nuclei

Note: Tumors with diffuse anaplasia and with extrarenal spread have the least favorable outcome
** Nephroblasmtomas have the potential to spread to regional lymph nodes. Also to distant lymph
nodes in the lung and liver
** The prognosis and treatment of nephroblastoma depends on:
- Stage, age and histology

** Surgery with chemotherapy for Stage I + II with favorable histology
** Surgery with chemotherapy and radiotherapy for higher stages and unfavorable histology

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Renal Cell Carcinoma
- Once known as hypernephroma because of their gross yellow color and resemblance of
the tumor cells to clear cells of the adrenal cortex
- 3% of all adult malignancies
- No racial predisposition
- Arises from mature renal tubules
- Tobacco is the most significant risk factor
- Obesity, hypertension, exposure to heavy metals, asbestos, unopposed estrogen therapy
- Increased incidence in patients with chronic renal failure and acquired cystic disease

** Most renal carcinoma is sporadic but unusual forms of autosomal dominant familial caners
occur:

1- Clear Cell Type- most common type and accounts for 70-80% of renal cancers
- Tumor made up pf cells with clear cytoplasm and are nonpapillary
- Can be familial, sporadic or associated with Von Hippel Lindau disease
- 98% of these tumors, irregardless of cause, there is a loss of sequences on the short arm of
chromosome 3
- This occurs by deletion or unbalanced chromosomal translocation

2- Papillary Type- Characterized by a papillary growth pattern and also occurs in both
familial and sporadic forms
- These tumors are associated with trisomies 7 + 17

Note: Renal carcinomas are generally sporadic but there are rare familial associations
- Also associated with acquired cysts and patients on chronic hemodilaysis

** The 3 classic, diagnostic features of renal cell carcinoma are:
- Hematuria
- Palpable abdominal mass
- Costovertebral pain (flank pain)

** The most reliable of the three is hematuria. However the hematuria may be intermittent or only
visible on microscopy
- Therefore renal carcinoma may be clinically occult
- 30% of persons present with a metastatic lesion
- Therefore the patients present with a large mass and constitutional symptoms
- Renal cancers have a tendency to metastasize widely before giving rise to any local signs or
symptoms
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** The most common locations of metastasis are:
- Lungs - >50%
- Bones- 33%
- Regional lymph nodes
- Liver + adrenals
- Brain

** The prognosis is influenced by multiple factors:
- Nuclear grade
- Tumor size
- Infiltrative margins
- Histological type
- Tumor stage

Renal Cell Adenoma
- Incidental findings at autopsy (22%)
- Well demarcated and unencapsulated
- Pale yellow gray, discrete cortical mass

MBBS/DDS 2K16
Lecture 4: Test of Glomerular Function

Chemical Pathology
Lecturer: Dr. D. McGrowder

Introduction

- The kidney has three major functions:
(i) excretion of metabolic waste,
(ii) ECF homeostasis: maintenance of extracellular (ECF) volume and composition and,
(iii) Endocrine functions (e.g. erythropoietin, 1:25 DHCC)

- The kidney has a rich blood supply and normally receives about 25% of the cardiac output.
Most of this is distributed initially to the capillary tufts of the glomeruli which acts as high
pressure filters. Blood is separated from the lumen of the nephron by three layers:
(a) the capillary endothelial cells,
(b) the basement membrane and,
(c) the epithelial cells of the nephron.

- The glomerular filtrate is an ultrafiltrate of plasma that is similar in composition to
plasma except that it is almost free of proteins. This is because the endothelium provides
a barrier to red and white blood cells.

- The basement membrane, although permeable to water and low molecular weight
substances, is largely impermeable to macromolecules. This impermeability is related to
both molecular size and electrical charge.

- Proteins with molecular weights lower than that of albumin (68 kDa) are filterable.
Negatively charged molecules are less easily filtered than those bearing a positive charge.

- Almost all the protein in the glomerular filtrate is reabsorbed and catabolized by proximal
convoluted tubular cells, with the result that normal urinary protein excretion is less
than 150 mg/24 h.

- Filtration is a passive process. The total filtration rate of the kidneys is mainly determined
by:
(i) the difference between the blood pressure in the glomerular capillaries and the
hydrostatic pressure in the lumen of the nephron,
(ii) the nature of the glomerular basement membrane and,
(iii) the number of glomeruli.

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- The normal glomerular filtration rate (GFR) is approximately 120 mL/min,
equivalent to a volume of about 170 L/24 h.

- Urine production is only 1 2 L/24 h, depending on fluid intake. The bulk of the filtrate
is reabsorbed further along the nephron.

- The glomerular filtrate passes into the proximal convoluted tubule where much of it is
reabsorbed. Under normal circumstances, all the glucose, amino acids, potassium and
bicarbonate, and about 70% of the sodium, is reabsorbed isotonically by energy-dependent
mechanisms.

Biochemical Test of Renal Function
Test of Glomerular Function
- The glomerular filtration rate (GFR) depends on the net pressure across the glomerular
membrane, the physical nature of the membrane and its surface area, which in turn reflects
the number of functioning glomeruli.

- All of the above three factors may be modified by disease, but in the absence of large
changes in filtration pressure or in the structure of the glomerular membrane, the GFR
provides a useful index of the number of functioning glomerular.

- The GFR gives an estimate of the degree of renal impairment.

- The GFR is the rate in millilitres per minute that substances are cleared from the
circulation through the kidneys glomeruli.

- Measurement of clearance requires an accurate measurement of the plasma and urine
concentrations of the marker used plus a reliable urine collection.

- A molecule has to meet certain criteria to be considered a suitable marker of glomerular
function. These are:
(i) freely filterable at the glomerular barrier,
(ii) not reabsorbed by the tubules,
(iii) not secreted by the tubules and,
(iv) present at a stable plasma concentration,
(v) if exogenous non toxic ,
(vi) reliable assay procedure.

- The assumption is made that the concentration in the glomerular filtrate is same as that in
plasma, so it is important to use a marker substance that has no protein binding.

- The renal clearance of a substance is defined as the volume of the plasma from which
the substance is completely cleared by the kidneys per unit time. The clearance of a
substance is given by the following equation:

Cx = (Ux x V)
Px
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where Cx = Clearance in units of millilitres of plasma cleared of a substance per minute
Ux = Urinary concentration of the substance (mol/L)
V = Volumetric flow rate of urine in milliliters per minute (mL/min)
Px = Plasma concentration of the substance (mol/L)

- Creatine clearance in adults is normally of the order of 120 mL/min, corrected to a standard
body surface of 1.73 m
2
. The clearance state is only valid for a steady state, i.e. when renal
function is not rapidly changing.

Exogenous markers
- Several compounds are used as exogenous markers to measure GFR. Inulin is considered
the gold standard. Iohexol and
51
Cr-EDTA are also used.

- A priming bolus injection of inulin (a plant polysaccharide) is administered followed by
constant intravenous infusion to maintain a steady state concentration. Blood and
accurately timed urine samples are collected during the constant infusion period.

- The measurement of inulin clearance is not suitable for routine use, and it is very time
consuming.

- The iohexol content of the plasma and urine samples collected are measured by high
performance liquid chromatography (HPLC).

- In hospitals with facilities for handling radioactive isotopes and measuring radioactivity, the
technique of choice for measuring GFR is based on the injection of
51
Cr-labelled EDTA
(ethylenediaminetetra-acetic acid). This substance is completely filtered by the
glomeruli and is neither secreted nor reabsorbed by the tubules.

- Serial blood samples are taken after injection of the isotope and the GFR is calculated from
the fall of plasma radioactivity as the isotope is cleared. In addition, blood and urine can be
collected and the standard clearance formula used.

Endogenous markers

Creatinine Clearance

- Creatinine meets some of the criteria. It is freely filtered, but its concentration may not
remain constant over the period of urine collection.

- It is secreted by the tubules and its measurement in plasma is subjected to analytical
overestimation.

- The creatinine clearance provides an approximate value for the GFR.

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- Creatinine is actively secreted by the renal tubules and, as a result, the creatinine
clearance is higher than the true GFR. The difference is of little significance when the
GFR is normal but when the GFR is low (< 10 mL/min), tubular secretion make a major
contribution to creatinine excretion and creatinine significantly overestimates the GFR.

- As the GFR falls progressively, however, creatinine clearance deviates further from the true
GFR.

- In the calculation of creatinine clearance, two measurements of creatinine concentration
and one of urine volume are required. Each of these has an inherent imprecision which can
affect the accuracy of the overall result.

- Accurate measurement of the GFR is required in:

(i) assessment of potential kidney donors,
(ii) investigation of patients with minor abnormalities of renal function, and
(iii) calculation of the initial doses of potentially toxic drugs that are eliminated from the
body by renal excretion.

- The majority of patients with established renal disease do not require repeated
measurements of creatinine clearance. In most cases, their renal function can be more
reliably monitored by serum measurements of the plasma creatinine concentration.

- In any individual serum creatinine is inversely related to the GFR (creatinine clearance).

- The Cockcroft and Gault formulas for the calculation of GFR (creatinine clearance)
are:

eGFR = 1.23 x (140 age) x body weight (kg) for men
Serum creatinine in mol/L

eGFR = 1.04 x (140 age) x body weight (kg) for women (lower muscle mass)
Serum creatinine in mol/L

Plasma Creatinine

- Creatinine is synthesized in the liver, kidneys and pancreas, and is transported to its sites of
usage, principally muscle and brain.

- Creatinine is an end-product of nitrogen metabolism, and as such undergoes no further
metabolism, but is excreted in the urine.

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- Creatinine production reflects the bodys total muscle mass.

- A low [creatinine] is found in patients with a small total muscle mass. Low plasma
[creatinine] may therefore be found in children, and values are, on average, normally lower
in women than in men.

- Abnormally low values may be found in wasting diseases and starvation, and in patients
treated with corticosteroids, due to their protein catabolic effect.

- Plasma [creatinine] tends to be higher in subjects with a large muscle mass. Other
nonrenal causes of increased plasma [creatinine] include:
(i) a high meat intake can cause a temporary increase,
(ii) transient, small increases may occur after vigorous exercise,
(iii) some analytical methods are not specific for creatinine. For example, plasma
[creatinine] will be overestimated using some methods in the presence of high
concentration of acetoacetate or cephalosporin antibiotics.
(iv) some drugs (e.g. salicylates, cimetidine) compete with creatinine for tubular
transport mechanism, thereby reducing tubular secretion of creatinine and
elevating plasma [creatinine].
- If non-renal causes can be excluded, the finding of increased plasma [creatinine] indicates a
fall in GFR. The renal causes include:
(a) any disease in which there is impaired renal perfusion (e.g. reduce blood
pressure, fluid depletion, renal artery stenosis),
(b) most diseases in which there is loss of functioning nephrons (e.g. acute and
chronic glomerulonephritis), and
(c) diseases where pressure is increased on the tubular side of the nephron (e.g.
urinary tract obstruction due to prostatic enlargement).

- Plasma creatinine is the most reliable simple biochemical test of glomerular function.

- Measurement of plasma [creatinine] is more precise than creatinine clearance, as there are
two extra sources of imprecision in clearance measurements, i.e. timed measurement of
urine volume and urine [creatinine].

- The reference range for plasma creatinine in the adult population is 9 124 mol/L.

- If endogenous production of creatinine remains constant, then the amount of it excreted in
the urine each day becomes constant. The plasma [creatinine] will then be inversely
proportional to creatinine clearance.

- GFR can decrease by 50% before plasma [creatinine] rises beyond the normal range.
Plasma [creatinine] doubles for each further 50% fall in GFR. Consequently, normal
plasma [creatinine] does not necessarily imply normal renal function, although a raised
creatinine does usually indicate impaired renal function.

- In most circumstances, assessment of glomerular function can be made and changes in GFR
over time can be monitored biochemically by measurement of plasma [creatinine] rather
than measurement of creatinine clearance.
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Plasma Urea

- Urea is synthesized in the liver, primarily as a by-product of the deamination of amino acids.
Its elimination in urine represents the major route for nitrogen excretion.

- Urea is filtered from the blood at the glomerulus but significant tubular reabsorption occurs
through passive diffusion.

- Although plasma urea concentration is often used as an index of renal glomerular
function, measurement of plasma creatinine provides a more accurate assessment.
- Plasma [urea] is inferior to plasma [creatinine] since 50% or more of urea filtered at the
glomerulus is passively reabsorbed through the tubules, and this fraction increases if
urine flow decreases, such as in dehydration.

- High plasma [urea] is observed in:
(i) prerenal uraemia which may develop when ever there is impaired renal
perfusion (e.g. ECF losses, cardiac failure, and hypoproteinaemia). In response to
hypovolaemia or a drop in blood pressure, there is renal vasoconstriction and a
redistribution of blood such that there is a decrease in
GFR, but preservation of tubular function. There is reduced urine flow which
in turn causes increased passive tubular reabsorption of urea.

(ii) renal uraemia which may develop due to acute or chronic renal failure, with
reduction in glomerular filtrate.

(iii) postrenal uraemia which occurs due to outflow obstruction, which may occur at
different levels (i.e. in the ureter, bladder or urethra), due to various causes (e.g.
renal stones, genitourinary cancer). Back-pressure on the renal tubules enhances
back-diffusion of urea, so that plasma [urea] rises disproportionately more than
plasma [creatinine].

- Less urea is synthesized in the liver if there is reduced availability of amino acids for
deamination, as may occur in starvation or malabsorption. However, in extreme starvation
plasma [urea] may rise as increased muscle protein breakdown then provides the major
source of fuel.

- In patients with severe liver disease (usually chronic), urea synthesis may be impaired
leading to a fall in plasma [urea].

- Plasma [urea] may fall as a result of water retention associated with inappropriate
vasopressin secretion or dilution of plasma with intravenous fluids.

- Urea diffuses readily across dialysis membranes and during renal dialysis a fall in plasma
urea concentration is a poor guide to the efficacy of the process in removing other toxic
substances from the blood.

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Cystatin C

- Cystatin C is a cysteine protease inhibitor. This low molecular weight peptide (13 kDa) is
produced by all nucleated cells at a rate that is unaffected by inflammation and other
pathological processes.

- It is cleared from the plasma by glomerular filtration and its plasma concentration
reflects the GFR.

- An increased serum Cystatin C corresponds to a decreased GFR and hence to kidney
dysfunction.

- Cystatin C may be used as an alternative to creatinine and creatinine clearance to screen
for and monitor kidney dysfunction in those with known or suspected kidney diseases.

- It may be especially useful in those cases where creatinine measurement is not
appropriate: for instance in those who have liver cirrhosis, are very obese, are
malnourished or have a reduced muscle mass.

- Measuring Cystatin C may also be useful in the early detection of kidney disease when
other parameters might still be normal, especially in the elderly.

- It is not secreted or re-absorbed and its measurement is more sensitive and specific
than creatinine.

- Measurement of cystatin C is not influenced by muscle mass, or diet or sex of subjects
(single reference range for males and females).

- Cystatin C is measured by immunoassay.

Plasma 2-microglobulin

- 2-microglobulin is a small peptide molecular weight 11.8 kDa), which forms part of the
class 1 antigens of the major histocompatibility complex. It is present on the surface of
most cells and in low concentrations in the plasma.

- 2-microglobulin is completely filtered by the glomeruli and is absorbed and catabolized by
proximal tubular cells.

- The plasma concentration of 2-microglobulin is a good index of GFR in normal
individuals, being unaffected by diet or muscle mass. However, it is increased in
certain malignancies and inflammatory diseases.
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- Since it is normally reabsorbed and catabolized in the tubules, measurement of 2-
microglobulin excretion provides a sensitive method of assessing tubular
integrity.

Renal Disorders

Acute Renal Failure

- Failure of renal function may occur rapidly, producing the syndrome of acute renal failure
(AFR). It is potentially reversible since if the patient survives the acute illness, normal renal
function can be regained.

- Acute renal failure is characterized by a rapid loss of renal function, with retention of
urea, creatinine, hydrogen ions and other metabolic products and, usually but not
always, oliguria (< 400 mL urine/24 h).

- AFR is conventionally divided into three categories, according to whether renal functional
impairment is related to a decrease in renal blood flow (prerenal), to intrinsic damage to
the kidneys (intrinsic), or to urinary tract obstruction (postrenal).

- Chemical investigations help to determine the severity of the disease and to follow its
course, but do not help in determining the cause.

Prerenal Acute Renal Failure

- This is caused by circulatory insufficiency, as may occur with severe haemorrhage,
burns, fluid loss, cardiac failure or hypotension that leads to renal hypo-perfusion
and a decrease in GFR.

- Renal hypo-perfusion induces intense renal vasoconstriction, which initially result in a
decrease in GFR with relative preservation of tubular function.

- However, if adequate perfusion is not rapidly restored prerenal uraemia may
progress to intrinsic failure (acute tubular necrosis). It may be possible to prevent this
if renal perfusion can be restored before structural damage has occurred.

- Prerenal uraemia is essentially the result of a normal physiological response to
hypovolaemia or a fall in blood pressure.

- Stimulation of renin-angiotensin-aldosterone system and vasopressin secretion results
in the production of concentrated urine with a low sodium concentration.

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- Renal tubular function is normal, but the decreased GFR results in the retention of
substances normally excreted by filtration, such as urea and creatinine.
- Decreased excretion of hydrogen ions results in a tendency to metabolic acidosis, and
of potassium to hyperkalaemia.

- Assessment of the urine will find the following:

(i) Urine sodium (spot) < 20 mmol/L
(ii) Urine: plasma osmolality > 1.5:1
(iii) Microscope : normal
Intrinsic Acute Renal Failure

- Many causes of intrinsic renal failure are due to nephrotoxic drugs (e.g.
aminoglycosides and non-steroidal anti-inflammatory drugs) or renal ischaemia (e.g.
following severe blood loss or hypotension) leading to acute tubular necrosis.

- Although glomerular damage is uncommon in acute tubular necrosis, the GFR falls due to
glomerular hypo-perfusion, itself a result of afferent arteriolar vasoconstriction.

- Characteristic biochemical values in oliguria due to prerenal and intrinsic renal failure:

Increased Decreased
Potassium Sodium
Urea Bicarbonate
Creatinine Calcium
Phosphate
Magnesium
Hydrogen ion
Urate

- Hyponatraemia is common and contributory factors include increased water formation
from oxidative metabolism, continued intake of water, decreased excretion and possibly
loss of intracellular solute.

- Hyperkalaemia occurs as a result of decreased excretion of potassium together with loss of
intracellular potassium to the ECF (due to tissue breakdown) and intracellular buffering of
retained hydrogen ions.

- Decreased hydrogen ion excretion causes metabolic acidosis.

- Retention of phosphate and leakage of intracellular phosphate into the interstitial
fluid leads to hyperphosphataemia, which inhibits the -hydroxylation of 25-
hydroxycholecalciferol to calcitriol.

- The resulting decreased plasma concentration of calcitriol causes skeletal resistance to the
actions of parathyroid hormone, and there is a tendency to hypocalcaemia.
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- Hypermagnesaemia is also often present as a result of decreased magnesium
excretion.

- Proteinuria is always present and the urine is often dark owing to the presence of
haem pigments from the blood.

- There are typically three phases to the course of acute tubular necrosis: the initial
oliguric phase, a diuretic phase and a recovery phase.

- Assessment of the urine will find the following:

Microscope : Red blood cells, cast (Tamm Horsfall protein)

Postrenal Renal Failure

- Obstruction to the flow of urine leads to an increase in hydrostatic pressure, which
acts in opposition to glomerular filtration. If prolonged, leads to secondary renal
tubular damage.

- Causes of obstruction include renal calculi, prostatic enlargement (hypertropic or
neoplastic), other neoplasms of the urinary tract.

- Obstruction which occurs above the level of the vesicourethral junction must be bilateral to
have a major effect on urine flow.

- Obstruction is either intermittent or incomplete and urine production may even be normal
in obstruction with overflow.

Chronic Renal Failure

- Many disease processes can lead to progressive, irreversible impairment of renal
function. Glomerulonephritis, diabetes mellitus, hypertension, pylenephritis and
polycystic kidneys account for the majority of cases where a cause can be
determined.

- All the above conditions lead to a decrease in functioning nephrons.

- Patients may remain asymptomatic until the GFR falls below 15 mL/min or lower. The
natural history is progression to end-stage renal failure, the state when conservative
measures are no longer sufficient and dialysis or transplantation becomes necessary to save
the patients life.

MBBS/DDS 2K16
- The major pathological and clinical features are similar in all patients with chronic renal
failure, whatever the cause. The metabolic features are:
(i) impairment of urinary concentration and dilution,
(ii) impairment of electrolyte and hydrogen ion homoeostasis
(iii) retention of waste products of metabolism
(iv) decrease calcitriol synthesis
(v) decrease erythropoietin synthesis.

- Biochemical changes in the plasma include decrease sodium, bicarbonate and calcium.
Other biochemical changes in the plasma include increased potassium, urea, creatinine,
hydrogen ion, phosphate and magnesium.

- Although there is impairment of urinary concentration, polyuria is never gross (not more
than 4 L per day) because the GFR is so low. The urine tends to be of a fixed specific gravity.

- The lack of urinary concentration is particularly noticed by the patient at night and nocturia
is a common complaint.

- The ability to dilute the urine may be lost late in the course of renal failure and patients
become very sensitive to the effects of either fluid loss or overload.

- Sodium balance is usually maintained until the GFR falls below 20 mL/min. The majority of
patients tend to retain sodium but severe renal sodium wasting is occasionally seen.

- Hyperkalaemia is a late feature of chronic renal failure and may be precipitated by a
sudden deterioration in renal function or by the injudicious use of potassium-sparing
diuretics.

- Patients with chronic renal failure tends to be acidotic. The urinary buffering
capacity is impaired as a result of decreased phosphate excretion and ammonia
synthesis. There is a fall in the renal capacity to form NH4
+
.

- The ability of individual nephrons to reabsorb filtered bicarbonate is often impaired.

- Although plasma hydrogen ion concentration increases and bicarbonate decreases, these
changes progress slowly, owing to buffering of excess hydrogen ions in bone.

- Most patients with chronic renal failure become hypocalcaemic and, in time may develop
renal osteodystrophy. Retention of phosphate causes a tendency to hyperphosphataemia,
inhibiting calcitriol synthesis and leading to hypocalcaemia.

- This causes increased parathyroid hormone secretion (secondary hyperparathyroidism),
which decreases the reabsorption of phosphate from each nephron. Eventually, the falling
GFR becomes the limiting factor in phosphate excretion and persistent
hyperphosphataemia ensues.
MBBS/DDS 2K16

- With advanced renal failure, the decrease in functioning renal tissue may also contribute to
the decrease in calcitriol production.

- Another factor of importance is buffering of hydrogen ions by bone, leading to
demineralization.

- In addition to the effect on calcitriol synthesis, other endocrine consequences of chronic
renal failure include testosterone and oestrogen synthesis, abnormalities of thyroid
function tests, and abnormal glucose tolerance with hyperinsulinaemia due to insulin
resistance.

- Insulin-dependent diabetic patients who develop renal disease often have decreased insulin
requirements since insulin is metabolized in the kidney.

- A normochromic normocytic anaemia is usual in end-stage renal failure, owing to
depression of bone marrow function by retained toxins and a decrease in the renal
production of erythropoietin. A bleeding tendency may also be present and bleeding may
exacerbate the anaemia.

MBBS/DDS 2K16
Lecture 5: Test of Tubular Function

Chemical Pathology
Lecturer: Dr. D. McGrowder

Introduction

- The tubules modify the composition of about 150 L of glomerular filtrate that are normally
formed each day by removing water and other solutes, and adding ammonia and hydrogen
ion.

- Renal tubular disorders can be congenital or acquired. They can involve single or
multiple aspects of tubular function.

- Inborn errors primarily affecting specific tubular transport mechanisms include:
(i) renal glycosuria
(ii) nephrogenic diabetes insipidus
(iii) cystinuria (affecting cysteine and the dibasic amino acids),
(iv) iminoglycinuria (affecting glycine, proline, and hydroxyproline),
(v) the proximal and distal forms of isolated tubular acidosis and,
(vi) the hypophosphataemias.

- Specific disorders affecting the renal tubules may affect the ability to concentrate urine or to
excrete an appropriate acidic urine, or may cause impaired absorption of amino acids, or
glucose, or phosphate, etc.

- Chemical investigations are required for specific identification of these abnormalities and
may include amino acid chromatography, or investigations of calcium and phosphate
metabolism.

- The functions tested most often are renal concentrating power and the ability to
produce an acid urine.

- Renal function tests have two main purposes. Either they detect possible renal
damage in a patient who has a disorder which may involve the kidneys, or they
determine the degree of functional damage of kidneys which are known to be
diseased.

- Examination of the urine for protein, cells and casts checks for an active lesion, whilst
clearance studies and related tests investigate the loss of function.

MBBS/DDS 2K16
- Once renal damage has been detected, renal function tests may reveal the principal site and
degree of the disturbance in the nephron, but rarely the cause of the renal injury.

- About two-thirds of the renal tissue must be functionally damaged for renal function
tests to show any abnormality, and renal failure occurs when there is inability to
maintain homeostasis.

Renal Tubular Disorders

Renal Tubular Acidosis

Proximal tubular acidosis

- Proximal renal tubular acidosis (type 2) is due to proximal loss of HCO3
-
, caused by a
low renal threshold for HCO3
-
.

- The impaired bicarbonate reabsorption occurs in some patients with Fanconi syndrome.

- Diagnosis requires assessment of the renal threshold for HCO3
-
.

- Treatment consists of administering large amounts of bicarbonate, for example 10
mmol/kg bodyweight/24 h.

Distal tubular acidosis

- Distal tubular acidosis (type 1) occurs more frequently and can be either inherited or
acquired, for example secondarily to hypercalcaemia or autoimmune diseases.

- It is due to inability to maintain a gradient of [H
+
] across the distal tubules and
collecting ducts. There is a deficit in [H
+
] excretion and the urine cannot be acidified.

- In this type of RTA the impaired ability off the kidneys to excrete hydrogen ions
necessitates increased potassium excretion when sodium is reabsorbed in the distal
tubules, and this may cause potassium depletion and hypokalaemia.

- Treatment involves the administration of bicarbonate in sufficient quantities to buffer
normal hydrogen ion production (1 3 mg/kg body weight/24 h) and potassium
supplements.

Fanconi Syndrome
- The Fanconi syndrome is a generalized disturbance of the proximal renal tubule affecting
reabsorption of amino acids, glucose, phosphate, urate and low molecular weight proteins.

MBBS/DDS 2K16
- This generalized disorder is characterized by glycosuria, amino aciduria, phosphaturia
and acidosis.

- Causes of Fanconi syndrome are:

(i) Idiopathic inherited metabolic disease: cystinosis galactosaemia, fructose
intolerance, glycogen storage diseases, tyrosinaemia, and Wilsons disease,

(ii) Nephrotoxins: heavy metals, drugs, paraproteinaemia and amyloid.

- Cystinosis is a rare genetic disorder that causes an accumulation of cystine within
cells leading to accumulation and deposition of cysteine crystals in many body tissues,
including the kidney.

- Fanconi syndrome is sometimes seen in patients with Bence-Jones proteinuria.

Amino acidurias

- Amino aciduria may be due to diseases of the renal tubule (renal or low threshold type), or
raised plasma amino acids (generalized or overflow type).

- There may be non-specific abnormality due to tubular damage, together with reabsorption
defects affecting glucose or phosphate, or both.

- The overflow types of amino acid aciduria result when the renal threshold for amino
acids is exceeded, due to overproduction or to accumulation of amino acids in the body
when the tubular transport mechanism is saturated (e.g. phenylketonuria).

- Cystinuria has an incidence of about 1 in 7000 live births. Defective tubular reabsorption
of cystine, ornithine, arginine and lysine leads to their excretion in the urine.

- The loss of these amino acids would alone be of little consequences, but cystine is relatively
insoluble and cystinuria predisposes the patient to renal calculus formation.

- Renal acidurias may occur in combination with normal plasma concentrations of amino
acids as a result of defective tubular reabsorption, for example Hartnup disease and
cystinuria.

- Hartnup disease is a rare inherited disorder of the epithelial transport of neutral amino
acids, due to decreased intestinal absorption of tryptophan from the gut.

Hypophosphataemic rickets

MBBS/DDS 2K16
- This condition, also known as vitamin D-resistant rickets, has a dominant X-linked pattern
of inheritance.

- A defect in tubular phosphate reabsorption leads to severe rickets.

- It does not respond to treatment with vitamin D alone, even if administered in massive
doses, but can be treated effectively with a combination of oral phosphate supplements and
-hydroxylated derivative.

Assessment of renal concentrating ability

- Measurements of the osmotic concentration of urine are considered more valid than
specific gravity measurements in the assessment of the concentrating ability of the kidneys.

- This is because regulation of water excretion is determined in part by the osmolality of the
fluid compartments of the body.

- The urine osmolality of normal individuals varies widely, depending on the state of
hydration.

- After excessive intake of fluids, for example, the osmotic concentration may fall as
low as 50 mOsmoles/kg, whereas individuals with severely restricted fluid intake,
concentrations of up to 1200 mOsmoles/kg have been observed.

- In individuals on average fluid intakes, values of 300 to 900 mOsmoles/kg are found
most frequently.

- If a random urine specimen of an individual has an osmolality greater than 850
mOsmoles/kg after 12 hours of fluid restriction, renal concentrating ability is
assumed to be normal.

- The causes of failures to concentrate urine are:

(i) Insufficient secretion of vasopressin (e.g. trauma, neoplasm),
(ii) Inhibition of vasopressin release (e.g. psychogenic polydipsia, lesion of the thirst
centre causing polydipsia),
(iii) Inability to maintain renal medullary hyperosmolality (chronic renal failure,
lithium toxicity, hypercalcaemia etc.)
(iv) Inability to respond to vasopression (renal tubular defect nephrogenic diabetes
insipidus, Fanconis syndrome),
(v) Increased solute load per nephron (chronic renal failure, diabetes mellitus).

- In individuals with either hypothalamic or pituitary disorders causing complete ADH
deficiency or those who lack the normal response to ADH (nephrogenic diabetes
insipidus), urine osmolality rarely exceeds 300 mOsmoles/L.
MBBS/DDS 2K16

Fluid Deprivation Test

- The first test used to assess renal concentrating ability of the kidney is the fluid
deprivation test.

- The fluid deprivation test involves beginning at 10.00 pm the patient is told not to drink
overnight, and urine specimens are collected whilst the patient continues not to drink
between 8:00 a.m. and 3:00 p.m. the next day.

- During the test the patient should be weighed every two hours, and the test should be
stopped if weight loss of 3 5 % occurs. Blood and urine specimens are collected for
measurement of osmolality.

- Normal plasma osmolality (285 295 mOsmoles/kg) and urine osmolality > 850
mOsmoles/kg over the period of water deprivation is considered to reflect normal
renal concentrating ability.

- A rising plasma osmolality (> 300 mOsmoles/kg) and a failure to concentrate urine
(low urine osmolality, 200 400 mOsmoles/kg) are consistent with a failure to
secrete vasopressin or a failure to respond to vasopressin at the level of the distal
nephron.

DDAVP Test

- It is usual to proceed immediately to perform the 1-deamino-8-D-arginine vasopressin
(DDAVP) test. DDAVP is a synthetic analogue of vasopressin.

- The patient is allowed a moderate amount of water at the end of the fluid deprivation test,
to alleviate thirst.

- An intramuscular injection of DDAVP (4 g) is then given, and urine specimens are collected
at hourly intervals for a further three hours and their osmolality measured.

- Patients with diabetes insipidus of hypothalamic-pituitary origin produce insufficient
vasopressin. They respond to the DDAVP test with a marked increase in osmolality to
850 mOsmoles/kg or more.

- If there is tubular dysfunction or nephrogenic diabetes insipidus there is no change
in the urinary osmolality but the plasma osmolality may increase due to water loss
during the test.

- If the patient is receiving drugs that affect renal concentrating power (e.g. carbazepine,
chlorpropamide), these should be stopped for at least 48 h before testing.
MBBS/DDS 2K16

Urine Acidification Test

- Urine is normally acidic, compared to plasma in healthy subjects on a meat-containing diet.

- Urinalysis using dipticks can be used to give a rough estimate of urine pH over the range 5
9. It is important to measure urine pH on freshly voided urine specimens.

- Urine acidification is a function of the distal nephron, which can secrete H
+
until the limiting
intraluminal pH of approximately 5.0 or less is reached.

- Acidification occurs as a result of the kidney reabsorbing the large amounts of the
HCO3
-
that were filtered at the glomerulus, and excreting H
+
produced as nonvolatile
acids during tissue metabolism.

- The urinary acidification test is a procedure which is used to investigate the ability of
the renal tubules to form an acid urine and to excrete ammonia.

- It is useful if there is doubt whether a patients acidosis (confirmed by plasma analyses) is
due to a pre-renal cause, or to kidney damage as in renal tubular acidosis.

- It is possible to assess the capacity of the kidney to produce an acid urine after a metabolic
acidosis has been induced by administering ammonium chloride (NH4Cl).

- The patient is fasted from midnight until the conclusion of the test. The patient empties the
bladder completely and the urine is collected. The pH of the urine is determined.

- The patient is given a load of NH4Cl (100 mg/kg of body weight), and the urine samples are
collected at 2, 4, 6 and 8 h. The pH is measured in all the samples collected.

- NH4Cl loading test is used to investigate distal renal tubular acidosis.

- In normal subjects the urine pH falls below 5.5 in at least one sample.

- In an individual with RTA the pH of the urine does not decrease and it is unlikely to
fall below 6.5.

- It is essential to check that a satisfactory acidosis was induced, and this is assumed to have
occurred if plasma [HCO3
-
] falls by about 4 mmol/L after NH4Cl ingestion.

- More elaborate tests of urinary acidification (e.g. determining the renal threshold for HCO3
-
)
are needed to differentiate between proximal and distal renal tubular acidosis.

- Ammonium chloride should not be given to patients with liver disease. In this situation,
calcium chloride may be administered as an alternative.
MBBS/DDS 2K16
Urinalysis

- Examination of the urine is often the first step in the assessment of a patient suspected of
having or confirmed to have deterioration in renal function.

- The appearance (colour and odour) or urine itself is helpful, a darkening from the normal
pale straw colour indicating a more concentrated urine or the presence of another
pigment.

- Haemoglobin and myoglobin in urine produce a pink-red-brown colouration,
depending on the concentration.

- Turbidity in a fresh sample may indicate infection but also may be due to fat particles in an
individual with nephrotic syndrome.
- Foaming of urine when shaken suggests proteinuria.

- The presence of free haemoglobin or RBCs in the urine indicates the presence of renal or
bladder disease.

- Hematuria is present in individuals with a range of renal diseases, including
glomerular nephritis, polycystic disease, sickle cell disease, and a wide range of
infection.

- Because proteinuria is one of the most common findings in individuals with renal disease,
urine often is screened by use of simple, qualitative or semiquantitative dipstick tests.

Dipstick testing

- In the dipstick type of qualitative or semi-quantitative testing, strips of cellulose or
pads of cellulose on strips of plastic are coated or impregnated with reagents for the
analyte in question.

- The strip is dipped into a test solution, such as urine. A colour change occurs, which then is
compared to a colour chart for the test in question.

- Dipstick testing is used to detect substances such as glucose, ketones, bilirubin
diglucuronide, and urobilinogen that overflow into the urine.

- Urine samples for dipstick testing should be collected in sterile containers and dipstick
testing performed on the fresh urine.

- Dipstick tests are available for a variety of analytes, including total protein, haemoglobin,
glucose, nitrate, leukocytes, specific gravity and pH.

MBBS/DDS 2K16

Specific gravity

- The simple specific gravity test measures the density of urine relative to the density of
water, and in most circumstances, density bears a constant relationship to osmolality.

- The normal specific gravity of a pooled 24-hour sample is between 1.008 and 1.025.

- Under normal circumstances the specific gravity varies inversely with the urine volume.
The specific gravity of the urine is highest in the first morning specimen (overnight
urine), and is lowest in a specimen passed an hour after much fluid has been take.

- Disorders associated with oliguria lead to a urine of high specific gravity. Polyuria
tends to lead a urine of low specific gravity.

- In diabetes mellitus there is polyuria with urine of high specific gravity.

- A dipstick test is used to determine specific gravity.

Microscopic examination of urine

- Microscopic examination of the sediment obtained from the centrifugation of a fresh urine
sample shows the presence of a few cells (erythrocytes, leukocytes, and cells derived from
kidney and urinary tract), casts (composed predominantly of Tamm-Horsfall protein),
and possibly fat or pigmented particles.

- An increase in RBCs or casts implies hematuria possible due to glomerular disease.
WBC or casts implies the presence white cells in the tubules.

- Inflammation of the upper respiratory tract may result in polymorphonuclear leukocytes
and various types casts, whereas in lower urinary tract, inflammation of the casts is not
present.

- In individuals with acute glomerulonephritis, hematuria may lead to colouration of the
urine and the presence of large amounts of RBCs and WBCs as the duration of the
disease increases, the amount of sediment diminishes.

Proteinuria

- The glomeruli normally filter 7 10 g of protein per 24 hours, but almost all is reabsorbed
by endocytosis and subsequently catabolized in the proximal tubules.

- Normal urinary protein excretion is less than about 150 mg/24 h.

MBBS/DDS 2K16
- Approximately half of this is Tamm-Horsfall protein, a glycoprotein secreted by
tubular cells; less than 30 mg is albumin.

- The presence or absence of proteinuria is usually assessed using a reagent-impregnated
strip (dipstick) which is dipped into the urine.

- The dipstick reliably detects albumin at concentrations greater than 200 mg/L but is less
sensitive to other proteins.

- False positive results are obtained with urine that is alkaline, contaminated by various
antiseptics.

Investigation of proteinuria

- If a patients urine gives a positive reaction for protein using a dipstick, the presence of
protein should be confirmed by an independent test in the laboratory.

- Before investigating renal function, incidental extrarenal causes of proteinuria, such as fever,
strenuous exercise and burns, should be excluded. Orthostatic proteinuria should also be
excluded.

- When the presence of proteinuria has been confirmed, urinary protein excretion should be
measured and simple tests of renal function, measurement of complement (C3) and renal
ultrasound performed.

- Proteinuria in excess of 2g/24 h is virtually pathological and usually signifies
glomerular disease.

- Electrophoresis of a concentrated specimen of urine may help to distinguish between
various types of proteinuria.

Glomerular proteinuria

- Glomerular proteinuria is due to increased glomerular permeability, e.g. albumin.

- In glomerular proteinuria, high molecular weight proteins are present.

- Some patients, typically with excretion rates of less than 1 g/24 h, have benign or
functional proteinuria. This probably results from blood flow changes through a
glomeruli, and is found in association with exercise, fever, orthostatic proteinuria and
congestive cardiac failure.

- Glomerular proteinuria may or may not be of pathological significance and causes
include orthostatic proteinuria, and febrile proteinuria.

MBBS/DDS 2K16
- Pathological significance includes causes of glomerular proteinuria such as
glomerulonephritis and pathological causes altered haemodynamics (e.g. renal artery
stenosis).

Tubular proteinuria

- This may be due to tubular or interstitial damage resulting from a variety of causes.

- The proteinuria is due to failure of the tubules to reabsorb some of the plasma
proteins filtered by the normal glomerulus, or possibly due to abnormal secretion of
protein into the urinary tract.

- The proteins excreted in tubular proteinuria mostly have a low molecular mass, e.g. 2-
microglobulin (11.8 kDa) and lysozyme (15 kDa).

- The loss of protein is usually mild, rarely more than 2g/24 h.

- Urinary 2-microglobulin excretion is normally very small (under 0.4 mg/24 h). Its
measurement has been used as a sensitive test of renal tubular damage.

- The causes of tubular proteinuria are chronic nephritis, acute tubular necrosis, renal
tubular defects (e.g. renal tubular acidosis), heavy metal poisoning, renal
transplantation.

Orthostatic proteinuria

- This is usually a benign condition that affects children and young adults, who exhibit
proteinuria only after they have been standing up.

- Orthostatic proteinuria occurs as a result of an increase in the hydrostatic pressure
in the renal vein, itself a result of pressure of the liver on the inferior vena cava.

- Orthostatic (or postural) proteinuria is of no clinical significance and can confidently be
diagnosed if a sample of urine collected immediately on rising in the morning is protein-
free.

Overflow proteinuria

- Overflow proteinuria is due to presence in plasma of a high concentration of a low
molecular weight protein, which is filtered in a quantity exceeding tubular reabsorptive
capacity, e.g. Bence Jones protein.

- Several conditions may give rise to abnormal amounts of low molecular mass proteins (i.e
less than about 70 kDa) in plasma and in urine.

MBBS/DDS 2K16
- These proteins are filtered at the glomerulus and may then be neither reabsorbed
nor catabolized completely by the renal tubular cells.

- The proteins lost in overflow proteinuria are:
(i) Amylase (acute pancreatitis),
(ii) Bence Jones protein (multiple myeloma),
(iii) Haemoglobin (intravascular haemolysis)
(iv) Lysozyme (myelomonocytic leukaemia)
(v) Myoglobin (crush injuries).

Glomerulonephritis (glomerular disease)

- This is the commonest group of causes of persistent proteinuria.

- Many renal diseases are the result of glomerular injury. Among these are:

(i) Acute nephritic syndrome (acute glomerulonephritis) which is characterized by
the rapid onset of hematuria (blood in urine), proteinuria, reduced GFR, and
sodium and water retension with resulting hypertension and sometimes localized
peripheral oedema.

In a number of individuals with this disease, the pathological process is related to -
haemolytic streptococcal infection of the pharynx or less commonly the skin.

(ii) Autoimmune nephritis which is an autoimmune disorder characterized by the
presence of autoantibodies directed against basement membrane components.

(iii) Chronic glomerulonephritis which is a clinical syndrome that results from a number
of glomerular diseases that have a prolonged downhill course with progressive loss of
nephron mass.

In the late stages of chronic glomerulonephritis, hypertension is a frequent complication
and end stage renal disease becomes apparent, regardless of the initial cause.

(iv) Nephrotic syndrome.

- Plasma proteins escape in varying amounts, depending on their molecular mass, on the
amount of glomerular damage, and on the capacity of the renal tubule cells to reabsorb or
metabolize the proteins that have passed the glomerulus.

- It is important to distinguish mild or moderate proteinuria, in which the loss is not
sufficient to cause protein depletion, from severe proteinuria in which the protein loss
exceeds the bodys capacity to replace losses by synthesis (usually 5 10 g/24 h).

- Severe, persistent proteinuria is one feature of the nephrotic syndrome, in which urinary
protein loss is sometimes more than 30 g/24 h.
MBBS/DDS 2K16
Nephrotic syndrome

- Nephrotic syndrome is characterized by heavy proteinuria (total protein > 3g/24 h,
or albumin > 1.5 g/24 h), hypoalbuminaemia, hypercholesterolemia and massive
oedema.

- The oedema is a consequence of the decreased intravascular oncotic pressure due to the
loss of protein.

- The proteinuria is a consequence of a reduction in the charge-selective properties of the
filtration barrier, particular the basement membrane and podocytes (epithelial cells).

- Nephrotic syndrome results from a variety of causes, including minimal change
glomerulonephritis, membranous glomerulonephritis, drugs, or infection, systemic
lupus erythematosus, and diabetic nephropathy.

- The consequences of nephrotic syndrome include susceptibility to infection, venous
and arterial thrombosis, and abnormalities in lipid metabolism, such as hepatic
overproduction of very-low density lipoprotein (VLDL).

- Synthesis of high-density lipoprotein (HDL) also is increased, but a selective loss of HDL3
into the urine and reduced lecithin-cholesterol acyltransferase (LCAT) activity also occur,
resulting in decreased transport of cholesterol from the tissues to the liver.

Renal calculi

- Nephrolithias is a condition marked by the presence of renal calculi (kidney stones).

- The majority of these stones are composed of one or more of the following substances
calcium oxalate, calcium phosphate, uric acid, cystine, or a mixture of these with
magnesium ammonium phosphate (struvite). These substances crystallize within an
organic matrix.

- All the substances are poorly soluble in aqueous solution, with solubility influenced by the
urinary pH.

- The mechanisms responsible for the multiple recurrences of renal stones in only certain
individuals involve a multitude of factors, include:
(i) dehydration,
(ii) persistently alkaline urine,
(iii) urinary tract infection,
(iv) excretion of excess quantities of the relative insoluble substances listed above,
(v) the absence, in individuals who form stones of a substance or substances in the
urine that under normal circumstances, inhibit (s) precipitation of some of these
nearly insoluble agents.

MBBS/DDS 2K16
- Calcium oxalate stones are perhaps the most common stones encountered. They may
be associated with either persistently concentrated urine or consistently increased
excretion of urinary calcium or oxalate.

- Most commonly this type of stone is composed of predominantly calcium oxalate, with small
quantities of calcium phosphate and uric acid also present.

- The metabolic causes of calcium oxalate stones and mixed (calcium oxalate and
phosphate stones) is hypercalciuria and excessive absorption of dietary oxalate.

- Hypercalciuria is present in up to 25% of patients with calcium oxalate/phosphate stones.
It may be associated with hypercalcaemia, for example due to primary
hyperparathyroidism or vitamin D overdosage.

- The majority of urinary calculi contain oxalate, but excessive excretion of oxalate is
primarily responsible for the formation of stones in only a small percentage of cases.

- Other occasional causes of stone formation include cystinuria and xanthinuria.

- Hyperoxaluria predisposes to renal calculus formation. Primarily hyperoxaluria is a
rare inherited metabolic disorder.

- There are two types of hyperoxaluria. In type I there is increased hepatic oxalate synthesis,
and therefore increased urinary excretion of oxalic, glycoxylic and glycolic acids. Renal
failure develops in the majority of cases and calcium oxalate crystals develop in many body
tissues.

- Type II is a more benign condition in which there is increased urinary excretion of oxalic
and glyceric acids. Renal failure does not occur.

- Secondary hyperoxaluria is usually caused by increased absorption of dietary oxalate. This
may be seen in patients with a variety of gastrointestinal disorders, particularly with
inflammatory bowel diseases and conditions associated with malabsorption.

- Chemical investigations on patients with renal stones involves:
(i) Plasma calcium, albumin, phosphate, HCO3
-
, uric acid, and alkaline phosphatase
activity. Full acid-base assessment is rarely needed.
(ii) Urine dipstick testing (pH and protein), and 24 hour excretion of calcium,
phosphate and urate.
(iii) Renal function tests plasma [creatinine], and/or plasma [urea].

- The most useful chemical test involves the analysis of the stone.

- In addition to chemical tests, microbial examination of urine is usually performed.

- Radiological investigations of the urinary tract will be required to localize the stone.

MBBS/DDS 2K16
- Ultrasonic lithotripsy, also known as extracorporeal shock wave lithotripsy, is used
frequently to treat stones. This procedure uses sound waves delivered inside a water
bath to pulverize kidney stones painlessly inside the body.

- After treatment and successful removal of the stones, follow-up monitoring is required
because many patients experience recurrent stone formation.

MBBS/DDS 2K16
Lecture 6: Male Genital System- Penis, Testes & Epididymis

Lecturer: Dr. K. Coard

** The penis can be affected by the following:
i- Congenital anomalies
ii- Inflammations
iii- Tumors

Penis: Congenital Anomalies
- Congenital absence
- Aberrations in size and form
- Hypoplasia, hyperplasia and duplication
- Hypospadias & epispadias
- Phimosis

** Malformations of the urethral groove and urethral canal may create abnormal openings in two
places of the penis:
i- Ventral surface- hypospadia
ii- Dorsal surface- epispadia

** Either of these two anomalies may be associated with failure of normal descent of the testes and
with malformations of the urinary tract
- These openings should be corrected because they are associated with urethral stricture
and other infections
- The abnormal opening is constricted resulting in urinary tract obstruction
- An increased risk of ascending urinary tract infections
- If the orifices are near the base of the penis, normal ejaculation and insemination are
prevented or blocked
- Therefore these lesions are possible causes of sterility in men

Phimosis- when the orifice of the prepuce is too small to allow normal retraction
- Interferes with cleanliness
- Causes accumulation of secretions and detritus (smegma) under the prepuce
- Favors the development of secondary infections and possible carcinoma
- Phimosis can the congenital but more commonly associated with inflammation

Penis- Inflammation
** Inflammations of the penis usually involve the glans and prepuce. There are two types of
inflammation:
i- Non-specific- balanitis or balanoposthitis

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Balanoposthitis- refers to infection of the glans and prepuce caused by a wide variety of organisms
- Common agents- Candida albicans, anaerobic bacteria, Gardnerella, pyogenic bacteria
- Most cases occur as a consequence of poor local hygiene in uncircumcised males
- Accumulation of desquamated epithelial cells, sweat and debris (smegma) acting as a local
irritant
ii- Specific- sexually transmitted diseases
- Syphilis
- Chancroid- soft ulcers
- Granuloma inguinale- associated with granulation tissue
- Lymphogranuloma venerum
- Herpes simplex virus
- HPV

Tumors of the Penis
Benign Tumors
- Condyloma acuminatum
- Bowenoid papulosis

** Condyloma acuminatum is a benign tumor caused by HPV. May occur on any moist
mucocutanous surface of the external genitals in either sex
- Can also occur on the perineal areas
- These lesions occur most often occur on the coronal sulcus and the inner surface of the
prepuce
- The basement membrane is intact and there is no evidence of the underlying stroma
- Etiologic agent: HPV types 6 & 11
- Gross pathology = papillary lesion
- Histology = Hyperplastic epithelium overlying papillary processes
- Recurrences are common but malignant transformation is uncommon

Malignant Tumors
** The most frequent malignant tumor is carcinoma of the penis
Carcinoma- in- situ- is a histologic term used to describe epithelial lesions in which the cytologic
changes of malignancy are confined to the epithelium
- No evidence of local invasion or distant metastases
- Therefore it is full thickness carcinoma that does not invade the basement membrane
- Considered to be a precancerous condition because of its potential to evolve into invasive
cancer
- 5% go onto form invasive tumors

** In the external male genitalia, two lesions that display histologic features of carcinoma in situ
have been described:
Both these lesions have strong association with HPV infection

i- Bowens disease- occurs in the genital region of both men and women.
- In men it normally involves the skin of the penile shaft and the scrotum
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- Appears as a solitary, thickened, gray white, opaque plaque with shallow ulceration and
crusting
- Manifests on the glans and prepuce as red plaques known as Erythroplasia of Queyrat
- Epidermis shows proliferation with numerous mitoses. Cells are dysplastic with large
hyperchromatic nuclei
- The dermal-epidermal border is delineated by an intact basement membrane
-
ii- Bowenoid papulosis- occurs in sexually active adults
- Occurs in younger patients
- Presence of multiple rather than solitary pigmented popular lesions
- Histologically indistinguishable from Bowen disease
- Related to HPV 16
- However Bowenoid papulosis almost never develops into an invasive carcinoma and in
many cases it spontaneously regresses

Invasive Malignant Tumors
** The most common is squamous cell carcinoma of the penis
- Rare tumor but is more common in populations without routine circumcision
- Usually begins on the glans or inner surface of the prepuce
- High associations with HPV 16, 18
- Treated with surgery +/- irradiation or chemotherapy

** Two macroscopic patterns are seen:
i- Papillary- resemble condylomata acuminata
ii- Flat- appear as areas of epithelial thickening accompanied by fissuring of the mucosal
surface

Testis & Epididymis
- Congenital anomalies
- Inflammation
- Vascular lesions
- Tumors

Congenital Anomalies of Testis- Cryptorchidism

Crytorchidism- refers to maldescent of the testis
- Found in about 1% of boys at 1 year old
- Represents a complete or incomplete failure of the intraabdominal testis to descend into
the scrotal sac
- Most patients the undescended testis is palpable in the inguinal canal
- However the undescended testis due to is ectopic position is at risk of trauma and tumor
development
- Therefore surgical correction is recommended if they have not reached their correct
position by age 2 years

Note: The undescended testis is at higher risk for development of germ cell tumors

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Inflammation of the Testis & Epididymis
** Inflammation is more common in the epididymis than in the testis.
- Gonorrhea and tuberculosis usually arise in the epididymis first
- Syphilis tends to affect the testis first

** Non-specific Epidiymitis & Orchitis- usually related to infections in the urinary tract (cystitis,
urethritis, genitoprostatitis) which usually reach the epididymis and the testis through the vas
deferens or the lymphatics of the spermatic cord

** Granulomatous (Autoimmune) Orchitis- distinguished by granulomas that are restricted
within the spermatic tubules

Vascular Disturbances- Torsion of the Testis
- Twisting of the spermatic cord may cut off the venous drainage and the arterial supply to
the testis
- Usually the thick-walled arteries remain patent
- Therefore intense vascular engorgement and venous infarction follows
- Torsion is an urologic emergency
- The first signs are pain + swelling
- The testis must be manually untwisted surgically within the first 6hrs for the organ to
remain viable
- The predisposing factor is increased mobility of an already mobile structure. Associated
with a problem with the ligament of the scrotum

Tumors of the Testis
** Testicular neoplasms are divided into two main categories:
1- Germ cell tumors- (90-95%) usually highly aggressive capable of rapid, wide
dissemination
- Seminoma
- Yolk sac tumor
- Teratoma
- Combinations

2- Non-germinal tumors (Sex cord stromal tumors) (4%)- derived from the stroma or the sex
cord
- Generally benign
- Leydig cell tumor
- Sertoli cell tumor

Note: Mixed germ cell/sex cord stroma tumors are also possible
Seminoma
- The most common type of germinal tumor
- Usually seen in young adults 30-40 years
- Formed when neoplastic germ cells differentiate along gonadal lines
- Homogenous, gray-white lobulated cut surface appearance
- Tunica albuginea is usually not penetrated. Therefore they tend not to infiltrate the capsule
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- Microscopy: sheets of uniform cells separated into incomplete lobules by delicate septa.
Also with a lymphocytic infiltrate
- Seminomas are very sensitive to radiotherapy

Yolk Sac Tumor (Endodermal Sinus Tumor)
- Also known as infantile embryonal carcinoma
- Most common testicular tumor in infants and children up to 3 years
- If found in adults, the yolk sac elements are mixed with embryonal carcinoma
- Non encapsulated mass with a mutinous appearance

Microscopy: Lace like (reticular) network of medium-sized cuboidal or elongated cells
- Schiller-Duval Bodies- structures that consists of a mesodermal core with a central
capillary and a visceral and parietal layer of cells that resemble glomeruli
- These cells secrete alpha feto protein (AFP) which can be detected in tumor tissue, CSF,
urine, and serum

Teratoma
** A teratoma is a group of complex tumors with various cellular or organoid components that
resemble normal derivatives of more than one germ layer
- Contains tissues of more than one germ layer
- More common in children
- Although they can occur at any age from infancy to adult

Gross Appearance- usually large with variegated cut surface
- Because they are composed of various tissues, their gross appearance tends to be
heterogeneous
- May have solid, sometimes cartilaginous and cystic areas

Microscopic: Immature type or mature type
- Mature Type- the tissue is recognizable and therefore it is benign
- Immature Type- the type of tissue is unrecognizable and is usually a sign of malignancy

Testicular Tumors: Clinical Features
- Painless enlargement of the testis
- Spread mainly by lymphatics at early stage to para-aortic nodes
- Hematogenous spread occurs later to lungs, liver, bone + brain
- Two categories are recognized for treatment and prognostic purposes

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Lecture 7: PATHOLOGY OF THE BREAST

Lecture Outline

1. Review of Normal Anatomy and General Pathology Points
2. Benign Breast Disease
I. Non-neoplastic
II. Neoplastic
3. Overview of Breast Cancer: Epidemiology, Pathology and Prognostic Factors
4. Other Breast Tumours
5. Pathology of the Male Breast

Lecture Objectives

At the end of the lecture the student should be able to:

1. Discuss the etiology and pathologic features of the different forms of benign non-neoplastic
and neoplastic breast disease.
2. List the benign breast diseases that increase a patients risk of developing breast cancer and
classify these conditions according to the degree of relative risk.
3. Outline the other risk factors predisposing to breast cancer and the incidence/prevalence of
breast cancer.
4. Classify breast cancer into histologic subtypes and describe the pathologic features of each.
5. List the main prognostic factors for breast cancer.

Review of Normal Anatomy
The breast consists of six to ten major duct systems; the major excretory duct is the
lactiferous duct which drains through the nipple via the lactiferous sinus
The lactiferous duct divides successively into smaller branchesthe terminal duct gives
rise to approx. 30 acini which form the lobules, the functional breast units; many breast
diseases arise in the terminal duct-lobular unit
The ducts and acini are lined by columnar/cuboidal epithelium; a peripheral layer of
myoepithelium provides the contractility necessary for the expression of secretions
The breast stroma = dense fibroconnective tissue + adipose tissue (interlobular stroma) and
loose stroma surrounding the acini within the lobules (intralobular stroma)
The breast tissue responds to hormonal stimulation e.g. during the menstrual cycle and
lactation and shows involutional/atrophic changes at menopause

u PathologyGeneral Points
Breast disease affects mostly womenthe larger and more complex structure of the female
breast and sensitivity to hormonal influences predisposes to a variety of diseases.
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Breast diseases may present as palpable lumps, pain, inflammatory masses, nipple
discharges or as non-palpable abnormalities detected on breast ultrasound or
mammographic screening. Ultrasound and mammography are types of radiologic imaging
that allow for the detection of small non-palpable lesions not associated with breast
symptoms.
Methods of pathologic diagnosis include fine needle aspiration cytology (FNAC) and
incisional or excisional biopsies. Hook-wire localization biopsies or image-guided biopsies
are done for lesions detected on ultrasound or mammography i.e. non-palpable lesions
which include mass (solid or cystic) and calcifications.
In terms of overall frequency, most women who present with breast complaints will have
benign lesions, however breast cancer is one of the most common malignancies affecting
women in the Caribbean and the rest of the world.
BENIGN BREAST DISEASE
I. Non-neoplastic Diseases
1. Inflammation
u Acute Mastitis
This is the most clinically important form of mastitis; occurs as a complication of breast-
feeding when cracks in the nipples allow for bacterial infection (esp. Staphyloccoccus
aureus, less commonly streptococci)
Usually unilateralacute inflammation in the breast can lead to abscess formation which is
exquisitely tender and painful
Treatment = surgical drainage (often under general anesthesia) and antibiotics

u Periductal Mastitis (Recurrent Subareolar Abscess)
Occurs secondary to squamous metaplasia of the lining of a lactiferous duct (? related to
cigarette smoking90% of affected patients are smokers); affects both women and men
Keratin becomes entrapped leading eventually to dilation and rupture of the duct with
subsequent chronic/granulomatous inflammation; secondary infections with skin bacteria
can occur
A fistula tract can develop with recurrent cases; treatment involves removing the involved
duct/tract and drainage of any associated abscess

u Mammary Duct Ectasia
Chiefly affects multiparous women in the fifth and sixth decades
Marked periductal chronic inflammation leads to destruction of the walls of the ducts with
consequent dilation and inspissation of secretions
Affects mainly large ducts which become filled by lipid-laden macrophages and necrotic
debris; the underlying cause of the inflammatory response is unknown
As the inflammation subsides periductal fibrosis. Usually presents as a poorly defined
periareolar mass that can be confused clinically with carcinoma
Can also present as a thick, cheesy nipple secretion with or without the mass
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Mammographic appearance can also resemble carcinoma; carcinoma must be excluded by
cytologic (FNAC) or histologic evaluation (biopsy)

u Fat Necrosis
Uncommon lesion; majority of patients give a history of trauma, prior surgical intervention
or radiation therapy
Characterized initially by a central focus of necrotic fat cells surrounded by foamy, lipid-
laden macrophages and neutrophilsprogresses to chronic inflammation with infiltrating
lymphocytes and the formation of multinucleated foreign body giant cells (macrophages);
released fatty acids can combine with calcium salts to produce foci of calcification
As with duct ectasia, the major clinical significance of this lesion is its possible confusion
with carcinoma when fibrosis has created a clinically palpable mass or focal calcification is
seen on mammographyFNAC/biopsy to exclude malignancy

2. Non-Proliferative (Fibrocystic) Changes

Represents the single most common disorder of the breast
Older terminology is fibrocystic diseasemore recently referred to as non-proliferative
changes
Changes is generally considered to be more appropriate terminology than disease
because the alterations are present in most women and are not associated with any risk of
progression or development of cancer
Thought to be caused by hormonal imbalances e.g. relative in estrogens or of
progesterone, or abnormal end-organ metabolism of the hormones
The main pathologic features seen are:

Cystic change and Apocrine metaplasia
Cysts represent dilation of ducts (esp. terminal ducts) and vary in size from
microscopic to large cysts that can be palpated
Many of the cysts will be lined by large polygonal cells with abundant,
eosinophilic cytoplasm resembling apocrine epithelium of sweat glands
apocrine metaplasia
Calcification can occur within the cyst lumens

Adenosis
This is an increase in the number of acinar units in the lobules
Acini can be arranged in different patterns e.g. appear dilated with flattened
ends (blunt duct adenosis) or tubular (tubular adenosis)

Fibrosis
Cysts frequently rupture with the release of duct contents and subsequent
chronic inflammation and fibrosis

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Can present as palpable lumps, nipple discharge, mammographic densities/calcifications
Usually diagnosed between the ages of 20 and 40 years; often multifocal and bilateral
producing general lumpiness of the breast(s)
Cysts will yield clear fluid on aspiration e.g. compared to cysts that can develop during the
lactational periodgalactocelesthat yield turbid fluid
Benign features confirmed on FNAC or biopsy

3. Proliferative Disease without Atypia

u Epithelial Hyperplasia
Normal ducts/acini are lined by two cell layers epithelium and myoepithelium
Epithelial hyperplasia = in the number of layers of cells lining ducts and acini
Clinically significant hyperplasia is the presence of four or more layers of cellsso-called
moderate or florid epithelial hyperplasia
Involved ducts and acini are filled with overlapping, proliferating cells
N.B. No atypical architectural or cytologic features are present

u Sclerosing Adenosis
Special type of adenosis characterized by # acini + stromal fibrosis within lobules which
compresses and distorts acini
Can be associated with calcifications which may be detected on mammography

4. Atypical Hyperplasia
Certain types of epithelial hyperplasia are characterized by the presence of atypical
architectural and/or cytologic features
Can affect ductsatypical ductal hyperplasia, or lobulesatypical lobular hyperplasia
Atypical features resemble but fall short of in-situ cancer
There are no clinical or radiologic features that allow for diagnosis; need biopsy
As with proliferative disease without atypia, incidence has increased with the use of
screening mammography and the increase in the no. of breast biopsies being performed

II. Benign Tumours

1. Fibroadenoma
Most common benign tumour of the breast; composed of both proliferating glandular and
stromal elementsin a given lesion one element can predominate
Patients usually present before age 30 years; classic presentation is that of a firm, mobile
lump (breast mouse)
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Giant forms can occur, especially in younger patients
Approx. 20% of lesions are complex fibroadenomas characterized by certain specific
histologic features that have been shown to be clinically significant

2. Duct Papilloma
Benign papillary epithelial tumours that occur mainly in large ducts
Papillae are fibrovascular stalks lined by layers of proliferating epithelial and myoepithelial
cells with no atypical features
Most patients present with a serous or bloody nipple discharge

Relative Risk for Invasive Breast Cancer for Benign Breast Lesions

One of the most important developments in breast pathology in recent years is the
recognition that benign lesions have different levels of risk for the development of
invasive breast cancer
Risk is often quoted as a relative risk i.e. what a patients risk is when compared to
someone without breast disease.
The magnitude of risk may be modified by other factors e.g. menopausal status and family
history. Not all patients, even with higher levels of risk however, will develop cancer.

No Increased Risk
Mastitis
Fat necrosis
Mammary duct ectasia
Non-proliferative (fibrocystic) changes
Fibroadenoma (simple)

Slightly Increased Relative Risk (1.5-2 Times)
Moderate/florid hyperplasia
Sclerosing adenosis
Duct papilloma
Complex fibroadenoma

Moderately Increased Relative Risk (4-5 Times)
Atypical ductal hyperplasia
Atypical lobular hyperplasia

Women who are at mildly or slightly increased risk for breast cancer should receive follow-
up care. It is now recommended that women with atypical hyperplasia receive prophylactic
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treatment e.g. tamoxifen in addition to careful follow-up in an effort to reduce the likelihood
of cancer development

CARCINOMA OF THE BREAST

u Epidemiology
Breast cancer is the commonest malignancy in women worldwide
Accounts for approximately 18% of all female cancers compared with cervical cancer
(15%), colonic cancer (9%) and cancer of the stomach (8%)
Incidence rates are highest in North America, Australia and Western Europe; intermediate
in South America, the Caribbean and Eastern Europe and lowest in China, Japan and India
In Jamaica, breast cancer is the most common invasive tumour of women

Risk Factors
Age
The incidence of breast cancer increases with age; it is uncommon before 25 years but the
incidence increases steadily to the time of menopause and slows after this

Family History
Approximately 10% of breast cancer is due to inherited genetic predisposition
A woman whose first degree relative (mother, sister or daughter) has had breast cancer is
at an increased relative risk 2 to3 times compared to other women
At least two genes that predispose to breast cancer have been identifiedBRCA 1 and 2

Benign Breast Disease
As noted previously women with certain types of benign breast disease are at risk

History of Other Cancer
A history of cancer in the other breast or a history of ovarian or endometrial cancer

Hormonal Factors
Factors associated with exposure to increased levels of estrogen have been shown to
increase a womans risk for breast cancer
These factors include early age at menarche, late age at menopause, nulliparity, late age at
first child-birth and post menopausal hormone replacement treatment

Environmental Factors
Dietary factors e.g. high fat intake and excessive alcohol consumption, and exposure to
ionizing radiation have also been proposed as risk factors

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O The etiology of breast cancer in most women is unknown but most likely is due to a
combination of the risk factors listed above i.e. genetic, hormonal and environmental factors

u Pathology
Histologic Classification

Breast Cancer

Ductal Lobular

In-situ (DCIS) Invasive(IDC) In-situ (LCIS) Invasive(ILC)

Ductal Carcinoma In-situ (DCIS)

Increased incidence in certain countries related to increased use of mammographic
screening and early cancer detection; comprises approx. 50% screen-detected cancers
By definition these lesions are non-invasiveproliferating malignant cells within the duct
system do not breach the underlying basement membrane
Different patterns can be seen e.g. comedo (central necrosis); cribiform (cells arranged
around punched-out spaces); papillary and solid (cells fill spaces)
DCIS can be of different grades i.e. low, intermediate and high grade (e.g. comedo=high)
Often multifocalmalignant population can spread widely through the duct system
without breaching the basement membrane
Women with DCIS are at risk of recurrent DCIS following treatment and are also at marked
increased relative risk for the development of invasive cancer (8 to 10 times) especially
in the same affected breast

Lobular Carcinoma In-situ (LCIS)

Relatively uncommon lesion compared to DCIS; malignant proliferation of small, uniform
epithelial cells within the lobules which do not breach the basement membrane
Also at marked increased relative risk for the development of invasive cancer (8 to 10
times), but the invasive lesion can develop in either breast i.e. risk is bilateral

Invasive (Infiltrating) Ductal Carcinoma (IDC)
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Commonest form of breast cancer especially in poorer populations (less screening
mammography to detect early lesions such as DCIS)
Usually presents as a palpable lump (often hard and irregular) with or without evidence of
local spread e.g. tethering of the skin, retraction of the nipple, peau dorange (lymphatic
spreadthickening and dimpling of the skin), and Pagets disease of the nipple
(ulceration/inflammation due to intraductal spread to the nipple)
IDC detected by mammography is usually smaller (much better prognosis)
Can also present with an axillary mass (spread to regional lymph nodes) or with evidence of
distant metastases (e.g. lung, brain, bone)
Different histologic subtypes existthe most common is scirrhous carcinoma (also
known as invasive ductal of no special type). This type is characterized grossly by an
irregular, hard mass that on histology shows infiltrating clusters of malignant epithelial
cells surrounded by dense, fibrous stroma
Special histologic types of IDC include:
- Medullary carcinomasheets of malignant cells in a dense lymphoid stroma
- Tubular carcinomacharacterized by infiltrating tubular structures
- Mucinous/colloid carcinomamalignant cells in pools of mucin
- Papillary carcinomapapillary formations like papilloma + invasion
The importance of recognizing the different types is that most of the special types carry a
better prognosis than the more common scirrhous cancer

Invasive (Infiltrating) Lobular Carcinoma (ILC)

Much less common than its ductal counterpart; can present with similar features but more
likely to be bilateral and/or multicentric (multiple lesions within the same breast)
Classic histologic appearance - small, uniform cells arranged as strands within a fibrous
stroma (Indian-file); can also infiltrate around uninvolved ducts in bulls-eye pattern
Metastasize more frequently to CSF, serosal surfaces and pelvic organs compared to IDC

u Prognostic Factors
Stage
Different staging systems exist e.g. the TNM and the Manchester classificationtumour
size and axillary node status are important parameters. The 10-year survival rate for
lymph node negative disease is 80% versus 35% for tumours with positive nodes

Inflammatory carcinoma
Specific clinical presentation inflammatory - breast swelling and skin thickening.
Associated with underlying IDC or ILC that features prominent lymph-vascular invasion.
Particularly poor prognosis i.e. 3 year survival of 3-10%

Tumour Grade
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Different grading systems also exist; most popular is the Bloom-Richardson system based
on parameters that include mitotic rate; the higher the grade, the worse the prognosis

Histologic Subtypes (see IDC notes)

Hormone Receptors
Tumours that express receptors for estrogen and/or progesterone can be treated with
hormonal manipulation and generally have a better prognosis than those without

Molecular Markers
Newest category of prognostic markers that can be detected by immunohistochemistry or
molecular methods e.g. PCR; include c-erb-B2, c-myc and p53

OTHER BREAST TUMOURS
u Phyllodes Tumour
Stromal tumour arising from the intralobular stroma; range in size from few cm to massive
lesions and can be clinically confused with fibroadenomas
Most are low-grade lesions that can recur locally (irregular border) but do not metastasize
Others are of high-grade and exhibit aggressive clinical behaviour e.g. spread to distant sites
(these are sometimes called cystosarcoma phyllodes)

PATHOLOGY OF THE MALE BREAST
u Gynecomastia
Enlargement of the male breast related to hormonal imbalance (rel. estrogens)
Can be physiologicseen at puberty or old age, or pathologice.g. assoc. with cirrhosis,
functional testicular tumours, drugs (alcohol, marijuana and anabolic steroids)
Can be unilateral/bilateral and present as diffuse enlargement or as a defined mass
Most important clinically as a marker of hyperestrinismneoplasia needs to be excluded in
certain cases
u Carcinoma
Very rare occurrence; female cancer to male cancer ratio approx 100:1
Pathology and behavior is similar to cancers seen in women although with less breast
tissue, skin involvement is more frequent
NB. The following link can provide you with additional information and images for this topic:
http://www.breastpathology.info/

SEShirley
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Lecture 8: PATHOLOGHY OF THE URINARY BLADDER
AND PROSTATE GLAND

Lecturer: Dr. K. Coard

Diseases of the Bladder
Congenital abnormalities
Inflammation
Tumours
(Obstruction)
Bladder
- Congenital Anomalies
Exstrophy
Diverticula
Miscellaneous anomalies
Fistulas
Vesicoureteral reflux
Inflammation of Bladder (Cystitis)
- Causes
Bacteria
Fungi
Viruses
Protozoa
Drugs & radiation
Special types

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Factors Predisposing to Cystitis
Urinary tract malformations in children
Sexually active females
BPH with urinary retention in males
Miscellaneous
FB (stones, catheters)
Diverticula
Agents causing mechanical destruction of bladder mucosa
Cystitis
- Clinical Symptoms
Frequency
Lower abdominal pain
Dysuria
[+/- Systemic symptoms]
Neoplasms of the Bladder
Urothelial / Transitional Cell
Benign
Urothelial / Transitional Cell Papilloma
Inverted papilloma
Malignant
Urothelial / Transitional Cell Carcinoma (TCC) *
Others SCC, Adenocarcinoma, Mixed
(Mesenchymal)
Bladder Cancer
- Epidemiology and Pathogenesis
Incidence: The latest available rate in Jamaica is 4.1/100,000 in men
Age : 50-80 yr.
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Gender: M > F
Histologic type: Mostly urothelial (TCC)
Causative agents: Variety of suspects
Bladder Cancer
- Risk Factors
Chemicals
Cigarette smoking
Phenacitin-containing analgesics
Schistosomiasis
Previous irradiation & long-term exposure to cyclophosphamide
Genetic factors
Bladder Cancer
- Pathology/Morphology
Papillary / Flat
Invasive / Non invasive
Grading of tumour - Different systems (WHO and ISUP Most recent)
Papillary urothelial neoplasms of low malignant potential
Low-grade papillary urothelial carcinoma
High-grade papillary urothelial carcinoma
Bladder Cancer
- Clinical Course and Prognosis
Symptoms - Painless haematuria
Recurrences common
Prognosis - Depends on grade and stage of tumour at diagnosis
Clinical challenge - Early detection and adequate follow-up
Obstructive Uropathy

This entity refers to the changes that result from obstruction of urine in any part of the urinary tract
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- Causes
BPH
Congenital anomalies PUV, ureteropelvic junction narrowing
Strictures of urethra
Mechanical obstruction Calculi, FB
Inflammatory fibrosis and contraction of bladder
Invasion of bladder neck by perivesical structures
Neurogenic bladder
- Pathology
Thickening & trabeculation of bladder wall
Diverticula formation
Complications - Hydroureters
- Hydronephrosis
- Pyelonephritis
Pathologic Processes Affecting the Prostate Gland
Inflammation
Benign nodular enlargements
Tumours
Inflammation of the Prostate
Acute bacterial prostatitis
Chronic bacterial prostatitis
Chronic abacterial prostatitis
Granulomatous prostatitis

Nodular Hyperplasia of the Prostate (BPH)
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Synonyms - Benign Prostatic Hyperplasia
- Benign Prostatic Hypertrophy
Incidence - Increases with age
- Major problem in elderly
Etiology & pathogenesis - Androgens (DHT)
- ? Oestrogens
BPH
- Pathology
Gross
- Gland enlarged
- Nodular cut surface
Microscopic
- Proliferation of glandular, fibrous and
muscular components
BPH
- Clinical Course
Symptoms related to:
Compression of urethra
Difficulty in urination
Retention of urine
Distention of bladder
Hypertrophy
Infection
Treatment TURP most common
Carcinoma of Prostate Gland
- General
Most common cancer in men
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Different biologic forms -Latent /clinically evident
Geographic & racial differences notable
Incidence in Jamaica 78.1/100,000 *
Etiology unknown- Many risk factors suggested
- Methods of Diagnosis
DRE (Digital Rectal Examination)
TRUS (Trans Rectal Ultra Sound)
Biochemistry - PSA (Prostate Specific Antigen)
Biopsy
- Grading and Staging
Both used to assess prognosis
Grading - Assesses degree of differentiation
Gleason system most commonly used
Good correlation between grade and prognosis
Staging - Assesses extent of spread
Different staging systems used
Important for selecting appropriate therapy
- Treatment Options
Surgery
Radiation
Hormonal therapy
Active surveillance

MBBS/DDS 2K16
Lecture 9: Disorders of water and electrolyte balance

Lecturer: Dr. Lowell Dilworth

Consequences of water and electrolyte imbalance
Disorders of altered isotonic fluid volume
Disorders of electrolyte balance
Disorders of altered isotonic fluid volume
- Isotonic fluid deficit
- Isotonic fluid volume excess
Dehydration

OP=pressure required to keep the water within a specific space. Rise in OP means it will require
more pressure to be applied to water in ECF for it to move to ICF. Hence the potential for water to
move intracellularly is reduced.

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Isotonic fluid deficit: Dehydration

Hypotonic Hydration: water excess

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Isotonic fluid excess
Causes ???

Disorders of electrolyte balance
Sodium
Hyponatraemia
Hypernatraemia
Potassium
Hypokalaemia
Hyperkalaemia

Disorders of altered sodium concentration
Hyponatraemia
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Main causes of Hyponatraemia
1) Depletion of sodium (hypovolaemic hyponatraemia)
2) Excess of water (euvolaemic hyponatraemia)
3) Excess of water and sodium (hypervolaemic hyponatraemia)

1) Depletion of sodium (hypovolaemic hyponatraemia)
Na
+
not lost without water
Hyponatraemia can occur in sodium-depleted patients due to either inappropriate replacement of
fluid (containing insufficient sodium) or in severe sodium depletion, to the hypotonic stimulus to
vasopressin secretion, which overrides the osmotic control and permits water retention at the
expense of a decrease in osmolality.
MBBS/DDS 2K16
Management involves correcting underlying cause and appropriate fluid replacement (0.9% saline)
or plasma expanders
Eg Cerebral Salt wasting- Hyponatraemia and natriuresis in the presence of cerebral pathology

2) Excess of water (euvolaemic hyponatraemia)
Gives rise to dilutional hyponatraemia with reduced plasma osmolality
TBW increases while total sodium remains normal. The ECF volume is increased minimally to
moderately but without the presence of oedema.
May occur acutely due to excessive water intake
-rare as kidneys can excrete up to 1 L of water per hour. Water intoxication and hyponatraemia will
thus occur when large quantities of fluid are ingested rapidly (PP) or if loads of weak beer are
ingested.. smh.
Impaired diuresis the main contributor.
SIADH is an example of euvolaemic hyponatraemia
Underlying causes of SIADH (Syndrome of Inappropriate Antidiuretic Hormone)
Hypothyroidism
Drugs (particularly antipsychotics): Nonsteroidal anti-inflammatory drugs (NSAIDs),
Carbamazepine, Selective Serotonin reuptake inhibitors (SSRIs),
Methylenedioxymethamphetamine (MDMA), Clorpropamide, Clofibrate, Phenothiazine,
Cyclophosphamide
CNS: brain surgery, meningitis, head injury
Infections: Lung abscess or pneumonia
Tumours: lung or brain
3) Excess of water and sodium (hypervolaemic hyponatraemia)
A frequent cause of hyponatraemia.
Occurs when extracellular sodium is normal or even slightly elevated, but extracellular fluid is
greatly elevated.
It underlies the hyponatraemia of congestive cardiac failure, patients with liver failure and
hypoproteinaemic states.
Na excess is indicated by signs of increased ECF volume.
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Treatment measures to treat underlying cause, and removing excess water and Na (diuretics).
Saline should not be given (despite hyponatraemia) since the patient is already Na overloaded.
Hypernatremia

Disorders of altered potassium concentration
Hypokalaemia- Any foods that responsible??
Hyperkalaemia-Any foods responsible?
Hypo-eating large amounts of licorice or using products such as herbal teas and chewing tobaccos
that contain licorice
Potassium rich foods include:
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Oranges
Honeydew melons
Bananas
Nuts
Dried apricots
Raisins
Hypokalaemia

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Hyperkalaemia

Disturbance of Potassium Balance on cardiac function
Disrupt electrical conduction in the heart
Lead to sudden death
Hypokalaemia

Sinus bradycardia
Electrocardiographic (ECG) signs of U waves and progressive flattening of T waves and
depression of ST segment)
Licorice
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Hyperkalaemia

Serum or Plasma?
The in vitro release of potassium from cells and platelets during blood clotting (particularly in
patients with blood clotting disorders) increases serum potassium, on average, by 0.4 mmol/L.
Take tube type into consideration.Some tubes have clot activators e.g. micronised silica particles.
How will tissue trauma (cell damage/lysis) affect K
+
?
Normal serum potassium levels are between 3.5 and 5.0 mMol/L.
At least 95% of the body's potassium is found inside cells.
Potassium ions move passively into cells from the ECF in exchange for sodium which is actively
excluded by a membrane-bound energy-dependent sodium pump.
Hyperkalaemia can result if the activity of this sodium pump is impaired or if there is damage to cell
membranes.
Warm weather and exercise?
Two sides to the story
Prolonged exercise leading to excessive sweating can result in potassium loss.
On the other hand Hutchinson and Barksdale suggests that increase seen in serum potassium levels
with aerobic exercise may be due to hemoconcentration (which appears to occur rather quickly)
could also be due in part to the local release of potassium from skeletal muscle into the interstitial
fluid.
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There is debate about part B, but one explanation is that the simple squeezing action of muscular
contraction might force potassium out of muscle cells and into the circulation. One might also
speculate that transient, momentary ischemia of muscle cells could occur even with aerobic
exercise and be associated with the escape of some potassium from the exercising muscle.
Stimulators of potassium uptake
Insulin
Beta adrenergic stimulation
On that note, alpha adrenergic stimulation has the opposite effect
Other factors that may influence potassium shift
Transcellular shifts of hydrogen can cause reciprocal shifts in potassium and vice versa.
In acidosis, intracellular buffering of hydrogen ions results in displacement of potassium into the
ECF.
In alkalosis, there is a shift of hydrogen ions from the ICF to the ECF and a net movement of
potassium ions in the opposite direction. This leads to hypokalaemia.
Having said that, it is not hard to see how potassium depletion can lead to systemic alkalosis.
Points to remember
Potassium depletion occurs when output exceeds intake
Except in fasting patients, inadequate intake rarely results in K
+
depletion
K
+
loss occurs frequently from the gut or via kidneys
++

Beware of drug therapy which is an important cause of hypokalaemia

Clinical Case
Following surgery for major abdominal injuries sustained in a knife fight (prior to the Man U,
Arsenal Match), a young man was fed parenterally and artificially ventilated. On the 5
th
day after
his operation, serum biochem profile results which were normal prior were as follows.
Na 150 mmol/L
K 4.2 mmol/L
Urea 10.2 mmol/L
Glucose 25 mmol/L
MBBS/DDS 2K16
During the previous 24hr he had become pyrexial and positive blood cultures were subsequently
obtained. His fluid intake had been 3000 mL, urine output had been steady at 90-100 mL/h (normal
30-40) and 300 mL of fluid had been aspirated via a nasogastric tube. Na intake was ~70 mmol/L.
Comments??
Is sodium intake excessive?
What is the most likely cause of hypernatraemia?
Is he diabetic?
Urea??
Should he switch sides and become a Man U fan since this Arsenal fan had well umm.. nothing in
his arsenal
Comments
Sodium input is not excessive
Likely cause of hypernatraemia is water depletion. His net fluid intake is about 400 mL which is
insufficient to balance insensible losses How does pyrexia contribute to this water loss??
Urine output was not decreased hence there was an excessive renal water loss due to osmotic
diuresis as a result of glycosuria and high urea output.
Glucose intolerance may be a problem in patients receiving parenteral nutrition and can be
exacerbated by sepsis which causes insulin resistance.
Parenteral administration of excessive nitrogen will result in increased formation of urea which
will also contribute to an osmotic diuresis.
Summary
Na, K and water homeostasis are closely linked. Na is the main extracellular cation and the amount
of sodium in the body is the main determinant of ECF volume.
Na and K are transported actively in the body, water moves passively in response to changes in the
solute contents of the bodys fluid compartments
Sodium excretion is primarily controlled by aldosterone, a hormone secreted in response to a
decrease in ECF volume that causes sodium retention and loss of potassium.
Water secretion is controlled by vasopressin. This promotes water retention and is secreted in
response to an increase in in ECF osmolality and a decrease in ECF volume.
K excretion is regulated in part by aldosterone but also depends on extracellular hydrogen ion
concentration and sodium and water excretion
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Changes in plasma sodium concentration can be due to changes in the amounts of extracellular
sodium or water or both. Hyponatraemia is common; it is sometimes an appropriate physiological
response to disease. Hypernatraemia is less common and is usually related to a decrease in body
water.
Potassium depletion is a poor guide to overall potassium status. Depletion is not always associated
with hypokalaemia.
Hypokalaemia is most frequently a result of excessive gastrointestinal or renal loss of potassium
and may be exacerbated by poor intake. It may also be a consequence of increased cellular intake of
potassium from plasma.
Hyperkalaemia is most frequently due to decreased renal excretion or to a loss of potassium from
cells. Hyperkalaemia is often iatrogenic occurring as a result of drug treatment or inappropriate
potassium administration.

MBBS/DDS 2K16
Lecture 10: Acid Base Balance

Lecturer: Dr. Lowell Dilworth
Main Objectives
- Assess the importance of acid base homeostasis
- Discuss the main species involved in regulation of acid base status
- Discuss the 3 main regulatory mechanisms of acid base status
- Identify the effects of acidosis and alkalosis on some physiological functions eg.
nerves and muscles
- The responses to disruptions in acid base status

ACID BASE HOMEOSTASIS
Acid-Base homeostasis involves chemical and physiologic processes responsible for the
maintenance of the acidity (pH) of body fluids at levels that allow optimal function of the whole
individual.
The chemical processes represent the first line of defense to an acid or base load and include the
extracellular and intracellular buffers
The physiologic processes modulate acid-base composition by changes in cellular metabolism and
by adaptive responses in the excretion of volatile acids by the lungs and fixed acids by the kidneys
The need for the existence of multiple mechanisms involved in Acid-Base regulation stems from the
critical importance of the hydrogen ion (H
+
) concentration on the operation of many cellular
enzymes and function of vital organs, most prominently the brain and the heart
EFFECTS OF pH
The most general effect of pH changes are on enzyme function
Also affect excitability of nerve and muscle cells
ACID-BASE BALANCE
Acid - Base balance is primarily concerned with two ions:
Hydrogen (H
+
)
Bicarbonate (HCO3
-
)
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Derangements of hydrogen and bicarbonate concentrations in body fluids are common in disease
processes

H
+
ion has special significance because of the narrow ranges that it must be maintained in order to
be compatible with living systems

Primarily controlled by regulation of H
+
ions in the body fluids
Especially extracellular fluids
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ACID-BASE REGULATION
Maintenance of an acceptable pH range in the extracellular fluids is accomplished by three
mechanisms:
1) Chemical Buffers
React very rapidly
(less than a second)
2) Respiratory Regulation
Reacts rapidly (seconds to minutes)
3) Renal Regulation
Reacts slowly (minutes to hours)

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Chemical Buffers
The body uses pH buffers in the blood to guard against sudden changes in acidity
A pH buffer works chemically to minimize changes in the pH of a solution
Respiratory Regulation
Carbon dioxide is an important by-product of metabolism and is constantly produced by cells
The blood carries carbon dioxide to the lungs where it is exhaled
When breathing is increased,
the blood carbon dioxide level
decreases and the blood
becomes more Basic
When breathing is decreased,
the blood carbon dioxide level
increases and the blood becomes more Acidic
By adjusting the speed and depth of breathing, the respiratory control centers
and lungs are able to regulate the blood pH minute by minute
Kidney Regulation
Excess acid is excreted by the kidneys, largely in the form of ammonia
The kidneys have some ability to alter the amount of acid or base that is excreted, but this generally
takes several days
ACIDS
Acids can be defined as a proton (H
+
) donor
Hydrogen containing substances which dissociate in solution to release H
+

Many other substance (carbohydrates) also contain hydrogen but they are not classified as acids
because the hydrogen is tightly bound within their molecular structure and it is never liberated as
free H
+

Physiologically important acids include:
Carbonic acid (H2CO3)
Phosphoric acid (H3PO4)
Pyruvic acid (C3H4O3)
Lactic acid (C3H6O3)
These acids are dissolved in body fluids
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BASES
Bases can be defined as:
A proton (H
+
) acceptor
Molecules capable of accepting a hydrogen ion (OH
-
)
Physiologically important bases include:
Bicarbonate (HCO3
-
)
Biphosphate (HPO4
-2
)
pH SCALE
pH refers to Potential Hydrogen
Expresses hydrogen ion concentration in water solutions
Water ionizes to a limited extent to form equal amounts of H
+
ions and OH
-
ions
H2O H
+
+ OH
-

H
+
ion is an acid
OH
-
ion is a base
- Normal blood pH??
- pH range compatible with life??
ACIDOSIS / ALKALOSIS
Acidosis and alkalosis are not diseases but rather are the results of a wide variety of disorders
The presence of
acidosis or
alkalosis provides
an important clue
to physicians that
a serious
metabolic
problem exists

pH changes have dramatic effects on normal cell function
1) Changes in excitability of nerve and muscle cells
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2) Influences enzyme activity
3) Influences K
+
levels

CHANGES IN CELL EXCITABILITY
pH decrease (more acidic) depresses the central nervous system
Can lead to loss of consciousness
pH increase (more basic) can cause over-excitability
Tingling sensations, nervousness, muscle twitches
INFLUENCES ON ENZYME ACTIVITY
pH increases or decreases can alter the shape of the enzyme rendering it non-functional
Changes in enzyme structure can result in accelerated or depressed metabolic actions within the
cell

MBBS/DDS 2K16
INFLUENCES ON K
+
LEVELS
When reabsorbing Na
+
from the filtrate of the renal tubules K
+
or H
+
is secreted (exchanged)
Normally K
+
is
secreted in much
greater amounts
than H
+

If H
+
concentrations are high
(acidosis) then H
+
is secreted in
greater amounts
This leaves less K
+
than usual
excreted
The resultant K
+
retention can
affect cardiac function and other systems
Normal ratio of HCO3
-
to H2CO3 is 20:1
H2CO3 is source of H
+
ions in the body
Deviations from this ratio are used to identify Acid-Base imbalances
Acidosis and Alkalosis can arise in two fundamentally different ways:
1) Excess or deficit of CO2
(Volatile Acid)
Volatile Acid can be eliminated by the respiratory system
2) Excess or deficit of Fixed Acid
Fixed Acids cannot be
eliminated by the
respiratory system
Normal values of bicarbonate (arterial)
pH = 7.4
PCO2 = 40 mm Hg
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HCO3
-
= 24 meq/L
ACIDOSIS
A decrease in a normal 20:1 base to
acid ratio
An increase in the number of
hydrogen ions
(ex: ratio of 20:2 translated to 10:1)
A decrease in the number of bicarbonate ions (ex: ratio of 10:1)
Caused by too much acid or too little base
ALKALOSIS
An increase in the normal 20:1 base to acid ratio
A decrease in the number of hydrogen ions
(ex: ratio of 20:0.5 translated to 40:1)
An increase in the number of bicarbonate ions (ex: ratio of 40:1)
Caused by base excess or acid deficit
SOURCES OF HYDROGEN IONS
1) Cell Metabolism (CO2)
2) Food Products
3) Medications
4) Metabolic Intermediate by-products
5) Some Disease processes
SOURCES OF BICARBONATE IONS
1) CO2 diffusion into red blood cells
2) Parietal cell
secretion of the
gastric mucosa
1) CO2 DIFFUSION
Hemoglobin buffers H
+

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Chloride shift insures electrical neutrality
Parietal cell secretion
Secrete hydrogen ions into the lumen of the stomach
Bicarbonate ions diffuse into the bloodstream to maintain electrical neutrality in the parietal cell
In pancreatic cells the direction of ion movement is reversed
H+ ions are secreted into the blood and bicarbonate ions diffuse into pancreatic juice
If the two processes are balanced, there is no net change in the amount of bicarbonate in blood
Loss of gastric or pancreatic juice can change that balance
BICARBONATE SECRETION
Cells of the gastric mucosa secrete H
+
ions into the lumen of the stomach in exchange for the
diffusion of bicarbonate ions into blood
The direction of the diffusion of these ions is reversed in pancreatic epithelial cells
Acidosis and Alkalosis are categorized as Metabolic or Respiratory depending on their primary
cause
Metabolic Acidosis and Metabolic Alkalosis
caused by an imbalance in the production and excretion of acids or bases by the kidneys
Respiratory Acidosis and Respiratory Alkalosis
caused primarily by lung or breathing disorders
ACIDOSIS
May be caused by:
An increase in H2CO3
A decrease in HCO3
-

Both lead to a decrease in the ratio of 20:1
RESPIRATORY ACIDOSIS
Caused by hyperkapnia due to hypoventilation
Characterized by a pH decrease and an increase in CO2
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RESPIRATORY ACIDOSIS
The speed and depth of breathing control the amount of CO2 in the blood
Normally when CO2 builds up, the pH of the blood falls and the blood becomes acidic
High levels of CO2 in the blood stimulate the parts of the brain that regulate breathing, which in
turn stimulate faster and deeper breathing
If a patient has lung disease preventing him/her from properly blowing off CO2, what will happen?
Respiratory acidosis develops when the lungs don't expel CO2 adequately
This can happen in diseases that severely affect the lungs, such as emphysema, chronic bronchitis,
severe pneumonia, pulmonary edema, and asthma
Respiratory acidosis can also develop when diseases of the nerves or muscles of the chest impair
the mechanics of breathing
In addition, a person can develop respiratory acidosis if overly sedated from narcotics and strong
sleeping medications that slow respiration
The treatment of respiratory acidosis aims to improve the function of the lungs
Drugs to improve breathing may help people who have lung diseases such as asthma and
emphysema
RESPIRATORY ALKALOSIS
Causes Hyperventilation
Leads to eliminating excessive amounts of CO2
Increased loss of CO2 from the lungs at a rate faster than it is produced
Decrease in H
+

Respiratory Alkalosis
Can be the result of:
1) Anxiety, emotional disturbances
2) Respiratory center lesions
3) Fever
4) Salicylate poisoning (overdose)
5) Assisted respiration
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6) High altitude (low PO2)
Kidneys compensate by:
Retaining hydrogen ions
Increasing bicarbonate excretion
METABOLIC ACIDOSIS
Any acid-base imbalance not attributable to CO2 is classified as metabolic
Metabolic production of Acids
Or loss of Bases
If an increase in acid overwhelms the body's pH buffering system, the blood can become acidic
As the blood pH drops, breathing becomes deeper and faster as the body attempts to rid the
blood of excess acid by decreasing the amount
of carbon dioxide
Eventually, the kidneys also try to compensate by excreting more acid in the urine
However, both mechanisms can be overwhelmed if the body continues to produce too much acid,
leading to severe acidosis and eventually a coma
The causes of metabolic acidosis can be grouped into five major categories
1) Ingesting an acid or a substance that is metabolized to acid
2) Abnormal Metabolism
3) Kidney Insufficiencies
4) Strenuous Exercise
5) Severe Diarrhea
Treating the underlying cause of metabolic acidosis is the usual course of action
Eg control diabetes with insulin or treat poisoning by removing the toxin
Occasionally dialysis is needed to treat severe
overdoses and poisonings
METABOLIC ALKALOSIS
Elevation of pH due to an increased 20:1 ratio
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May be caused by:
An increase of bicarbonate
A decrease in hydrogen ions
Imbalance again cannot be due to CO2
Increase in pH which has a non-respiratory origin
Can be the result of:
1) Ingestion of Alkaline Substances
2) Vomiting ( loss of HCl )
Treatment of metabolic alkalosis is most often accomplished by replacing water and electrolytes
(sodium and potassium) while treating the underlying cause
Occasionally when metabolic alkalosis is very severe, dilute acid in the form of ammonium chloride
is given by IV
RESPONSES TO:
ACIDOSIS AND ALKALOSIS
Mechanisms protect the body against life-threatening changes in hydrogen ion concentration
1) Buffering Systems in Body Fluids
2) Respiratory Responses
3) Renal Responses
4) Intracellular Shifts of Ions
Case
A 60 yo man was admitted to hospital with severe abdominal pain that had begun 2.5 hr earlier. He
was not taking drugs. On examination he was shocked and had a distended right abdomen; neither
femoral pulse was palpable.
Arterial blood: H
+
ion 90 nmol/L (35-46)
PCO2 3.5 kPa (4.5-6)
PO2 12 Kpa (11-15)
bicarb 7mmol/L (22-30)
1. Is the patient acidotic or alkalotic?
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2. How do you know?
3. Is it respiratory or non-respiratory in origin?
4. What does the PCO2 suggest?
1. Acidotic
2. Low ph
3. Non-respiratory as pO2 is not raised
4. Low PCO2 suggests compensatory hyperventilation
Low bicarbs is reflective of the primary abnormality, as H+ ions are buffered, bicarbonate ions are
consumed.
END OF PATHOLOGY SECTION

MBBS/DDS 2K16
Lecture 1: Introduction to Renal Physiology

Lecturer: Dr. O. Prashad

** The weight of the kidney indicates the functional status of the kidney

** The primary function of the kidneys are to form urine and the excretion of various metabolic
waste products
- Also to regulate both blood volume + blood pressure
- Controls the volume and composition of all body fluids
- For water and most electrolytes of the body, the balance between intake and output is
maintained mostly by the kidneys
- Therefore this maintains the stable environment of the cells necessary for them to
perform their various activities.
- Regulates acid-base balance (H+ ions)
- Regulation of body fluid osmolality and electrolyte concentrations
- Regulation of arterial pressure
- Secretion, metabolism and excretion of hormones
- Gluconeogenesis
- Regulates the production of red blood cells- in certain chronic conditions where there is a
low partial pressure of oxygen in the blood, the kidneys help stimulate production of RBCs
via erythropoietin
- Regulation of calcium ion concentration- via productions of the active form of vitamin D
(calcitriol)

** The kidneys are the primary means for eliminating waste products of metabolism that are no
longer needed by the body:
- Urea- from metabolism of amino acids
- Creatinine- from muscle creatinine
- Uric acid
- End products of hemoglobin breakdown
- Metabolites of various hormones

** The kidneys also eliminate most toxins and other foreign substances that are produced by the
body or ingested:
- EX: pesticides, food additives, drugs

Nephron
** The nephron is the functional unit of the kidney
- Each kidney has about 800,000 1 million nephrons
- The kidney can not regenerate new nephrons
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- Therefore with renal injury, disease, or normal aging, there is a gradual decrease in nephron
number
- After age 40, the number of functioning nephrons usually decreases about 10% every 10
years

** Each nephron contains:
1- Glomerulus- tuft of glomerular capillaries through which large amounts of fluid are filtered
from the blood
- Contains a network of branching and anastamosing glomerular capillaries
- These glomerular capillaries have a high hydrostatic pressure as compared with other
capillaries
- The capillaries are covered by epithelial cells and the whole glomerulus is encased in
Bowmans capsule
- Fluid filtered from the glomerular capillaries flows into the Bowmans capsule and then into
the proximal tubule (cortex)

2- Tubule- in which filtered fluid is converted into urine on its way to the pelvis of the
kidney
- From the proximal tubule, fluid flows into the loop of Henle
- Each loop consists of an ascending and a descending limb
- Thin segment of the Loop of Henle- consists of the descending limb and the lower end of the
ascending limb
-

- Note: After the ascending limb of the loop has returned partway back to the cortex, its wall
becomes much thicker and it is known as the thick segment of the ascending limb

** The thick ascending loop of Henle is the only place where active transport of substances occurs.
- Continues back into the cortex to form the distal tubules

** The distal tubule is found in the renal cortex. This is followed by the connecting tubule and the
cortical collecting tubule, which lead to the cortical collecting duct
- The collecting ducts merge to form progressively larger ducts that empty into the renal
pelvis through the tips of the renal papillae

Note: The collecting tubule is impermeable to water except in the presence of ADH

Types of Nephrons
** The nephrons are different anatomically not physiologically
1- Cortical Nephrons (Superficial)- these have their glomeruli in the outer cortex
- They have short loops of Henle that penetrate only a short distance into the medulla
- Therefore the glomeruli of cortical nephrons are further away from the corticomedullary
junction
- Cortical nephrons have no thin loop of Henle

MBBS/DDS 2K16
2- Juxtamedullary Nephrons- Have glomeruli that lie deep in the renal cortex near the
medulla
- Have long loops of Henle that penetrate the medulla deeply
- Therefore these nephrons are closer to the corticomedullary junction

** There are also differences in the vascular structures supply the two types of nephrons:
1- Cortical Nephrons- the entire tubular system is surrounded by an extensive network of
peritubular capillaries

2- Juxtamedullary Nephrons- long efferent arterioles extend from the glomeruli down into
the outer medulla
- Then divided into specialized peritubular capillaries (vasa recta)
- The vasa recta extends downward into the medulla, adjacent to loops of Henle
- The vasa recta also return toward the cortex and empty into the cortical veins

Note: The only physiological difference between the two nephrons is that the filtration rate in the
juxtamedullary nephrons is slightly higher than the cortical nephrons

- 85%- cortical nephrons
- 15%- juxtamedullary nephrons
- Therefore most of the urine produced by the body is formed by cortical nephrons

Renal Blood Supply
** Blood flow to the kidneys is about 22% of cardiac output (1100 ml/min)
** The renal artery enters the kidney through the hilum and then branches to form:
i- Interlobar arteries
ii- Arcuate arteries
iii- Interlobular arteries
iv- Afferent arterioles

** The afferent arterioles lead to the glomerular capillaries. In the capillaries large amounts of
fluid and solutes are filtered to begin urine formation
- The afferent arterioles enter the renal corpuscle and divides into glomerular capillaries

** The distal ends of the capillaries of each glomerulus coalesce to form the efferent arteriole
- The efferent arteriole leads to a second capillary network (peritubular capillaries) that
surrounds the renal tubules
- Therefore the efferent arterioles takes blood out of the glomerulus

** The renal circulation has 2 capillary beds:
i- Glomerular capillaries- high pressure system because the blood is entering from the
arterial system
- 60 mmHg
- The high hydrostatic pressure facilitates rapid filtration
ii- Peritubular capillaries- low pressure bed (13 mmHg)
MBBS/DDS 2K16
- This low pressure allows rapid fluid reabsorption

** Therefore by adjusting the resistance of the afferent and efferent arterioles, the kidneys can
regulate the hydrostatic pressure in both the glomerular and peritubular capillaries
- Therefore they can change the rate of glomerular filtration, tubular reabsorption or both in
response to body homeostatic demands

** The peritubular capillaries empty into the vessels of the venous system
- The venous vessels run parallel to the arteriolar vessels
- They progressively form the interlobular vein, arcuate vein, interlobar vein + renal vein,
which leaves the kidney beside the renal artery and ureter

** One of the peritubular capillaries descends deep into the medulla and wraps around the loop of
Henle to form the vasa recta
- This capillary is associated with the juxtamedullary nephron
- Supplies blood to various organs of the medulla
- BUT all other peritubular capillaries are in the cortex

Renal Blood Flow
CALCULATION PAGE- NEED PRASHAD PWRPT

** Urine formation begins when a large amount of fluid that is virtually free of protein is filtered
from the glomerular capillaries into the Bowmans capsule
- As filtered fluid leaves the Bowmans capsule and passes through the tubules it is
modified by reabsorption of water and specific solutes back into the blood
- Or modified by secretion of other substances from the peritubular capillaries into the
tubules

** Factors that decrease renal blood flow include:
1- Sympathetic Stimulation- an increase in sympathetic stimulation causes
vasoconstriction of the afferent arteriole and renal artery and therefore decreases renal
blood flow

2- Systemic Blood Pressure- if the blood pressure decrease, the renal blood flow also
decreases

3- Inhalation Anesthesia

4- Severe Hypoxia- causes increased sympathetic stimulation which leads to decreased renal
blood flow

5- Exercise- vasoconstriction to the kidneys.

6- Stressful Conditions- decrease RBF because the blood is diverted from the kidneys to the
brain + heart

MBBS/DDS 2K16
7- Prolonged Standing- increases the blood flow to the medulla of the kidney but decreases
the flow to the cortex

8- 4
th
Decade of Life- RBF decreases because the blood vessels become more fragile

MBBS/DDS 2K16
Lecture 2: Renal Physiology II: Glomerular Filtration


Formation of Urine
** Urine formation begins when a large amount of fluid that is virtually free of protein is filtered
from the glomerular capillaries into Bowmans capsule

** Most substances in the plasma are freely filters; therefore their concentration in the glomerular
filtrate in the Bowmans capsule is almost the same as in the plasma

** As filtered fluid leaves the Bowmans capsule and passes through the tubules, it is modified by
reabsorption of water and specific solutes back into the blood
- Or modified by secretion of other substances from the peritubular capillaries into the
tubules

** Tubular reabsorption is more important than tubular secretion in the formation of urine
- But secretion plays an important role in determining the amounts of potassium and
hydrogen ions and a few other substances that are excreted in the urine

** Most substances must be cleared from the blood, especially the end products metabolism such
as urea, creatinine, uric acid, and urates
- These substances are poorly reabsorbed and therefore excreted in large amounts in the
urine

** Electrolytes such as sodium ions, chloride ions and bicarbonate ions are highly reabsorbed
- Therefore only small amounts appear in the urine
- Certain nutritional substances such as amino acids + glucose are completely reabsorbed
from the tubules

Note: Each of the processes (glomerular filtration tubular reabsorption, tubular secretion) is
regulated according to the needs of the body

** The advantages of having a high glomerular filtration rate are numerous:
1- Removal of Waste Products- a high GFR allows the kidneys to rapidly remove waste
products from the body
- Especially those that depend primarily on glomerular filtration for their excretion
- Most waste products are poorly reabsorbed by the tubules, therefore the depend on a high
GFR for effective removal from the body
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2- Filtration of Body Fluids- allows all the body fluids to be filtered and processed by the
kidney many times each day
- Allows the kidney to precisely and rapidly control the volume and composition of the body
fluids

Glomerular Filtration
** Urine formation begins with the filtration of large amounts of fluids through the glomerular
capillaries into Bowmans capsule
- The glomerular capillaries are relatively impermeable to proteins
- Therefore the filtered fluid (glomerular filtrate) is basically protein free and free of
cellular elements

Glomerular Capillary Membrane
** The glomerular capillary membrane is similar to other capillaries, except that is has 3 instead of
the usual 2 layers
1- Endothelium- of the capillary
2- Basement membrane
3- Podocytes- layer of specialized epithelial cells surrounding the outer surface of the
capillary basement membrane

** The high filtration rate across the glomerular capillary membrane is due partly to its special
characteristics

Determinants of GFR
** The glomerular filtration rate (GFR) is determined by:
1- Balance of hydrostatic and colloid osmotic forces acting across the capillary membrane-
this provides the net filtration pressure
- Therefore GFR depends on Starling Forces
- All other capillaries in the body filter about 2ml/min
- However the GFR is 125 ml/min. This is 60x more than the regular capillaries

2- Capillary filtration co-efficient (Kf)- the product of the permeability and filtering surface
area of the capillaries
- Kf- @ 1mmH the net filtration is 12.5ml per min

GFR = Kf x Net filtration pressure

Note: Glomerular capillaries have a higher rate of filtration than other capillaries because of a high
glomerular hydrostatic pressure and a large Kf

** The net filtration pressure represents the sum of the hydrostatic and colloid osmotic forces
that either favor or oppose filtration across the glomerular capillaries

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** These forces include:
i- Hydrostatic pressure inside the glomerular capillaries (PG)- promotes filtration
ii- Hydrostatic pressure in the Bowmans capsule outside the capillaries (PB)- this force
opposes filtration
iii- Colloid osmotic pressure (HG)- of the glomerular capillary plasma proteins that opposes
filtration
iv- Colloid osmotic pressure of the proteins in the Bowmans capsule (HB )- which promotes
filtration

Note: Under normal conditions, the concentration of protein in the glomerular filtrate is so low that
the colloid osmotic pressure of the Bowmans capsule fluid is considered to be zero
GFR = Kf x (Pg Pb- HG + HB

Net Filtration Pressure = Glomerular Hydrostatic Pressure Bow Capsule Pressure Glo Oncotic
Pressure

MBBS/DDS 2K16
Print Slide # 13
** In the average adult human, the GFR is about 125ml/min or 180L/day
- The fraction of the renal plasma flow that is filtered (filtration fraction) averages about 0.2
- Therefore about 20% of the plasma flowing through the kidneys is filtered through the
glomerular capillaries

Note: The filtration fraction is calculated as:
- Filtration fraction = GFR/ Renal plasma flow

** The Kf is a product of permeability of the glomerular capillaries and the surface area of the
glomerular capillaries
- Cannot be measured directly
- Estimated experimentally by dividing the rage of glomerular filtration by net filtration
pressure
- Kf = GFR/Net filtration pressure

Total GFR = 125 ml/min
Net filtration pressure = 10 mmHg
Therefore the normal Kf is about 12.5 ml/min/mmHg of filtration pressure
- The value of Kf for the glomerular capillaries is much higher than in the other tissues
- This high Kf contributes to the rapid rate of fluid filtration in glomerular capillaries

** Some diseases lower Kf by reducing the number of functional glomerular capillaries, thereby
reducing the surface area for filtration
- Also by increasing the thickness of the glomerular capillary membrane

Ex: Chronic uncontrolled hypertension or diabetes mellitus gradually reduce Kf by increasing the
thickness of the glomerular capillary membrane

Inulin- is a non-absorbable, non-metabolized, non-toxic substance
- Therefore the amount given is the amount excreted

Creatinine- is a metabolic end product that is produced in the urine
- Therefore the clearance of creatinine can be noted to determine the GFR

Note: GFR is 10% lower in females than in males

Increased Glomerular Capillary Osmotic Pressure Decreases GFR
** As the blood passes from the afferent arteriole through the glomerular capillaries to the
efferent arterioles the plasma protein concentration increase by 20%
- This is because 1/5 of the fluid in the capillaries filters into the BC
- This concentrates the glomerular plasma proteins that are not filtered
- Therefore the normal colloid osmotic pressure of plasma entering the glomerular capillaries
is increased by the time the blood reaches the efferent end of the capillaries

** Therefore the 2 factors that influence glomerular capillary colloid osmotic pressure are:
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1- Arterial plasma colloid osmotic pressure
2- Fraction of the plasma filtered by the glomerular capillaries (filtration fraction)

Note: Increasing the arterial plasma colloid osmotic pressure raises the glomerular capillary
osmotic pressure, and this in turn decreases GFR

** Increasing the filtration fraction also concentrates the plasma proteins and raises the
glomerular colloid osmotic pressure
- Filtration Fraction = GFR/RBF
- Therefore the fraction can be increased by either increasing GFR or by reducing renal
plasma flow

Increased Glomerular Capillary Hydrostatic Pressure Increases GFR
** Increases in glomerular hydrostatic pressure increase GFR and decreases reduce GFR
** Glomerular hydrostatic pressure is determined by 3 variables:
i- Arterial pressure- increased arterial pressure tends to increase glomerular hydrostatic
pressure and increase GFR. However this effect is buffered by autoregulatory
mechanisms
- Therefore this maintains a relatively constant glomerular pressure as blood pressure
fluctuates

ii- Afferent arteriolar resistance- Increased resistance reduces glomerular hydrostatic
pressure and decreases GFR
- Vasodilation of the afferent arterioles increases both glomerular hydrostatic pressure and
GFR
iii- Efferent arteriolar resistance- Constriction of the efferent arterioles increases the
resistance to outflow from the glomerular capillaries
- This raises the glomerular hydrostatic pressure and can increase GFR slightly
- BUT efferent arteriolar constriction also reduces renal blood flow.
- Therefore the filtration fraction and glomerular colloid osmotic pressure increase as
efferent arteriolar resistance increases
- As a result if efferent arteriole constriction is severe the net force for filtration decreases
causing a reduction in GFR

Note: Efferent arteriolar constriction has a biphasic effect on GFR
- At moderate levels of constriction there is a slight increase in GFR
- Severe constriction = decrease in GFR.
- This is because the plasma protein concentration increases along with an increase in colloid
osmotic pressure which opposes GFR

Summary: Factors that Decrease GFR
1- Decreased renal blood flow
2- Decreased capillary pressure
3- Increased colloid osmotic pressure- can be increased by increased protein in the diet.
Therefore kidney patients are recommended a low-protein diet
4- Increased Bowmans capsular pressure
5- Increased co-efficient of filtration
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Note: An increase or decrease of GFR by even 2% can cause excessive wash out or retention
- If the GFR decreases by 10-15% of normal the result is frank uremia

Renal Blood Flow and Solute Filtration
** The charges on the capillary pores are negative on the inside
- Therefore cations pass through easily but anions are prevented from passing
- As a result proteins are not normally filtered through because of their large size and
negative charge

EX: Albumin is smaller than the size of the capillary pores but does not pass through the pores of
the glomerulus because of its negative charge

** However if the negative charges are dissipated as a result of infection, inflammation or allergy,
then smaller proteins like albumin can pass through
- The result is albuminuria
- Nephritis- inflammation of the nephrons (glomerular capillaries)

** Blood flow to the kidneys supplies the organ with nutrients and removes waste products
- However the high flow exceeds need
- The additional flow supplies enough plasma for the high rates of glomerular filtration that
are needed for regulation of body fluid volume and solute concentrations

** Renal blood flow is determined by the pressure gradient across the renal vasculature divided
by the total renal vascular resistance

Renal artery pressure Renal vein pressure
Total renal vascular resistance

** Most of the renal vascular resistance is found in 3 segments:
- Interlobular arteries
- Afferent arterioles
- Efferent arterioles

** Resistance in these vessels is controlled by the sympathetic nervous system, various hormones
and local internal renal control mechanism

** Renal blood flow is directly proportional to the GFR

Autoregulation of GFR & Renal Blood Flow
** Feedback mechanisms intrinsic to the kidneys keep the RBF and GFR relatively constant despite
marked changes in arterial blood pressure
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- Autoregulation is the relative constancy of GFR and renal blood flow that is maintained by
the kidneys
- Kidney autoregulation is intrarenal
- Autoregulation occurs of the blood pressure is in the range of 75-160 mmHg
- Therefore the kidney can auto regulate via tubulo-glomerular feedback mechanisms
- The signal comes form the tubular system and the glomerulus acts accordingly

Note: This is a flow-sensitive mechanism not a pressure-sensitive mechanism

** The primary function of autoregulation in the kidneys is to maintain a relatively constant GFR
- To allow the precise control of renal excretion of water and solutes

Note: The function of autoregulation in tissues other than the kidneys is to maintain delivery of
oxygen and nutrients at a normal level
- To remove the waste products of metabolism despite changes in arterial pressure

** Therefore the autoregulatory mechanisms of the kidney prevent potentially large changes in GFR
and renal excretion of water and solutes that would otherwise occur with changes in BP

** Autoregulation is linked to a feedback mechanism that links changes in the sodium chloride
concentration at the macula densa with the control of renal arteriolar resistance
- This feedback helps to ensure a constant delivery of NaCl to the distal tubule

** The tubuloglomerular feedback mechanism has 2 components that act together to control GFR
1- Afferent arteriolar feedback mechanism
2- Efferent arteriolar feedback mechanism

** These feedback mechanism depends on the arrangement of the juxtaglomerular complex. This
complex consists of:
i- Macula densa cells- in the initial portion of the distal tubule, where the loop of Henle
exits the cortex and the distal tubule begins
- Specialized group of epithelial cells in the distal tubules that come into close contact with
the afferent + efferent arterioles
- Macula densa cells produce an unknown substance
- This substance causes vasodilation of afferent arterioles

ii- Juxtaglomerular cells- in the walls of the afferent and efferent arterioles
- Modified endothelial cells of afferent arterioles
- Produce rennin which is an enzyme that causes vasoconstriction indirectly
- Renin cleaves angiotensinogen to form angiotensin I
- Angiotensin I is converted to angiotensin II
- The result of angiotensin II is vasoconstriction of the efferent arteriole

** The macula densa cells sense changes in volume delivery to the distal tubule
- Decreased GFR slows the flow rate in the loop of Henle
- This causes increased reabsorption of sodium and chloride ions in the ascending loop of
Henle
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- This reduces the concentration of sodium chloride at the macula densa cells

Note: Slow movement may be a result of low blood pressure
- Therefore there is an increase in reabsorption especially of NaCl
- As a result the fluid going to the macula densa is more dilute
- The low sodium fluid is a signal to produce a substance that causes vasodilation of the
afferent arterioles

** The decrease in sodium chloride concentration initiates a signal from the macula densa that
causes:
1- Decreases resistance to blood flow in the afferent arterioles by causing vasodilation
- This raises glomerular hydrostatic pressure and helps return GFR to normal

2- Increases renin release from the juxtaglomerular cells at the afferent and efferent
arterioles
- Renin through the eventual formation of angiotensin II cause vasoconstriction of the
efferent arterioles
- This increases glomerular hydrostatic pressure and helps to return GFR to normal

** Therefore both mechanisms assist in maintaining GFR

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Myogenic Autoregulation of RBF and GFR
** Another mechanism that contributes to the maintenance of a relatively constant RBF and GFR is
the ability of individual blood vessels to resist stretching during increased arterial pressure
- This is known as the myogenic mechanism
- Stretch of the vascular wall allows increased movement of calcium ions from the
extracellular fluid into the cells causing them to contract
- This contraction prevents over distention of the vessel
- By raising vascular resistance it helps prevent excessive increases in RBF and GFR when
arterial pressure increases

Neural Regulation
- Sympathetic stimulation decreases RBF
- Ex: exercise, fight, fright, pain, stress

Hormonal Regulation
- Angiotensin, ADH, serotonin, aspirin

Blood Pressure Regulation via Kidney
- Angiotensin II increases vasoconstriction of all blood vessels including the afferent
arterioles
- GFR is maintained because in addition both efferent arterioles are constricted
- This keeps fluid in the glomerulus
- Therefore GFR and RBF are independent of each other

MBBS/DDS 2K16
Lecture 3: Tubular Reabsorption & Secretion: Formation of
Urine


** As the glomerular filtrate enters the renal tubules, it flows sequentially through the successive
parts of the tubule before it is excreted as urine:
- Proximal tubule
- Loop of Henle
- Distal tubule
- Collecting tubule
- Collecting duct

** Along this course some substances are selectively reabsorbed from the tubules back into the
blood
- Other substances are secreted from the blood into the tubular lumen
- Eventually the urine that is formed and all the substances in the urine represent the sum of
3 basic renal processes:
- Urinary excretion = Glomerular filtration Tubular reabsorption + Tubular secretion

Note: Secretion accounts for significant amounts of potassium ions, hydrogen ions and a few
other substances that appear in the urine

Note: Aspirin decreases renal blood flow
- Headaches are due to increased blood flow that are a result of vasodilation caused by
prostaglandins
- Therefore by decreasing prostaglandins there is headache relief

Tubular Reabsorption

** Tubular Reabsorption is the movement of materials from the tubules to peritubular blood
- 124ml out of 125 ml of filtered fluid is reabsorbed per minute
- Tubular reabsorption can be an active or a passive process
- Most substances are reabsorbed in the proximal tubule system
- Active reabsorption is limited by the transport maximum (Tm)

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** The rate at which each of these substances is filtered is calculated as:
- Filtration = GFR x Plasma concentration

** The calculation assumes that the substance is freely filtered and not bound to plasma proteins
- Ex: If plasma glucose concentration is 1g/L, the amount of glucose filtered each day is about
180L/day x 1g/L or 180g/day
- Because none of the filtered glucose is normally excreted, the rate of glucose reabsorption
is also 180g/day

** Glomerular filtration is relatively non-selective. Therefore essentially all solutes in the plasma
are filtered EXCEPT the plasma proteins or substances bound to them

** However, tubular reabsorption is highly selective
- Some substances such as glucose and amino acids are almost completely reabsorbed from
the tubules
- Therefore their urinary excretion rate is essentially zero

** Many of the ions in the plasma (sodium, chloride, bicarbonate) are also highly reabsorbed, but
their rates of reabsorption and urinary excretion are variable
- Therefore their rates of reabsorption depends on the needs of the body

** Certain waste products (urea, creatinine) are poorly reabsorbed from the tubules and excreted
in relatively large amounts

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** Therefore by controlling the rate at which they reabsorb different substances, the kidneys
regulate the excretion of solutes independently of one another
- This is essential for precise control of the composition of body fluids

Transport Maximum
** The transport maximum is the limit to the rate at which the solute can be transported
- This value applies to most substances that are actively reabsorbed or secreted
- This limit is due to saturation of the specific transport systems involved
- This occurs when the tubular load exceeds the capacity of the carrier proteins and specific
enzymes involved in the process
- Tubular load- is the amount of solute delivered to the tubule
- Filtered load- the amount of substance entering the glomerulus
- Saturation occurs when the load exceeds the transport maximum

EX: Glucose transport system in the proximal tubules
- Normally measurable glucose does not appear in the urine because all the filtered glucose
is reabsorbed in the proximal tubule
- However when the filtered load exceeds the capacity of the tubules to reabsorb glucose,
urinary excretion of glucose does occur

** In adult humans, the transport maximum for glucose is about 375mg/min
- The filtered load of glucose is only about 125 mg/min
- (GFR x plasma glucose = 125 ml/min x 1mg/ml)
- Therefore with large increases in GFR or increase in plasma glucose concentration that
increase the filtered load of glucose above 375mg/min, the excess glucose filtered is not
reabsorbed
- Instead it passes into the urine

** When the plasma concentration of glucose rises above 200mg/100 ml, the filtered load increase
to about 250 mg/min
- At this point a small amount of glucose begins to appear in the urine
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- Therefore this point is the threshold for glucose and this occurs before the transport
maximum is reached
- The overall transport maximum is about 375 mg/min and this is reached when all the
nephrons have reached their maximal capacity to reabsorb glucose

Note: Threshold is the point at which the plasma glucose levels exactly saturate the glucose load
- Therefore at 220 mg/min the system is exactly saturated and some glucose may at this
point spill over into the urine
- Due to the heterogeneous nature of the nephrons

Clinical Application: In uncontrolled diabetes mellitus, plasma glucose rises to high levels
- This causes the filtered load of glucose to exceed the transport maximum
- This results in urinary glucose excretion
- Therefore the transport maximum can be an important diagnostic tool to determine
tubular function

** Substances that are passively reabsorbed do not demonstrate a transport maximum. This is
because their rate of transport is determined by other factors:

i- Electrochemical gradient- for diffusion of the substance across the membrane
ii- Permeability- of the membrane for the substance
iii- Time- that the fluid contain the substance remains within the tubule

** This type of transport is known as gradient-time transport.
- This is because the rate of transport depends on the electrochemical gradient and the
time the substance is in the tubule
- This in turn depends on the tubular flow rate

EXAMPLE: Sodium Reabsorption in the proximal tubule
- Sodium transport in the proximal tubule does not exhibit a transport maximum
- Other factors limit the reabsorption rate of besides the maximum rate of active transport
- In the proximal tubules, the maximum transport capacity of the basolateral sodium-
potassium ATPase pump is greater than the actual rate of net sodium reabsorption
- A large amount of sodium transported out of the cell leaks back into the tubular lumen
through the epithelial tight junctions

** The rate at which this leakage occurs depends on several factors:
i- Permeability- of the tight junctions
ii- Interstitial physical forces- which determine the rate of bulk flow reabsorption from
the interstitial fluid into the peritubular capillaries

** Therefore sodium transport in the proximal tubules obeys mainly gradient-time transport
principles rather than tubular maximum transport characteristics
- The greater the concentration of sodium in the proximal tubules, the greater its
reabsorption rate
- Also the slower the flow rate of tubular fluid, the grater the percentage of sodium that can
be reabsorbed form the proximal tubules
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Note: In the more distal parts of the nephron, the epithelial cells have tighter junctions and
transport smaller amounts of sodium

Regulation of Tubular Reabsorption
** Na+ ion reabsorption is more regulated by a Tm value.
- The reabsorption is load dependent
- Therefore an increase in sodium ion load results in an increase in Na+ reabsorption

** Primary active transport moves solutes against an electrochemical gradient
- The energy for this active transport comes from the hydrolysis of ATP by the membrane-
bound ATPase
- The primary active transporter of sodium is: sodium potassium ATPase

** Sodium reabsorption across the proximal tubular membrane is via a primary active transport
system
- The Na-K ATPase system is found on the basolateral sides of the tubular epithelial cell
- The system hydrolyzes ATP and uses the released energy to transport sodium ions out of
the cell into the interstitium
- At the same time potassium is transported from the interstitium to the inside of the cell
- This maintains low intracellular sodium and high intracellular potassium concentrations
- Pumping the sodium out the cell across the basolateral membrane of the cell favors passive
diffusion of sodium across the luminal membrane of the cell from the tubular lumen into
the cell

Note: In the proximal tubule, there is an extensive brush border on the luminal side of the
membrane that multiples the surface area
- Also contains sodium carrier proteins that bind sodium ions on the luminal surface and
release them inside the cell
- This provides facilitated diffusion of sodium through the membrane into the cell

** Therefore the net reabsorption of sodium ions from the tubular lumen back into the blood
involves at least 3 steps:
1- Sodium diffuses across the luminal membrane into the cell down an electrochemical
gradient
- The electrochemical gradient was established by the Na-K+ ATPase pump on the basolateral
side of the membrane

2- Sodium is transported across the basolateral membrane against an electrochemical gradient
by the Na-K ATPase pump
3- Sodium, water and other substances are reabsorbed from the interstitial fluid into the
peritubular capillaries by ultrafiltration
- Ultrafiltration is a passive process derived by the hydrostatic and colloid osmotic pressure
gradients

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** When sodium is reabsorbed through the tubular epithelial cell, negative ions such as chloride
are transported along with the sodium because of electrical potentials
- Therefore transport of positively charged sodium ions out of the lumen leaves the inside of
the lumen negatively charged
- This causes chloride ions to diffuse passively through the paracellular pathway
- Reabsorption of chloride also occurs because of a chloride concentration gradient that
develops when water is reabsorbed from the tubule by osmosis
- This concentrates the chloride ions in the tubular lumen
- Therefore active reabsorption of sodium is coupled to the passive reabsorption of chloride
via an electrical potential and a chloride concentration gradient

** Urea is also passively reabsorbed form the tubule but to a lesser extent than chloride
- As water is reabsorbed from the tubules by osmosis coupled to sodium reabsorption, urea
concentration in the lumen increases
- This creates a concentration gradient that favors the reabsorption of urea
- BUT urea does not permeate the tubule as readily as water

** In some parts of the nephron (inner medullar collecting duct), passive urea reabsorption is
facilitated by specific urea transporters.
- However only a small amount of urea filtered by the glomerular capillaries is reabsorbed
from the tubules
- The rest of the urea passes into the urine
- This allows the kidneys to excrete large amounts of this waste product of metabolism
- Only 20% of urea is reabsorbed and 80% is excreted in the urine
- Urea reabsorption is directly proportional to water reabsorption

** Creatinine is a waste product of metabolism and is a larger molecule than urea
- Creatinine is virtually impermeable to the tubular membrane
- Therefore all the creatinine that is filtered by the glomerulus is excreted in the urine

Summary: Regulation of Tubular Reabsorption
** A feature of tubular reabsorption is that reabsorption of some solutes can be regulated
independently of others
Note: Hydrostatic and colloid osmotic forces govern the rate of reabsorption across the peritubular
capillaries

1- Peritubular Capillary Pressure- if the peritubular capillary pressure is higher then
sodium will not be reabsorbed and will stay in the lumen
- The peritubular capillary hydrostatic pressure is influenced by the arterial pressure and
resistances of the afferent + efferent arterioles
- Increases in arterial pressure increases PTCHP and therefore decreases reabsorption rate
- Increases in resistance of the afferent or efferent arterioles reduces PTCHP and tends to
favor reabsorption

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2- Peritubular Capillary Oncotic Pressure- At the peritubular capillaries, if the colloid
osmotic pressure increases it tends to pull sodium inside and facilitates
reabsorption

3- Tubular Flow rate- when tubular flow rate is high more substances are flowing
through the lumen. This factor is independent of time
- Therefore if there is increased glucose reabsorption there is also increased sodium reabsorption
because they are used to facilitate the others reabsorption

4- Anti-diuretic Hormone- increase water reabsorption by increasing the water
permeability of the distal tubule, collecting tubule and collecting duct
- This effects helps the body to conserve water
- In the absence of ADH, the permeability of the distal tubules and collecting ducts to water is
low
- The result is the production of a large amount of dilute urine

5- Sympathetic Stimulation- activation of the sympathetic system can decrease sodium
and water excretion by constricting renal arterioles
- This reduces GFR
- Sympathetic activation also increases sodium reabsorption in the proximal tubule, thick
ascending limb of Henle
- SNS stimulation also increases renin release and angiotensin II formation
- This adds to the overall effect to increase tubular reabsorption and decrease renal
excretion of sodium

6- Glomerulo-tubular balance- refers to the intrinsic ability of the tubules to increase
their reabsorption rate in response to increased tubular load
- Therefore the total rate of reabsorption increases as the filtered load increases
- Glomerulotubular balance helps to prevent overloading of the distal tubular segments
when GFR increases
- Therefore prevents large changes in fluid flow in the distal tubules when the arterial
pressure changes

Pinocytosis- is an active transport mechanism for the reabsorption of proteins
- Some parts of the tubule, especially the proximal tubule, reabsorb large molecules such as
proteins by pinocytosis
- The protein attaches to the brush border of the luminal membrane
- This part of the membrane invaginates to the interior of the cell and a vesicle is formed
that contains the protein
- Once inside the cell the protein is digested into amino acids
- These amino acids are reabsorbed through the basolateral membrane into the interstitial
fluid
- All proteins in the glomerular filtrate must be reabsorbed via pinocytosis

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Tubular Secretion
** Tubular secretion is the movement of materials from the peritubular blood to the tubular
lumen
- Weak acids and bases are secreted passively
- Most drugs are secreted passively (eg aspirin)

Ex: In cases of aspirin overdose because aspirin is an acidic drug and urine is also acidic (pH 6), to
remove the acidic drug through the urine one must make the urine as alkaline as possible
- Can give ammonium chloride orally to alkalinize the urine

** Strong acids and bases are secreted actively. An example of this is hydrogen ions

** Hydrogen ion secretion and bicarbonate reabsorption occurs in virtually all parts of the
tubules
- EXCEPT: the descending + ascending thin limbs of the loop of Henle
- For each bicarbonate reabsorbed, an H+ ion must be secreted
- 80-90% of the bicarbonate reabsorption and H+ secretion occurs in the proximal tubules

** Hydrogen ions are secreted into the tubular fluid by sodium-hydrogen counter transport
- The secondary active secretion of H+ is coupled with the transport of Na+ into the cell at
the luminal membrane by the sodium-hydrogen exchanger protein
- The energy for H+ secretion against a concentration gradient is derived from the sodium
gradient
- The gradient is established by the Na-K ATPase pump

MBBS/DDS 2K16
Lecture 4: Tubular Excretion I


** All substances are that are actively reabsorbed have an upper limit of reabsorption based on
their transport maximum value
- Therefore any substances above the transport maximum value are excreted

** The tubular fluid/plasma inulin concentration ratio can be used to measure water reabsorption
by the renal tubules
- Inulin is a polysaccharide used to measure GFR
- Inulin is not reabsorbed or secreted by the renal tubules
- Therefore changes in inulin concentration at different points along the renal tubule, reflect
changes in the amount of water present in the tubular fluid

Glomerulotubular Balance
** If there is a sudden change in the GFR due to internal causes, reabsorption at the proximal
tubule helps to compensate for these changes
- Therefore the fluid driven to the loop of Henle and the distal tubule can be processed
normally
- Increased fluid or Na+ intake leads to an increased blood pressure
- As a result of the rise in blood pressure, the GFR will also be increased beyond the
physiological capacity
- Therefore the mechanism of glomerulotubular balance will not work optimally because
excesses will now have to be excreted
- Therefore the glomerulotubular balance helps to regulate GFR in relation to endogenous
changes in the body rather than exogenous

** Therefore if the increased GFR is due to exogenous causes, the glomerulotubular balance will not
be optimal
- The result is glomerulotubular imbalance but this is dependent on the needs of the body at
the time

Tubular Excretion
** Tubular excretion is the appearance of some materials in the urine
- Filtration reabsorption + secretion

Plasma Clearance
** Plasma clearance is the ability of the kidneys to clean the plasma of various substances per
minute
- Unit for plasma clearance = mL/minute
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- Unit for substance clearance = mg/ min

** The rates at which different substances are cleared from the plasma provide a way of
quantitating the effectiveness with which the kidneys excrete various substances

** The renal clearance of a substance is the volume of plasma that is completely cleared of the
substance by the kidneys per unit time
** If the plasma passing through the kidneys contains 1 mg of a substance in each milliliter
- And 1 mg of the substance is also excreted into the urine each minute, then 1 ml/min of
the plasma is cleared of the substance
- Therefore clearance refers to the volume of plasma that would be necessary to supply the
amount of substance excreted in the urine per unit time

Formula:
Qty of Urine (ml/mt) X Conc of a substance in urine (mg/mt) / Conc in plasma (mg/ml)

Note: In a healthy subject the quantity of urine produced is 1 ml/minute

EXAMPLE: Plasma urea = 0.26 mg/ml
- Urea passes in urine = 18.2 mg/min
** Therefore plasma urea clearance will be 1ml/min x 18.2 mg/min/ 0.26 mg/ml
= 70 ml/min

Fluid Volume Excretion
** Alterations in filtration and reabsorption can alter the rate of fluid volume excretion
Factors:
1- Plasma colloid osmotic pressure- is a major determinant of peritubular capillary
reabsorption
- An increase in colloid osmotic pressure increases peritubular capillary reabsorption
- Determined by the systemic plasma colloid osmotic pressure
- Increasing the plasma protein concentration in the systemic blood raises the peritubular
capillary colloid osmotic pressure
- The filtration fraction also affects the PCOP. The higher the filtration fraction, the greater
the fraction filtered through the glomerulus
- Therefore the more concentration the protein becomes in the plasma that remains behind

2- Osmolar clearance- polyuria
- Increased excretion of osmotic substances leads to osmotic diuresis
- Osmolar substance are not reabsorbed if they are passing in excess
- Therefore due to the increase in the osmotic gradient within the tubular lumen, water is
also pulled in and excreted

3- Sympathetic Stimulation

4- Anti-diuretic Hormone- A lack of ADH leads to a decrease in water reabsorption at the
level of the distal tubule and the collecting ducts
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- Therefore there is an increase in fluid volume of the urine
- Seen in patients with diabetes insipidus

Note: If there is increased blood pressure, the GFR will also increase. This leads to an increased
urine output by as much as 7x to regulate the blood pressure and fluid volume
- This is known as pressure diuresis

Urine Concentration
Osmolarity is the total concentration of solutes in the extracellular fluid
- Determined by the amount of solute divided by the volume of the extracellular fluid

** The volume of body water is controlled by:
i- Fluid intake- which is regulated by factors that determine thirst
ii- Renal excretion of water- which is controlled by factors that influence glomerular
filtration + tubular reabsorption

** When there is excess water in the body and body fluid osmolarity is reduced, the kidney can
excrete urine with an osmolarity as low as 50mOsm/L
- The kidney can regulate water excretion independently of solute excretion

** The kidneys have the ability of form urine that is more concentrated than plasma
- Water loss from the body is occurring continually
- Fluid intake is required to match this loss
- BUT the ability of the kidneys to form a small volume of concentrated urine minimizes the
intake of fluid required to maintain homeostasis

** When there is a water deficit (dehydration), the kidney forms concentrated urine by continuing
to excrete solutes while increasing water reabsorption and decreasing the volume of urine formed

** The requirements for forming concentrated urine are:
1- ADH- high levels of ADH increase the permeability of the distal tubules + collecting ducts
to water
- This allows the tubular segments to reabsorb water
-
2- High osmolarity- of the renal medullary interstitial fluid- This provides the osmotic
gradient needed for water reabsorption to occur in the presence of ADH
- The renal medullar interstitium surrounding the collecting ducts is very hyperosmotic
- Therefore when ADH levels are high, water moves through the tubular membrane by
osmosis into the renal interstitium
- From the interstitium it is carried by the vasa recta back into the blood

Note: The process by which the renal medullary interstitial fluid becomes hyperosmotic involves
the countercurrent mechanism

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** The countercurrent mechanism depends on the arrangement of the loops of Henle and the vasa
recta
- The vasa recta are the specialized peritubular capillaries of the renal medulla
- The vasa recta acts as a counter current exchanger and maintains the high gradient in the
interstitium that was produced by the loop of Henle
- Therefore the counter-current multiplies occurs only in the loop pf Henle
- Functions to increase the concentration of the interstitial medullary fluid

** The osmolarity of the interstitial fluid of the medulla is much higher than osmolarity in other
parts of the body (1200-1400 mOsm/L)
- Therefore the renal medullary interstitium has accumulated solutes in excess of water

** The major factors that contribute to the build up of solute concentration into the renal medulla
are:
1- Active Transport/Co-transport- active transport of sodium ions and co-transport of
potassium, chloride and other ions out of the thick part of the ascending limb of Henle into
the medullary interstitium
- This pump is able to establish a 200milliosmole concentration gradient between the tubular
lumen and the interstitial fluid
- The thick ascending limb is virtually impermeable to water. Therefore solutes that are
pumped out are not followed by osmotic flow of water into the interstitium

2- Active Transport- of ions from the collecting ducts into the medullary interstitium
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3- Facilitated Diffusion- of large amounts of urea from the inner medullary collecting ducts
into the medullary interstitium

4- Diffusion- of small amounts of water from the medullary tubules into the medullary
interstitium
- Water diffusion is far less than the reabsorption of solutes into the medullary interstitium

Note: There is some passive reabsorption of NaCl from the thin ascending limb of Henle
- This limb is also impermeable to water
- This further promotes a high solute concentration in the renal medullary interstitium
- The thick ascending limb is only permeable to Na+ and urea
- It is the only place in the kidney where there is active transport of Na+, K+, Cl-, urea and
bicarbonate

Note: The descending limb of Henle is very permeable to water
- Therefore in this area the tubular fluid osmolarity quickly becomes equal to the renal
medullary osmolarity
- Therefore water diffused out of the descending limb into the interstitium and the tubular
fluid osmolarity gradually rises as it flows towards the tip of the loop of Henle

Descending Limb = Concentrating segment
Ascending Limb = Diluting segment

Hyperosmotic Renal Medullary Interstitium- Summary
** Initially the loop of Henle is filled with fluid that has the same concentration as the fluid leaving
the proximal tubule

** The active pump of the thick ascending limb, reduces the concentration of the fluid inside the
tubule and increases the interstitial concentration

** The tubular fluid in the descending limb and the interstitial fluid quickly reach osmotic
equilibrium because of osmosis of water out of the descending limb
- However the interstitial osmolarity is maintained because of the continued transport of
ions out of the thick ascending limb

** There is additional flow of fluid into the loop from the proximal tubule. This causes the
hyperosmotic fluid previously formed in the descending limb to flow into the ascending limb
- Additional ions are pumped into the interstitium with water remaining behind
- Once again the fluid in the descending limb reaches equilibrium with the hyperosmotic
medullary interstitial fluid
- As the hyperosmotic tubular fluid form the descending limb flows into the ascending limb,
more solute is continuously pumped out of the tubules and deposited into the medullary
interstitium

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** These steps are repeated with the net effect of more and more solute being added to the medulla
in excess of eater
- This process gradually traps solutes in the medulla and multiples the concentration
gradient established by the active pumping of ions out of the thick ascending loop of Henle

** The countercurrent multiplies is the repetitive reabsorption of NaCl by the thick ascending
limb and continued inflow of new NaCl from the proximal tubule into the loop of Henle

Note: The function of the loop of Henle is to create a high osmotic gradient in the interstitium

Role of Urea
** Urea also contributes about 40-50% of the osmolarity of the renal medullary interstitium when
the kidney is forming maximally concentrated urine
- Unlike NaCl, urea is passively reabsorbed from the tubule

** When there is water deficit (dehydration) and blood concentrations of ADH are high, large
amounts of urea are passively reabsorbed from the inner medullary collecting ducts into the
interstitium

** As water flows up the ascending loop of Henle and into the distal and cortical collecting tubules,
very little urea is reabsorbed because these segments are impermeable to urea
- In the presence of ADH, water is reabsorbed rapidly from the cortical collecting tubules
- Therefore the urea concentration increases rapidly because it is left behind in the tubules
- As the tubular fluid flows into the inner medullary collecting ducts, more water
reabsorption occurs
- This cause an even higher concentration of urea in the tubular fluid

** The high concentration of urea in the tubular fluid of the inner medullary-collecting duct causes
urea to diffuse out of the tubule into the renal interstitium
- This diffusion is facilitated by specific urea transporters
- UT-AI is a urea transporter that is activated by the presence of ADH
- Therefore the transport of urea out if the inner medullary duct is increased when ADH
levels are elevated

** Some of the urea that diffuses into the medullary interstitium eventually diffuses into the thin
loop of Henle
- Therefore it passes upward through the ascending loop of Henle, distal tubule, cortical
collecting tubule and back down into the medullary collecting duct again
- In this way urea can recirculate through these terminal parts of the tubular system
several times before it is excreted
- Each time around the circuit contributes to a higher concentration of urea

Function of the Vasa Recta
** There are 2 features of the renal medullary blood flow that contribute to the presentation of
the high solute concentration:
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1- Low medullary blood flow- medullary blood flow is <5% of total renal blood flow
- This slow blood flow is enough to supply the metabolic needs of the tissues
- Also helps to minimize solute loss from the medullary interstitium

2- Vasa Recta- the vasa recta act as countercurrent exchangers. This minimizes the washout of
solutes from the medullary interstitium
- The function of the vasa recta is to maintain the high osmotic gradient created by the loop
of Henle within the medullary interstitium

** Blood enters and leaves the medullary via the vasa recta. The vasa recta is found at the
boundary of the cortex and medulla
- The vasa recta is highly permeable to solutes except plasma proteins
- Therefore as the blood descends into the medulla it becomes progressively more
concentrated
- This is due to solute entry from the interstitium and loss of water into the interstitium
- In the vasa recta there is little net dilution of the concentration of the interstitial fluid at
each level of the renal medulla because of the U-shape of the vasa recta capillaries
- The shape minimizes the loss of solute from the interstitium

** In dehydration or loss of fluid volume there is a need to excrete a minimum of water but also
maintain the excretion of waste products

**In cases of over hydration or where ADH is decreased or absent, the kidney must remove the
large amounts of water
- But still retain the ability to keep salt
- Therefore aldosterone is produced

Note: The distal nephron is impermeable to water unless ADH is secreted
- Also at the tip of the collecting duct no urine is formed
- Before this point it is known as tubular fluid

MBBS/DDS 2K16
Lecture 5: Regulation of Kidney Function I


** The thick ascending limb of the loop of Henle is the diluting part, because salt is lost here
- Anything that affects the loop of Henle will change the concentration of the interstitium
- Ex: number of nephrons, length, diuretics, blood flow in vasa recta

** Aldosterone increases sodium reabsorption and increases potassium excretion
- Aldosterone is secreted by the zona glomerulosa cells of the adrenal cortex
- The primary site of aldosterone action is on the principal cells of the cortical collecting
tubules
- Aldosterone stimulates the Na-K+ ATPase pump on the basolateral side of the cortical
collecting tubule
- Aldosterone increases the sodium permeability of the luminal side of the membrane
- The potassium concentration is the main signal for the release of aldosterone
- There increased aldosterone, increases potassium excretion

** Angiotensin II formation increases in circumstances associated with low blood pressure and low
extracellular fluid volume
- The increased formation of angiotensin II helps to return blood pressure and extracellular
fluid volume to normal by increasing sodium + water reabsorption from the renal
tubules through 3 main effects:

i- Angiotensin II stimulates aldosterone secretion- which in turn increases sodium
reabsorption
ii- Angiotensin II constricts the efferent arterioles- Efferent arteriolar constriction reduces
peritubular capillary hydrostatic pressure and this increases net tubular
reabsorption
- Efferent constriction reduces renal blood flow and raises the filtration fraction in the
glomerulus
- This increase the concentration of proteins in the peritubular capillaries
- Therefore the reabsoprtive force at the peritubular capillaries is increased and there is
increased tubular reabsorption of sodium and water

iii- Angiotensin II directly stimulates sodium reabsorption- in the proximal tubules, loops of
Henle, distal tubules and the collecting tubules
- Stimulates the Na-K ATPase pump on the tubular epithelial cell membrane
- Stimulates sodium-hydrogen exchange in the luminal membrane

** Therefore the multiple actions of angiotensin II cause marked sodium retention by the kidneys
when levels are increased

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** Atrial Natriuretic Peptide is a hormone that decreases sodium and water reabsorption
- Released by cells of the cardiac atria when they are distended because of plasma volume
expansion
- Increased levels of the peptide inhibit the reabsorption of sodium and water by the renal
tubules, especially in the collecting ducts
- The decreased sodium and water reabsorption increases urinary excretion
- This helps to return blood volume back toward normal

** Parathyroid hormone increases calcium reabsorption
- In the kidneys it increases tubular reabsorption of calcium
- Especially in the distal tubules and the loops of Henle
- The hormone inhibits phosphate reabsorption at the proximal tubules
- Stimulates magnesium reabsorption b y the loop of Henle

Osmoreceptor-ADH Feedback System
** The kidney responds to a low sodium diet by decreasing ECF and responds to a high sodium diet
by increasing ECF

** When plasma sodium concentration (osmolarity) increases above normal due to water deficit
there is a feedback system at work

** An increase in extracellular fluid osmolarity cause the osmoreceptor cells in the anterior
hypothalamus near the supraoptic nuclei to shrink

** Shrinkage of the osmoreceptor cells causes them to fire and stimulate the supraoptic nuclei
which then relays signals down the pituitary stalk to the posterior pituitary

** This stimulates the release of ADH, which is stored in the nerve endings. ADH enters the blood
stream and is transported to the kidneys
- Increases the water permeability of the late distal tubules, cortical collecting tubules and
medullary collecting ducts
- The increased water permeability in the distal nephron segments causes increased water
reabsorption and excretion of a small volume of concentrated urine

** Therefore water is conserved in the body while sodium and other solutes continue to be
excreted in the urine.
- This causes dilution of the solutes in the extracellular fluid

Note: The opposite happens when the extracellular fluid becomes too dilute

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MBBS/DDS 2K16
Lecture 6: Regulation of Kidney Function II


Renal Control of Acid-Base Balance
** The kidneys control acid-base balance by excreting acidic or basic urine

** Large numbers of HCO3- ions are filtered continuously into the tubules and if they are excreted
into the urine this removes the base from the blood

** Large numbers of hydrogen ions (H+) are also secreted into the tubular lumen by the tubular
epithelial cells
- This removes acid from the blood

Note: IF more H+ is secreted than HCO3- is filtered there will be a net loss of acid from the
extracellular fluid
- If more HCO3 is filtered than H+ is secreted, there will be a net loss of base from the
extracellular fluid

** Both the reabsorption of bicarbonate and excretion of H+ are accomplished through the
process of H+ secretion by the tubules
- This is because the HCO3 must react with a secreted H+ to form H2CO3 before it can be
reabsorbed
- Therefore 4320 milieq of H+ must be secreted daily to reabsorb the filtered bicarbonate
- In addition more H+ needs to be secreted to rid the body of the non-volatile acids produced
each day

** When there is a reduction in the extracellular fluid concentration (alkalosis), the kidneys fail to
reabsorb all the filtered bicarbonate
- Therefore this increases the excretion of bicarbonate

** In acidosis, the kidneys do not excrete bicarbonate into the urine, but reabsorb all the filtered
bicarbonate and produce new bicarbonate
- This is added back to the extracellular fluid
- This reduces the extracellular fluid H+ concentration back toward normal

Hydrogen Ion Secretion + Bicarbonate Reabsorption
** Hydrogen ion secretion and bicarbonate reabsorption occur in virtually all parts of the tubules
- EXCEPT: descending + ascending thin limbs of the loop of Henle
- For each bicarbonate reabsorbed an H+ ion must be secreted

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** 80-90% of the bicarbonate reabsorption (H+ secretion) occurs in the proximal tubule
- Therefore only a small amount of bicarbonate flows into the distal tubules and collecting
ducts
- In the thick ascending loop of Henle another 10% of the filtered bicarbonate is reabsorbed
- The remainder of the reabsorption takes place in the distal tubule and collecting duct

** The epithelial cells of the proximal tubule, thick segment of the ascending limb, early distal
tubule all secrete H+ ions into the tubular fluid by the Na-H+ counter transport
- This secondary active secretion of H+ is coupled with the transport of Na+ into the cell at
the luminal membrane
- This occurs via the Na-H+ exchanger protein
- The energy for H+ secretion against a concentration gradient is derived from the sodium
gradient that favors Na+ movement into the cell

Fig 30-5 pg. 391

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** The process of H+ secretion begins when CO2 diffuses into the tubular cells or is formed by the
metabolism in the tubular epithelial cells
- Under the influence of carbonic anhydrase CO2 combines with water to form H2CO3
- H2CO2 dissociates into HCO3 and H+ ions
- The H+ ions are secreted from the cell into the tubular lumen by the Na-H+ counter
transport
- Therefore when a Na+ moves from the lumen of the tubule to the interior of the cell, it first
combines with a carrier protein in the luminal border of the cell membrane.
- Simultaneously a H+ ion in the interior of the cell also combines with the carrier protein
- The HCO3 moves across the basolateral membrane into the renal interstitial fluid and the
peritubular capillary blood
- Net Result: For every H+ secreted into the tubular lumen, an HCO3 enters the blood

** Bicarbonate ions do not readily permeate the luminal membranes of the renal tubular cells
- Therefore HCO3 that is filtered by the glomerulus cannot be directly reabsorbed
- The reabsorption of HCO3 is initiated by a reaction in the tubules between HCO3 filtered at
the glomerulus and H+ secreted by the tubular cells

** In acidosis there is excess H+ relative to HCO3-. This causes complete reabsorption of the
bicarbonate and the excess H+ passes into the urine
- The excess H+ ions is buffered in the tubules by phosphate and ammonia and eventually
excreted as salts

** Beginning in the late distal tubules and continuing through the rest of the tubular system, the
tubular epithelium secretes H+ by primary active transport

Fig 30-6 pg 392

** Primary active secretion of H+ ions occurs at the luminal membrane of the tubular cell
- At this point H_ is transported directly by a hydrogen-transporting ATPase

** Primary active secretion of H+ occurs in the intercalated cells of the late distal tubule and in the
collecting tubules. Hydrogen ion secretion in these cells is accomplished in two steps:

1- Dissolved CO2 combines with water to form H2CO3
2- H2CO3 dissociates into HCO3- which is reabsorbed into the blood, plus H+ which is
secreted into the tubule by means of the hydrogen-ATPase mechanism
- For each H+ secreted, an HCO3- is reabsorbed, similar to the process in the proximal
tubules
- DIFFERNCE- H+ moves across the luminal membrane by an active H+ pump instead of by
counter-transport

Note: The secretion of H+ in the late distal tubule and collecting tubules accounts for only about
5% of the total H+ secreted
- However this mechanism is important in forming a maximally acidic urine

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Buffer Systems
** The excretion of large amounts of H+ in the urine is accomplished mainly by combining H+ with
buffers in the tubular fluid
- The most important buffers are phosphate buffer and ammonia buffer
- Other weak buffer systems include: urate + citrate

** When there are excess H+ ions in the urine they combine with buffers other than HCO3
- This results in the generation of new HCO3 that can also enter the blood
- Therefore when there is excess H+ in the extracellular fluid, the kidneys reabsorb all the
filtered HCO3 and also generates new HCO3
- This helps to replenish the HCO3 lost from the extracellular fluid in acidosis

** The phosphate buffer system is composed of HPO4 and H2PO4
- Both become concentrated in the tubular fluid because their relatively poor reabsorption
and because of reabsorption of water from the tubular fluid
- Phosphate is an important tubular buffer because the pK of the system is bout 6.8
- Normally urine is acidic and the urine pH is near to the pK of the phosphate buffer system
- Therefore in the tubules the phosphate buffer system normally functions near its most
effective range of pH

** The ammonia buffer system is made up of ammonia (NH3) and the ammonium ion (NH4+)
- Ammonium ion is synthesized from glutamine
- The glutamine delivered to the kidneys is transported into the epithelial cells of the
proximal tubules, thick ascending limb of loop of Henle, and distal tubules
- The NH4+ is secreted into the tubular lumen by a counter-transport mechanism in
exchange for sodium

** In collecting tubules the addition of NH4+ to the tubular fluids occurs via a different mechanism
- H+ is secreted by the tubular membrane into the lumen
- Combines with NH3 to form NH4+ which is then excreted\
- The collecting ducts are permeable to NH3 but not to NH4+
- Therefore once the H+ ion combines, the NH4+ is trapped in the lumen and eliminated in
the urine

Note: Chronic acidosis increases NH4+ excretion
- An increase in extracellular H+ concentration stimulates renal glutamine metabolism
- Therefore increases the formation of NH4+ and new HCO3 to be used in H+ buffering
- With chronic acidosis the dominant mechanism by which acid is eliminated is excretion of
NH4+

MBBS/DDS 2K16
Lecture 7: Renal Endocrine Function & Neonatal Kidney


Regulation of Renal Tubular Hydrogen Ion Secretion
** H+ secretion by the tubular epithelium is necessary for HCO3- reabsorption and generation of
new HCO3-

** Normally the kidney tubules secrete enough H+ to reabsorb almost all the HCO3 that is filtered
- There also muct be enough H+ left over to be excrted to rid the body of the non-volatile
acids produced each day from metabolism

** In alkalosis, tubular secretion of H+ must be reduced to a level that is too low to achieve
complete HCO3 reabsorption
- This enables the kidneys to increase HCO3- excretion
- Therefore in this condition, titratable acid and ammonia are not excreted because there is
no excess H+ available to combine with nonbicarbonate buffers

** In acidosis the tubular H+ secretion must be increased sufficiently to reabsorb all the filtered
HCO3 and still have enough H+ left over to excrete large amounts of NH4+

** The most important stimuli for increasing H+ secretion by tubules in acidosis are:
1- An increase in PCo2 of the extracellular fluid
2- An increase in H+ concentration of the extracellular fluid (decreased pH)

** The tubular cells respond directly to an increase in the partial pressure of carbon dioxide in the
blood, with an increase in the rate of H+ secretion
- The increase in PCO2 causes increased formation of H+ in the tubular cells
- This in turn stimulates secretion of H+

** The tubular cells respond to a decrease in H+ concentration (alkalosis) by reducing H+ secretion

Erythropoiesis
** Renal erythropietic factor (erythropoietin) is a glycoprotein hormone synthesized in epithelial
cells of glomeruli and in the juxtaglomerular cells
- The liver is the primary source in fetuses and neonates
- Acts as a primary regulatory of red blood cell formation in the bone marrow
- Often produced in response to arterial hypoxia

MBBS/DDS 2K16
Lecture 8: Sex Differentiation: Genetic Basis & Methods of
Determining Gender

Lecturer: Dr. Mills

** The human body has:
- 44 autosomal chromosomes
- 2 sex chromosomes( XY or XX)

Karyotype- is the characteristic chromosome complement of a eukaryote species. The normal
human karyotype contains 22 pairs of autosomal chromosomes and 1 pair of sex chromosomes
- Female Karyotype: 46XX
- Male Karyotype: 46 XY

** Examples of abnormal karyotypes are: 45X, 47XXY, 47XXX

Mitosis
** The mitotic cell division creates a diploid number (46) of chromosomes

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Meiosis
** The meiotic cell division creates a haploid number (23) of chromosomes

First Meiotic Division- creates a haploid number. Therefore reduction to the number of
chromosomes
Second Meiotic Division- leads to the creation of 4 daughter cells

Non-disjunction- the failure of the chromosomes to separate
- The result is an uneven distribution of chromosomes to daughter cells
- Leads to disorders of sex differentiation

Lyonisation
** Lyonisation is the inactivation of the X chromosomes that are in excess of one
- The chromosomes that are left active are random paternal or maternal
- Therefore in an XX individual, one X chromosome is inactivated
- In an XXX individual, 2 X chromosomes would be inactivated
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Sex Chromatin- is any sex chromosomes that has been inactivated and appears as a Barr body or
as a drumstick

Barr Body- is an inactive X chromosome
- In epithelial cells there is a condensation near the nuclear membrane
- Can be found in buccal smear, skin sample, amniocentesis

Drumstick- Nuclear appendages in 1-15% of polymorphnuclear leukocytes in females

Sex Differentiation
- The Y chromosome contains a gene on the short arm (SRY gene)
- This gene produces the protein testis-determining factor
- TDF develops the medulla of the indifferent gonad into a testis
- Therefore the cortex of the indifferent gonad regresses
- HCG causes secretion of testosterone from Leydig cells
- The testosterone develops the male internal genitalia from the Wolffian duct

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** MIS produced by the Sertoli cells causes the regression of the Mullerian duct

Indifferent gonad- medulla- Testis

** In the absence of TDF (no Y chromosome) no message is given to the indifferent gonad
- Therefore the medulla regresses and the cortex develops into an ovary
- As a result the Y-chromosome is the determining factor in the direction of sex
differentiation to male or female

Note: If the Y-chromosome is present but no TDF is formed the individual is XY with an ovary

** During fetal development, the testes are stimulated by HCG from the placenta to produce
testosterone
- This is responsible for the development of male body characteristics
- Formation of penis, scrotum, prostate gland, seminal vesicles and male genital ducts
- The testosterone also suppresses the formation of female genital organs

** The Wolffian ducts differentiate into the internal genitalia
- Epididiymis, vas deferens, seminal vesicles

** Mullerian inhibiting substance (MIS) is produced by Sertoli cells and causes regression of the
Mullerian duct in the male

** The effect of testosterone and MIS are seen on the same side of the body, due to the high
concentration of these hormones required to be effective
- This is achieved by diffusion rather than by systemic transport of these hormones to the
testis
**Mllerian ducts (or paramesonephric ducts) are paired ducts of the embryo that run down the
lateral sides of the urogenital ridge and terminate at the Mllerian eminence in the primitive
urogenital sinus. In the female, they will develop to form the Fallopian tubes, uterus, cervix, and the
upper two-thirds of the vagina;
[1]
in the male, they are lost.

MBBS/DDS 2K16
** The testes provide a high local concentration of testosterone for unilateral duct
differentiation
- Therefore systemic administration of androgens to the embryo does not cause regression
of the mullerian structures
- This is because systemic administrion will not achieve high enough concentrations on each
side to produce the effects of testosterone that has been locally released

EX: If before 6 weeks of gestation the ovaries/testis are removed (early stage of development) there
will be a development of a female structure
- This is because there is no MIS or testosterone to influence development to male
- However this also shows that female development is not contingent on the presence of an
ovary
- Therefore development of the uterus and tubes occurs if no gonad is present. In the
absence of influencing factors, the fetus preferentially becomes female

EX: In early unilateral castration, therefore before 6 weeks the testis on one side is removed
- Normal Side= development of normal internal male genitalia
- Absent Side = the influence of MIS and testosterone is removed; therefore a rudimentary
Wolffian duct and Mullerian duct will be present.
- This occurs because a high local concentration of testosterone is needed to achieve the
effect of Mullerian regression and Wolffian transformation
- Therefore even though the testes on the opposite side is producing MIS and testosterone, it
is not high enough concentration to influence the developmental needs on the absent side
- Development requires unilateral, local influences on each side

Ex: In a male, late castrate (after 6 weeks)- initially the Wolffian ducts were developing into male
genitalia
- However once the local influence is disturbed the Wolffian duct remains hypoplastic and
the Mullerian duct begins to develop

Note: A systemic increase in androgens does not facilaite the development of internal genitalia to
their maximum
- However it will have an effect on the external genitalia

** XY patients with tissue unresponsiveness to androgens demonstrate sexual disorders
- The epididymis and vasa differentia in these patients are hypoplastic or rudimentary

MBBS/DDS 2K16
External Genitalia
- 5-alpha reductase changes testosterone to dihydrotestosterone
- The dihydrotestosterone develops the external genitalia in males

MBBS/DDS 2K16
Lecture 9: Sex Differentiation: Phenotype & Genotype

Lecturer: Dr. Mills

MBBS/DDS 2K16

** IMPACT OF MEIOTIC NON-DISJUNCTION OF THE OVUM BEFORE FERTILISATION WITH THE
SPERM

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Klinefelters Syndrome
- Testosterone secretion at puberty is often great enough for the development of male
characteristics However seminiferous tubules are abnormal
- Mental Retardation

YY Syndrome
- Associated with the presence of more than one Y chromosome in the single cell
- Ex: 47 XYY, 48 XYYY
- Excessive tallness
- Aggressiveness
- Anti-social behavior
- Criminal tendencies
- With or Without mental subnormality

Triple X Syndrome
- Form of chromosomal variation characterized by the presence of an extra X-chromosome
in each cell of a human female
- Occurs as a result of non-disjunction
- However due to lyonisation only one of the X chromosomes will be active
- Maybe common but no definite characteristics

Mosaic
** Mosaicism is the presence of two populations of cells with different genotypes in one
individual who has developed from a single fertilized egg
- More than one karyotype in the same individual
- Caused by non-disjunction during mitosis or meiosis
MBBS/DDS 2K16

Ex: Milder form of Klinefelters (46/47 XY/XXY mosaic)-
- Therefore some of the cells have an extra chromosomes and other cells are normal

MBBS/DDS 2K16
Lecture 10: Disorders of Sexual Differentiation

Lecturer: Dr. Mills

True Hermaphrodite- has both gonads, male and female in the same individual
- Ovo-testes- gonads that have both testicular and ovarian parts
- There is ambiguity in the external genitalia

Pseudo Hermaphrodite- has only one type of gonad
- But has a mixture of both types of internal and external genitalia

** Some causes of hermaphroditism include:
- Mitotic mosaicism
- Androgen resistance

True Hermaphroditism
- Lateral- A testis on one side and an ovary on the other 20%
- Bilateral- both testicular and ovarian tissues bilaterally- ovotestis- 30%
- Unilateral- testicular and ovarian tissues on one side and a testis or an ovary on the other
side

** These individuals demonstrate intersexuality because they have an unknown phenotypic
association
- External genitalia may appear male, female or ambiguous
- Most patients are reared as males because of the size of the phallus
- Hypospadia- an opening of the urethra that is not at the tip of the phallus, the opening is
below the phallus
- Inguinal hernias may also be present

** The gonad determines the duct development on the side that it is related to
- Therefore if a testis is present on the right, it wil influence the development of the Wolffian
duct
- However the presence of an ovo-testis tends to influence the development of female
internal apparatus
- This is because an ovotestis tends to secrete more estradiol

** Breast development is almost more common in the true hermaphrodite during puberty
- Ovotestis tends to secrete more estradiol than testosterone
- More than half tend to have menses
- Childbirth can occur in 46XX karyotype patients

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** Mosaicism is one of the means of forming a hermaphrodite
- Another way to form a hermaphrodite is by dispermy
- Dispermy- is the entrance of 2 sperm to fertilize one egg. This creates a zygote with an XXY
karyotype
- Other possible combinations by dispermy are: XXY, XYY
- Mitotic Y non-disjuncion at metaphase- results an XX gamete
- Mitoic X non-disjunction at metaphase results in an XY gamete

Weak Y Chromosome Drive
- Streak gonads (gonadal dysgenesis)
- Gonadal aplasia
- Gonadal hypoplasia
- When the Y chromosome is absent an ovary is formed, however this ovary is only
functional when XX is present
- If XO is present, there is formation of a streak ovary rather than a normal ovary

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Note: Therefore 2 X chromosomes are necessary to form a normal ovary

Note: Two Xs are necessary to form a normal ovary therefore an XO individual will have streak
ovaries

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Female Pseudohermaphrodite
** Has only one type of gonad but has ambiguous/abnormal genitalia either internal or external
- Therefore the genitalia does not correspond to the gonad that is present
- Adrenogenital disorder is an example of pseudohermaphroditism

Print Slide #66-67- separate pages

** 21-alpha hydroxylase is required for the conversion of progesterone to cortisol
- Therefore there are decreased levels of cortisol but increased levels of ACTH
- This results in an increase in the formation of sex hormones
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- The result is masculinization, female pseudohermaphroditism due to the early production of
excess androgens which now influence the development of the genitalia

Female pseudohermaphrodite = ovary + male external genitalia
- Formation of a hypospadia develops because before 12 weeks the urethra has already fused
with the vagina

Male Pseudohermaphrodite
Male Pseudohermaphrodite- caused by the androgen insensitivity syndrome
- The tissues may be insensitive and unresponsive to the androgen, therefore the problem
is a defect at the andgrogen receptor
- Or the problem may be with the enzyme. Therefore a deficiency in 5-alpha reductase
- Therefore the testosterone is present but cannot be converted to its active form
(dihydrotesttosterone)
- Therefore the inidivial has internal testes but feminized external genitalia. The testes are
present and secrete testosterone, but the target cells lack receptors for the hormone
- The external genitalia and secondary sex characteristics are feminine but there are no
ovaries, uterus or vagina
- The individual has a blind vagina that is only 2/3rds of the normal size

5-alpha Reductase Deficiency
** At the time of puberty- the body changes and now the external genitalia responds to testosterone
directly
- Therefore the individual before puberty looks female but after puberty there is virilization
- Penis begins to grow (Penis @ 12)- changed gender identities

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Testicuar Feminization
- Same as androgen insensitivity syndrome
- Inherited X-linked recessive or dominant
- Genotype: XY
- Phenotype: Female
- Primary Amenorrhea
- Testosterone level normal or higher
- Lack of androgen receptors, defect in receptor function or post-receptor defects
- At puberty large breasts, but scant or absent pubic and axillary hair

Levels of Sexual Development
Nursery Sex- labeling by external genitalia and this becomes the legal sex because it has been
registered
BUT the genital sex does not necessarily determine the true sex of the individual

Hormonal sex- at the time of puberty

Print Slide #83

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MBBS/DDS 2K16
Lecture 11: Puberty: Hormonal Basis

Lecturer: Dr. Mills

LHRH- Luteinizing hormone releasing hormone
GnRH- Gonadotrophin releasing hormone
GnRH = LHRH

LH- Luteinizing hormone
FSH- Follicle stimulating hormone

** Control of the sexual functions in males and females begins with secretion of gonadotrophin-
releasing hormone by the hypothalamus
- GnRH stimulates the anterior pituitary gland to secrete two other hormones
- Luteinizing hormone (LH)
- Follicle stimulating hormone (FSH)
- In turn LH is the primary stimulus for the secretion of testosterone by the testes
- FSH mainly stimulates spermatogenesis

**GnRH is released in a pulsatile fashion every 1-3 hours.
- LH secretion is also cyclical with LH following the pulsatile release of GnRH
- FSH secretion increases and decreases only slightly with each fluctuation of GnRH secretion

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Male Axis

Mother/Fetus:
- Gonad differentiation by TDF
- HCG stimulates testosterone production from the interstitial cells of Leydig

Prepubertal:
- Absent FSH/LH
- The Leydig cells regress
- No spermatogenesis although germ cells are present
- Therefore in the prepubertal male testosterone levels are negligible

** Mature Leydig cells are normally found in the childs testes for a few weeks after birth but then
disappears until after the age of about 10 years

Pubertal/Adult
- Hypothalamus activated FSH/LH production
- Leads to release of testosterone and spermatogenesis

Aging
- Spermatogenesis are less efficient
- No cessation of reproductive functions

** The testosterone secreted by the testes in response to LH has the reciprocal effect of
inhibiting anterior pituitary secretion of LH
- This is due to the direct effect of testosterone on the hypothalamus to decrease secretion of
GnRH
- This causes a corresponding decrease in secretion of both LH and FSH by the anterior
pituitary
- This decrease in LH reduces the secretion of testosterone by the testes

** Therefore low levels of testosterone allows the hypothalamus to secrete large amounts of GnRH
with a corresponding increase in anterior pituitary LH and FSH secretion
- This leads to an increase in testicular testosterone secretion

** FSH binds to FSH receptors attached to the Sertoli cells in the seminiferous tubules
- This causes the Sertoli cells to grow and secrete spermatogenic substances
- At the same time testosterone diffuses into the seminiferous tubules from the Leydig cells
and has a strong tropic effect on spermatogenesis

** FSH is controlled in relation to the hormone inhibin, which is produced by the testes
- When spermatogenesis occurs too rapidly, pituitary secretion of FSH decreases
- The cause of this negative feedback is secretion of inhibin from the Sertoli cells

** The initiation of the onset of puberty is not completely elucidated.
- During childhood the hypothalamus does not secrete significant amounts of GnRH
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- This is because during childhood the secretion of any sex steroid hormone exerts a strong
inhibitory effect on hypothalamic secretion of GnRH
- At puberty the section of hypothalamic GnRH breaks the childhood inhibition

Female Axis
Mother/Fetus
- The full complement of ova are present by the 20
th
week
- Hormonal activity is limited
- Therefore the ova are present but the there is no/limited hormonal activity

Prepubertal
- Absent FSH/LH

Pubertal
- Hypothalamus activated FSH/LH results in the production of estrogen
- Estrogen influences the development of secondary sex characteristics
- Arrival at anovulatory menarche

Adult:
- FSH/LH influences the release of estrogen + progesterone

Postmenopausal
- FSH and LH levels increase
- However there is no response from the ova

** The female hormonal system consists of 3 hierarchies of hormones:
1- GnRH- hypothalamic releasing hormone
2- Anterior pituitary sex hormones- FSH and LH are secreted in response to GnRH from the
hypothalamus
3- Ovarian hormones- estrogen + progesterone, which are secreted by the ovaries in response
to LH and FSH
- LH = production of progesterone
- FSH = production of estrogen

** These hormones are not secreted in constant amounts throughout the female monthly sexual
cycle
- Secreted at different rates during various parts of the cycle

Theories of Puberty
1- Gonadostat- Before puberty the hypothalamus is sensitive therefore minimal amounts of
estrogen/testosterone are sensed by the hypothalamus
- But at puberty (9-12 years) there is decreased hypothalamic sensitivity
- Therefore the hypothalamus no longer recognizes the minimal hormonal levels and the
result is an activation of a feedback response which increases the release of LH + FSH
- The gonadostat (biological clock) theory is based on the changes of sensitivity of the
hypothalamus

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2- Critical Body Weight-48 kg- Therefore females should attain this weight in order to
achieve puberty
- In anorexia nervosa patients there is a delay of puberty
- < 48kg leads to a stoppage of the menses
- On the opposite side, increases in body weight results in an earlier arrival at puberty
- Therefore in developed countries with good nutrition puberty tends to arrive earlier

GnRH
- The pulsatile GnRH secretions regulate FSH and LH
- Therefore if there was continuous release there would be no LH or FSH release
- This is because continuous exposure of gonadotrophs to GnRH results in desensitization
of GnRH receptors, leading to a decrease in LH and FSH release
- Hypogonadal eunuchoid men have low levels of LH and no pulsatile LH secretion
- Pulsatile injections of GnRH restore FSH and LH secretion and increased sperm count
- The pulsatile release of GnRH also leads to the release of LH in a pulsatile fashion

Puberty

1- Adrenarche (Pubarche)- growth of pubic + axillary hairs
- Girls- 8-10 years
- Boys- 10-12 years
- Adrenarche is due to sex hormones from the adrenal glands
- Therefore hair growth depends on androgens in both males and females

Note: The body has 2 sources of testosterone:
- Gonads
- Adrenal cortex

2- Gonadarche- activation of the hypothalamic/pituitary axis
3- Thelarche- breast development
4- Menarche- first menstrual bleeding

Note: The development of secondary sexual characteristic in females is under the control of
testosterone
- Penile growth in male is under the control of testosterone NOT dihydrotestosterone

Kallmans Syndrome (Hypogonadal Syndrome)
- Deficient FSH/LH production due to failure of the GnRH neurons to migrate from the
olfactory bulb (embryological origin) to the hypothalamus

Female Puberty- Oogenesis
Oogonia are germ cells undergoing mitosis
Oocyte- is a germ cell in prophase of the first meiotic division
- The oocyte remains in the first meiotic division

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** The primordial follicle consists of the oocyte (ovum) surrounded by a singles layer of flat
granulosa cells and the basement membrane
- Throughout childhood the granulosa cells provide nourishment for the ovum and secrete an
oocyte maturation-inhibiting factor that keeps the ovum suspended in its primordial state
(prophase)

** The primary follicle consists of one cuboidal layer of granulosa cells. Surrounded by the zona
pellucida

** During the first days of each monthly female sexual cycle, the concentrations of both FSH and LH
secreted by the anterior pituitary gland increase
- These hormones cause the growth of 6-12 primary follicles each month
- The initial effect is rapid proliferation of the granulosa cells
- Spindle cells from the ovary interstitium also collect in layers outside the granulosa cells
and give rise to a second mass of cells known as the theca

** The theca becomes divided into two layers:
i- Theca interna- cells take on epithelioid characteristics similar to the granulosa cells
- Develop the ability to secrete additional sex hormones (estrogen + progesterone)

ii- Theca externa- develops into a vascular connective tissue capsule that becomes the
capsule of the developing follicle

** After the early proliferative phase of growth, the mass of granulosa cells secretes a follicular
fluid tat contains a high concentration of estrogen
- Accumulation of the fluid causes the antrum of appear within the mass of granulosa cells

** The early growth of the primary follicle up to the antral stage is stimulated by FSH alone
- After this accelerated growth occurs leading to larger follicles known as vesicular follicles

** The accelerated growth is caused by the following:
1- Estrogen- secreted into the follicle and cause the granulosa cells to form increasing
numbers of FSH receptors
- This causes a positive feedback effect and makes the granulosa cells even more sensitive
to FSH

2- The pituitary FSH and the estrogens combine to promote LH receptors on the original
granulosa cells
- This allows LH stimulation to occur in addition to FSH stimulation

3- Increasing estrogens from the follicle plus the increasing LH from the anterior pituitary
gland act together to cause proliferation of the follicular theca cells and increase their
secretion as well

** After a week of growth but before ovulation occurs, one of the follicles begins to outgrow the
others.
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- The remaining 5-100 developing follicles become Atretic
- The single follicle continues to grow and becomes the mature follicle (dominant follicle)

Note: The formation of the Graafian follicle is the final stage of follicular development before
ovulation takes place
- The granulosa cells multiply to form antral spaces filled with fluid
- The spaces coalesce to form one fluid filled space
- The fluid pushes the granulosa cells to the periphery

MBBS/DDS 2K16
Lecture 12: Female Puberty Physiology

Lecturer: Dr. Mills

Oogenesis- Summary
1- Primordial follicle
2- Primary follicle
3- Secondary follicle- proliferation of the granulosa
- Vascularization of theca layers
- Gonadotrophin dependent
- Granulosa cells acquire FSH receptors and begin secreting estrogens

4- Tertiary follicle- antrum form around the granulosa cells
5- Graafian follicle- the antrum coalesces to form the large antrum. The oocyte is
then pushed to the periphery of the follicle
- The antrum contains FSH, LH, prolactin, estrogen, androgens, growth factors, inhibin,
activin, plasminogen activation

Estradiol Secretion by Ovaries
** The estrogens mainly promote proliferation and growth of cells of the body that are responsible
for the development of most secondary sexual characteristics of the female

** In the non-pregnant female, estrogens are secreted in significant quantities by the ovaries
- Minute amounts are secreted by the adrenal cortices

** The secretion of estradiol by the ovaries requires co-operation between the granulosa and
theca cells
- Also requires coordination between FSH and LH
- The actions of FSH are restricted to granulosa cells which alone have FSH receptors in the
ovary
- LH receptors are found on the theca, granulosa, stromal and corpus luteum cells

** FSH induces aromatase production in the granulosa cells
- The granulosa cells are deficient in 17-alpha hydroxylase and therefore cannot synthesize
androgens
- However these cells have aromatase and FSH receptors to convert androgens to estradiol

** Theca cells can synthesize androgens because it has the enzyme 17-alpha hydroxylase
- However they have no aromatase or FSH receptors and cannot convert androgens to
estradiol

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** Therefore there is cooperation between the theca and the granulosa cells.
- Growth of the ovum depends on FSH
- FSH leads to the production of estrogen
- Estrogen enters the blood and develops the body at puberty

Ovulation
** In a woman with a normal 28-day female sexual cycle, ovulation occurs 14 days after the onset
of menstruation

** LH is necessary for final follicular growth and ovulation. Without this hormone the follicle will
not progress to the stage of ovulation
- Once estrogen levels reach a concentration of more than 100 pg/ml in the blood for more
than 36 hours it no longer inhibits LH and FSH secretion
- Now begins to stimulate it.

** Therefore ovulation is due to positive feedback by estrogen at puberty.
- Normally there is a pattern of negative feedback at lower levels of estrogen
- At higher levels there is positive feedback and no longer inhibits LH

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** This results in the 48 hours mid-cycle surge of LH
- The LH surge induces ovulation and is due to positive feedback from the estradiol of the
body
- The rate of secretion of LH increase by 6-10x and peaks 16 hours before ovulation
- FSH also increase 2-3x at the same time
- FSH and LH act synergistically to cause rapid swelling of the follicle during the last few
days before ovulation

** LH also has a specific effect on the granulosa and theca cells. Converts them to progesterone
secreting cells
- Therefore the rate of secretion of estrogen begins to fall about 1 day before ovulation
- 35-45 hours prior to ovulation the first meiotic division is completed in the dominant
follicle

** FSH in the follicular phase increases the expression of LH receptors on the granulosa cells
- This in combination with the LH surge puts the follicle under the heavy influence of LH

** The dominant follicle has more estrogen and FSH receptors than others
- The corpus luteum is formed after the ovulation and it produces progesterone under the
influence of LH

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** After the ovum is released from the follicle, the remaining granulosa and theca interna cells
change into lutein cells
- The process of luteinization occurs when the lutein cells enlarge and become filled with
lipid inclusions
- The total mass of cells is known as the corpus luteum

** The granulosa cells in the corpus luteum develop intracellular SER hat form large amounts of
female sex hormones (progesterone + estrogen)
- The theca cells from mainly the androgens (androstenedione + testosterone)
- However most of these hormones are also converted by the granulosa cells into the female
hormones (aromatization)
- The corpus luteum involutes about 12 days after ovulation and becomes the corpus
albicans

Note: Post ovulation progesterone is the predominant hormone; although both progesterone and
estrogens are present

** The released ovum at the beginning of the second meiotic division has a haploid number of
chromosomes
- The perivitelline space is created by the zona pellucida encloses the secondary oocyte and
the polar body that is formed
- Therefore the zona pellucida cells allows the ovum to remain with its daughter cells

** The oocyte is ejected into the peritoneal cavity and clings to the ovarian capsule until it is
removed by the fallopian fimbriae
- The oocyte then begins its journey to the uterus via the fallopian tube
- The ovum survives 12-24 hours in the tube unless fertilized

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Actions of Estrogen
** A primary function of the estrogens is to cause cellular proliferation and growth of the tissues
of the sex organs and other tissues related to reproduction

Effects of Estrogens on the Uterus & External Female Sex Organs
- Responsible for growth of uterus from the infantile stage
- Ovaries, fallopian tubes, uterus & vagina all increase several times in size
- The external genitalia enlarge with deposition of fat in the mons pubis + labia majora
- Estrogens change the vaginal epithelium from a cuboidal type to a stratified type
- This type is more resistant to trauma and infection
- Estrogens also cause proliferation of the endometrial stroma
- Also cause increased development of the endometrial glands

Breasts
- Development of the stromal tissues of the breasts
- Growth of an extensive ductile system
- Deposition of fat in the breasts

Bone
- Inhibit osteoclastic activity in the bones
- Therefore stimulates bone growth
- Cause uniting of the epiphyses with the shafts of the long bones
- Estrogen also conserves calcium therefore during menopause when estrogen levels are low
it leads to osteoporosis

Other Effects
- Cause the skin to develop a smooth/soft texture
- Increases coagulability- patients on OCP (estrogen) have a tendency to develop thrombus
- Estrogen causes sodium + fluid retention therefore before the period when estrogen
levels are higher there is bloating
- Estrogens can lead to increased contraction and carries an increased risk of spontaneous
abortion

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Actions of Progesterone
** The most important function of progesterone is to promote secretory changes in the uterine
endometrium during the latter half of the monthly cycle
- This prepares the uterus for implantation of the fertilized ovum
- Progesterone also decreases the frequency + intensity of uterine contractions and helps to
prevent expulsion of the implanted ovum
- Therefore progesterone is produced in pregnancy because it keeps the uterus in a relaxed
state

** Progesterone promotes increased secretion by the mucosal lining of the fallopian tubes
- These secretions are necessary for nutrition of the fertilized, dividing ovum as it passes
through the fallopian tube

** Progesterone promotes development of the lobules and alveoli of the breasts, causing the
alveolar cells to proliferate and become secretory in nature
- However progesterone does not cause the alveoli to secrete milk

** Progesterone has a thermogenic effect and causes an increase in body temperature

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Menstrual Cycle

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** The endometrial cycle is associated with the monthly cyclical production of estrogens and
progesterone by the ovaries:
1- Proliferation- of the uterine endometrium
2- Secretory Phase- development of the secretory changes in the endometrium
3- Menstruation- desquamation of the endometrium

Proliferative Phase (Estrogen Phase)
** At the beginning of each monthly cycle, most of the endometrium has been desquamated by
menstruation
- Under the influence of estrogens, secreted in increasing quantities by the ovary during the
first part of the monthly ovarian cycle, the stromal cells and the epithelial cells proliferate
rapidly
- Over the next 10 days the endometrium increases in thickness
- The proliferative phase occurs before ovulation

Secretory Phase (Progestaitonal Phase)
- During most of the latter half of the monthly cycle, after ovulation occurred, progesterone
and estrogen are secreted by the corpus luteum

** The estrogens cause additional cellular proliferation in the endometrium
- Progesterone causes swelling and secretory development of the endometrium

** The glands increase in size. Excess of secretory substances accumulates in the glandular
epithelial cells
- The peak of the secretory phase occurs about a week after ovulation

Menstruation
** If the ovum is not fertilized, about 2 days before the end of the monthly cycle, the corpus luteum
involutes
- Therefore levels of ovarian hormones decrease and menstruation follows

** Menstruation is caused by the reduction of estrogens and progesterone at the end of the
monthly cycle
- 2 to 5 days in duration

** The first effect of menstruation is decreased stimulation of the endometrial cells by the two
hormones
- Followed by the involution of the endometrium
- The blood vessels become vasospasmatic

** Therefore the vasospasm, decrease in nutrients to the endometrium, loss of hormonal stimulation
initiate necrosis in the endometrium
- As a result the outer layers of the endometrium are shed
- During normal menstruation 30-80 mls are lost
- The blood is non-coagulatory with fibrinolytic activity

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** At menarche and the first 2 years of menstruation is anovulatory (55-90%)
- Decreases to less than 20% by 5 years after menarche
- Anovulatory menstruation is bleeding without ovulation taking place

** The menstrual cycle is divided into two phases:
i- Follicular Phase- first 14 days of the cycle
ii- Secretory Phase- between the 14
th
- 28
th
day

** Therefore in a 30 day cycle- the day of ovulation will be 30-14 days= 16
th
day
- Therefore even if the length of the cycle changes, the 14 day period for the follicular phase
is standard
- Changes in the duration of the cycle depends on the change in the proliferative phase

Clinical Indications of Ovulation
- Increase in body temperature
- Secretory phase- higher temperature
- Proliferative phase- lower temperature
- Therefore a measure of body temperature can be used to determine the best time to have
intercourse
- Disappearance of spinnbarkeit
- Aboration disappears
- Endometrium enters into the secretory phase

Note: Progesterone is only found when the corpus luteum is created; therefore ovulation must
occur for a corpus luteum to be formed
- Therefore if the curve is flat there is anovulatory menstruation where bleeding occurred
without ovulation

Follicle Atresia
Follicle Atresia- takes place at each ovulation time
- Also occurs before puberty
- Characterized by destruction of the oocyte and granulosa cells
- Due to lack of gonadotrophin support of the growing follicle

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** Threshold- is a level of estrogen within the body-
- If this estrogen level is maintained, there will be no bleeding from the uterus.
- If the level is very low there will be no bleeding and if the level is at the threshold or higher
there will also be no bleeding

Estrogen Withdrawal Hemorrhage- If the estrogen level goes higher than the threshold and then
the level falls, the result will be withdrawal bleeding
- Seen when taking the pill for 21 days to maintain the estrogen levels and then in the 7

day
pill free period the woman stops taking the estrogen and the level falls below threshold
- Leads to withdrawal bleeding

Estrogen Threshold Hemorrhage- Spotting that occurs because the levels of estrogen are not
sustained
- Occurs as a side effect of the depo provera shot
- The result is break-through bleeding

MBBS/DDS 2K16
Lecture 13: Male Puberty Physiology

Lecturer: Dr. Mills
READ TEXT FOR ADDITIONAL INFO

Secondary Amenorrhea- Patient initially had periods and thse stopped
Primary Amenorrhea- Patient never saw periods

Hormones of Testis

1- Leydig Cells- produce testosterone which inhibits LH
- Estrodial produced by armoatisation in the testis and this inhibits GnRH

2- Sertoli Cells-
i- Inhibin- inhibits FSH secretion
ii- Activin- stimulates FSH production
iii- FOllistatin- reduces FSH by binding to activin

END OF PHYSIOLOGY SECTION

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PHARMACOLOGY LAB

7- Comment on the onset and duration of diuresis of urea, glucose and
frusemide. Comment on the mode of action of these agents.
Frusemide produces the most sustained diuretic action of the three agents. Administration of
frusemide produces the largest amount of diuresis and this urine loss is sustained at a relatively
high level for the entire 18 minutes

The administration of urea demonstrates a brief diuresis that is rapid in onset. The urine output
peaks at 9 minutes and it produces a lower level of diuresis than frusemide. Therefore although
urea acts more rapidly than frusemide; the latter agent produces a more sustained diuretic effect

The onset of the diuretic effect of glucose is comparable to frusemide and both agents have a slower
onset of action than urea. However the duration of glucoses diuretic activity is longer than urea,
but not as long as frusemide.
8- Explain the mechanism which results in the fall in blood pressure produced by
these agents
The three agents cause a fall in blood pressure by promoting the elimination of water (blood
volume) and sodium from the body.
Frusemide is a loop diuretic; therefore it selectively inhibits sodium chloride reabsorption in the
thick ascending limb of the loop of Henle. As a result more NaCl will be excreted and water will be
pulled with the NaCl via osmosis into the lumen of the tubule. Therefore frusemide helps to reduce
blood pressure by decreasing blood volume and salts in the body

The diuretic effect of urea is due to a rise in blood urea after its ingestion. The excess urea in the
blood leads to filtration of large amounts of urea from the glomeruli. The increased urea
concentration increases the osmotic pressure in the renal tubules and this reduces reabsorption of
water. This is because the tubular fluid will be more concentrated than the interstitial fluid. As a
result this creates an osmotic gradient that tends to pull water from the body into the tubules to be
excreted. This causes a reduction in blood volume and consequently a reduction in blood pressure.

Glucose is a sugar that can act as an osmotic diuretic. If glucose exceeds its transport maximum in
the glomerular filtrate it will be excreted in the urine. The glucose in the filtrate can cause diuresis
because it causes osmotic retention of water in the urine. Therefore it can reduce blood pressure by
reducing blood volume. Therefore glucose produces diuresis in a similar manner to urea

9- How does sucrose compare to glucose in producing diuresis when both are
given intravenously

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Sucrose would have a similar osmotic diuretic effect as glucose. However sucrose would have a
greater diuretic effect because it is a larger molecule. Therefore it would create a larger osmotic
gradient in the tubule and result in pulling greater amounts of water from the interstitium to be
excreted in the urine.

10- Mersalyl and HgCl2 are both drugs that contain mercury ions. Why did HgCl2
not produce diuresis

The HgCl2 did not produce diuresis because mercury is an inorganic ion which ultimately blocked
the calcium channels in the heart of the test subject. As a result the heart of the subject was stopped
before diuresis could be achieved.

11- Give one clinical condition other than hypertension in which diuresis with
each of the following agents is useful

a- Frusemide- to reduce pulmonary congestion
b- Mannitol- raised intracranial pressure

MBBS/DDS 2K16
Lecture 1: Genital ulcerations

Lecturer: Dr Karen Roye-Green

Syphilis
Definition Syphilis is a chronic infectious disease caused by the spirochete Treponema pallidum
,which is transmitted during sexual intercourse and other intimate contact; it may also be vertically
transmitted by a pregnant woman to her feotus in utero or during birth by contact of infant with
maternal lesion.

Aetiology
The causative agent of syphilis is Treponema pallidum subspecies pallidum. The organisms
are slender ,tightly coiled, unicellular helical cells 5-15 m long and .09- 0.18m wide.

Pathogenesis
Within hours to days after T. pallidum penetrates the intact mucous membrane or gain
access through abraded skin ,it enters the lymphatics and / or blood stream and
disseminates throughout the body.
The primary stage refers to the development of the primary lesion ,known as chancre,
which occurs at the site of inoculation.
Chancres usually heal spontaneously in 2-8 weeks but often persist for longer periods in
immunocompromised host for eg HIV infected persons.
The secondary or disseminated stage becomes evident in 2-12 weeks (mean 6 weeks) after
contact.
This generalized condition with parenchymal ,constitutional, and mucocutaneous
manifestations occurs when the greatest number of treponemes are present in the body,
particularly in the blood stream.
After the secondary stage subsides ,the patient enters a latent period during which the
diagnosis can be made only by obtaining a positive serologic test response for syphilis.
Late syphilis refers to the clinically apparent or inapparent tertiary disease that develops
in up to one-third of untreated patients.

Epidemiology
Syphilis can be acquired by sexual contact ,by passage through the placenta, by kissing ,by
transfusion of fresh human blood, or by accidental direct inoculation.
From 1986 to 1990, an epidemic of syphilis occurred in the United States. Since 1991 there
has been yearly decline of primary and secondary syphilis.

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Clinical manifestations
Incubation period averages 21 days with a range of 10 -90 days.
Primary syphilis consist of 1 or more ulcerated lesions called chancres, which appear at the
site of initial infection. It appears as a painless papule, that quickly erodes and becomes
indurated. The base is usually smooth, and the borders are raised and firm . Untreated ,the
manifestations of primary syphilis resolve in 3-6 weeks.
Secondary syphilis begins 2-8 weeks after the appearance of a chancre.
The classic and most commonly recognized lesions occur in the skin. Macular
,maculopapular ,papular and pustular lesions occur on the entire body. Temporary patchy
alopecia or thinning and a loss of eyebrows and beard may develop
In warm ,moist intertriginous areas (perianal area ,vulva, scrotum, inner aspect of the
thighs ,the skin under pendulous breast, nasolabial folds, cleft of the chin, axillary and
antecubital folds, webs of the fingers and toes) ,the papules enlarge ,coalesce ,and erode to
produce painless, broad ,moist gray-white to erythematous highly infectious plaques called
condyloma lata.
Highly infectious lesions teeming with spirochaetes may also develop on mucous
membranes (lips, mouths, pharynx, tonsils, vulva, vagina, glans penis and anal canal). These
lesions are called mucous patches.
Constitutional symptoms also occur and include low-grade fever ,malaise, pharyngitis
,laryngitis, anorexia, weight loss ,arthralgia ,and generalized painless lymhadenopathy

Latent syphilis
The stage of the disease during which a specific treponemal test is positive but no clinical
manifestation of syphilis .
A history compatible with primary or secondary syphilis ,exposure to a syphilitic person ,or
delivery of an infant with congenital syphilis may be obtained.
Late syphilis
Late syphilis (tertiary syphilis) is a slowly progressive inflammatory disease that can affect
any organ in the body and can produce clinical illness years after the initial infection.
It is generally referred to as neurosyphilis, cardiovascularsyphilis or gummatous syphilis

Tertiary gummatous syphilis
The characteristic lesions of tertiary syphilis appear 3-10 years after infection and consist of
granulomas or gummas.
The granulomas appear as cutaneous plaques or nodules of irregular shape and outline
,and are often single lesions on the arms, back and face.
Punched-out lesions appear most commonly on the scalp, face, sternoclavicular areas of the
chest and lateral calf
Gummas can also cause palatal perforation ;destruction of nasal cartilage and painless
testicular swelling

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Cardiovascular syphilis
The typical lesion of cardiovascular syphilis is aortitis affecting the ascending aorta and
appearing 10-30 years after infection
The aortitis may be asymptomatic and detected as dilatation of the ascending aorta on chest
x-ray or it may lead to stretching and incompetence of the aortic valve, left ventricular
failure or aneurysm formation .

Neurosyphilis
The onset can occur weeks or decades after treponemal dissemination
Meningeal neurosyphilis usually has its onset during secondary disease and is characterized
by symptoms of headache ,confusion ,nausea and vomiting ,neck stiffness and photophobia
.
There may be focal seizures, aphasia ,delirium ,and papilledema .Cranial nerve palsies cause
unilateral or bilateral facial weakness and sensorineural deafness.

Congenital syphilis
Many infants with congenital syphilis are asymptomatic at birth.
Early congenital syphilis is manifest as rhinitis with serosanguinous nasal discharge ,
vesiculobulbous eruptions of the skin and oral mucous patches
Bone abnormalities characterized by diaphyseal periostitis and osteochondritis
.Chorioretinitis ,hepatosplenomegaly associated with jaundice and the nephrotic
syndrome.
In late congenital syphilis there may be high-arched palate, a protruding mandible ,frontal
bossing of the skull ,and saddle nose deformity.
Peg-shaped permanent incisors and mulberry multicusped molars and eight nerve
deafness.
Hydrocephalous and mental retardation , as well as other typical lesions of gummatous and
neurosyphilis

Laboratory diagnosis
Microscopy---darkfield examination
Collection of specimens --.specimens for both darkfield microscopy and direct
immunofluoresent antibody test for T.pallidum can be collected from genital and anal
lesions or from lymph nodes.
Serous fluid collected after wiping the first few drops of exudate .

Serologic test.
the standard nontreponemal test is the Veneral Disease Research Laboratory (VDRL) slide
test and the Rapid Plasma Reagin (RPR) card test.
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The specific treponemal antibody test include fluorescent treponemal antibody absorbed
test ,T.pallidum hemagglutination assay microhaemagglutination assay for antibodies to
T.pallidum, treponemal immobilization test.

Treatment

Early syphilis

1.Benzathine penicillin G, 2.4 million units im stat or
2.Aqueous procaine penicillin 2.4 million units im daily plus probenecid 1g po qd x 10 days.
3.For penicillin allergic patients.
Doxycycline 200mg po bid x 15 days or
Tetracycline hydrochloride 500mg po qid for 15 days
Erythromycin 500mg qid po 15 days or
Ceftriaxone 1g im daily for 10 days.

Late syphilis
1.Benzathine penicillin G 2.4 million U im weekly for 3 weeks or
2.Aqueous procaine penicillin 600,000-900,000 U im daily for 15 days.
3.For penicillin allergic patients
Doxycycline 200mg po q 12h for 30 days or
Tetracycline hydrochloride 500mg q6h x 30 days .

Neurosyphilis
1.Aqueous crystalline penicillin G 3-4 million U iv q4h for 10 days plus benzathine
penicillin G 2.4 million U im weekly for 3 weeks.
2.Aqueous procaine penicillin G 2.4 million U im daily for 10 days plus probenecid
500mg orally q6h for 10 days plus benzathine penicillin G 2.4 million U im weekly for 3 week
3.No proven effective alternative ..patients allergic to penicillin should be
desensitized.

Genital herpes
The agents of genital herpes are herpes simplex virus (HSV) type 2, and less commonly HSV
type 1.

Epidemiology
Human are the natural reservoir for HSV. Worldwide distribution .HSV -1 infection is
common early in life.HSV-2 antibodies increase in prevalence with increasing age after the onset of
sexual activity.

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Pathogenesis.
HSV are spread by direct contact ,including contact with infected secretions.
HSV-1 is typically spread through close contact with infected oral secretions and genital
herpes due to HSV-1 is usually due to oralgenital contact.
HSV-2 is primarily spread through intimate contact with infected genital secretions and
tissues.
Intact skin is fairly resistant to virus infection, but abraded skin or mucous membranes are
more susceptible.

Clinical features

Primary first episode genital herpes.
Incubation period lasts for 2-7 days.
Onset heralded by fever, headache, local genital pain and burning.
The characteristic painful lesion in the genital area initially present as erythematous
macules ,which then progress to vesicles on a erythematous base, pustules ,ulcers and
finally to crusts.
In males ,lesions typically appear on the penis and glans penis.
In females ,lesions may be present throughout the genital tract including the perineum, vulva ,labia,
perianal regions and buttock.
Tender bilateral inguinal adenopathy is generally present.

Recurrent genital herpes.
In approximately 50% of patients, a prodrome of symptoms precedes the onset of recurrent
disease.
These include local burning and itching, tingling and dysesthesia
Localized and unilateral crop of vesicular lesions
Lesions are present on the vulva ,glans penis and penile shaft, thigh ,or buttock and in the
rectum.
Local oedema, pain, regional adenopathy.

Direct microscopic examination of cells from the base of lesion using tzanck smear.
Cell culture can be used ,as HSV replicates and causes identifiable CPE in most cell cultures.
Assay of tissue biopsy ,smear or vesicular fluid for HSV antigen by enzyme immunoassay,
immunofluorescent stain .
Distinction between HSV1 and HSV can be done by type-specific antibody, DNA maps of
restriction enzymes and DNA probe analysis.

Viral isolation and identification

Specimen collection
-vesicle fluid, urine, CSF, rectal swab, urethral swab
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Tissue culture--------CPE with giant cells
Mice ---------------------paralysis and death
Chorioallantois membrane.pocks

Serology
Observation of specific IgG ,IgM or IgA antibody response.
Monoclonal antibodies used for typing of virus
Neutralization test ,complement fixation test, radioimmunoassay ,enzyme
immunoassays.
PCR
rapid and sensitive.

Treatment
Acyclovir indications ;primary genital herpes ,recurrent genital herpes ,suppression of
recurrent genital herpes.
Valacyclovir
Famciclovir
Foscarnet ---for acyclovir-resistant HSV.

Chancroid
The etiologic agent of chancroid is Haemophilus ducreyi

Epidemiology
Occurs worldwide.
Uncircumcised men are more susceptible to infection.

Pathogenesis
Chancroid is transmitted from person to person by direct contact.
A break in the skin may allow the organism to penetrate ,establish infection and evoke
humoral and cellular immune responses.
Despite the host immune response, re-infection and serial autoinfection can occur.

Clinical features
Incubation period varies from 1 day to several week, with a median of 5-7 days.
A painless papule develops into pustule and progresses to form a painful 1-2 cm ulcer.
The ulcer margins are raised ,irregular and sharply demarcated.
The friable ,granular base is often covered with a necrotic exudate.
Men are more symptomatic .The ulcer is usually located on the prepuce, coronal sulcus,
penile shaft, glans or urethral meatus.
In women ,it may present as dyspareunia, or dysuria. Ulcers are more likely to be painless
and are found on the labia ,perineum, perianal region and the medial aspect of the thigh .
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Inguinal lymphadenitis is seen in about 50% of men and 35% of women.
Lymph nodes progressively enlarge to become necrotic and fluctuant (buboes)
Untreated ulcers usually heal spontaneously ,but may become complicated by secondary
bacterial infection ,tissue destruction, scarring, fistulae, and stricture formation.

Specimen--- swab of ulcer base
Culture on mueller-hinton or gonococcal agar base. Confirmed by nitrate reductase,
cyctochrome oxidase, alkaline phosphatase.
PCR -------highly sensitive and specific.

Treatment
Azithromycin 1g orally in a single dose. Or
Ceftriaxone 250mg im in a single dose. or
Erythromycin base 500mg q6h for 7 days. Or
Ciprofloxacin 500mg orally. or
Spectinomycin 2g im.
Augmentin or bactrim.

Granuloma inguinale
Granuloma inguinale is caused by Klebsiella granulomatis

Epidemiology
Granuloma inguinale is endemic in tropical and subtropical regions such as Papua New
Guinea and India.
It can also be found in Southeast Asia, parts of Africa, the Caribbean, central Australia and
South America.

Pathogenesis
Exact mode of transmission is not known.
Widely believed to be sexually transmitted.
Occurrence in sexually inactive persons( including children) and the low rate of
transmission between sexual partners suggest the possibility of nonsexual transmission

Clinical features
Incubation period range between 3 and 30 days.
Initial lesion is a small firm papule at the site of infection, which erodes to form a painless
ulcer.
The ulcer is granulomatous and beefy red.
Lesions are usually found in the genital, perianal and inguinal regions.
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Without treatment ,lesions are slowly progressive ,often resulting in soft tissue destruction
and extensive scarring.

Laboratory diagnosis.
Demonstrate Donovan bodies on smear or biopsy.
The ulcer is scraped and spread on to a slide which is air dried and stained with wright or
giemsa stain.

Treatment
1.Bactrim 2 tablets q12h.
2.Doxycycline 100mg q12h
3.Teracycline or erythromycin 500 mg q6h
4.Chloramphenical 500mg q8h
5.Clindamycin,fluoroquinolones and gentamicin are also effective.

Lymphogranuloma venereum (LGV)
LGV is caused by three serovars of Chlamydia trachomatis :L1 ,L2 and L3.

Epidemiology
LGV is endemic in parts of Africa ,India ,Asia ,South America and the Caribbean.
Men are 6 times more likely than women to have a clinically evident infection.

Pathogenesis
LGV is acquired sexually ,through direct contact with infected tissues or fomites.
After exposure ,epithelial abrasions allow the organism to penetrate the mucosal barrier.
Replication within the macrophage is followed by spread via the lymphatic system

Clinical features
Clinical disease occurs in 3 stages.
The transient primary lesion is a small ,painless genital ulcer or papule. It appears 3-21 days
after inoculation.
It usually occurs on the coronal sulcus in men and on the cervix ,posterior vaginal wall or
vulva in women.
The second stage occurs days to weeks after the primary infection.
Characterized by painful regional lymphadenopathy and systemic symptoms.
In men inguinal lymph nodes are affected.
In women ,pelvic lymphadenopathy .
Tertiary or anorectal stage is predominantly seen in women and homosexual men.
Rectal infection may result from anal intercourse, lymphatic spread or from vaginal
secretions.
Patients present with fever,rectal pain and mucopurulent or bloody discharge.

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Growth of the organism in cell culture is the most specific diagnostic test.
Serology
1.complement fixation
2.microimmunofluorescence
3.enzyme-link immunosorbent assay and direct fluoescene-conjugated antibody
tests.
4.PCR

Treatment
Doxycycline 100 mg q12h for 3 weeks
Erythromycin 500mg po q6h
Bactrim q12h

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Lecture 2: Genital Discharges (demonstration)

Genital Discharges

Specimens:

Endocervical swab
High vaginal swab
Urethral swab

Aetiologic Agents:
Neisseria gonorrhoeae
Chlamydia trachomatis
Trichomonas vaginalis
Ureaplasma urealyticum
Mycoplasma genitalium

Urethral discharge syndrome

Urethritis:
Gonococcal urethritis
Non-gonococcal urethritis

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Vaginal discharge Syndrome

Cervicitis:
Endocervicitis

Vaginitis:
Candidiasis
Trichomoniasis
Bacterial vaginosis

Laboratory Diagnosis:

Specimens:
Discharges:
- Endocervical swab
- High vaginal swab
- Urethral swab

Disseminated gonococcal Infections
- Blood
- Joint fluid

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Laboratory Investigations:
1. Gram stain from specimen
2. Culture using appropriate media
3. Identification of isolate
4. Antimicrobial Susceptibility testing

Gram stain from Urethral Discharge

Gram stain from Vaginal Discharge

Gram stain showing normal vaginal
flora

A search of the slide may reveal
intracellular and extracellular Gram
negative diplococci

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Isolation of Neisseria gonorrhoeae
Culture
Chocolate agar
Thayer Martin agar

Isolation of Neisseria gonorrhoeae

Chocolate agar:
an enriched media used for the
isolation of Neisseria gonorrhoeae and
other fastidious organisms.

Thayer Martin agar:
Selective media used for the isolation of
Neisseria gonorrhoeae from an area that is
heavily populated with commensal organisms
e.g. Rectal swab, Vaginal swab

Inoculated plates are incubated in an
atmosphere enriched with 5-10
0
CO
2
at 37
0
C
for 48 hours.
Plates are examined after 48 hours

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Identification of Neisseria gonorrhoeae

Identification of Neisseria gonorrhoeae
1. A gram stain is done from suspected colonies

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2. An oxidase test is done on suspected colonies

Biochemical tests are done on colonies that are:
a) gram negative diplococci
b)oxidase positive

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Obligate intracellular parasites
Several serovars:
Serovars A, B, Ba, C: eye infections (trachoma)
Serovars D-K: Genital Tract Infections
Urethritis, cervicitis, salpingitis, bartholinitis, epididymitis, proctitis, conjunctivitis
SerovarsL1,L2,L2a,L3: Lymphogranulomavenereum(LGV)
Diagnosis

Specimens:
swab: urethral, cervical, conjunctival
Transport: CTM

Culture: grows in McCoy cells, HeLa, BHK
Microscope:
Iodine stain-cytoplasmic inclusions in infected host cells stain brown with
Iodine due to glycogen granules
Fluorescent Antibody Test

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Shell vial cultures
A variation on standard tissue culture in that it takes advantage of using a living cell system and
enhances viral recovery by centrifuging the clinical sample onto the monolayer of cells.
In this technique a small bottle (vial) with a removable round glass cover slip is used to grow the
cells as a monolayer on the cover slip

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Identification of Chlamydia trachomatis

Direct antigen detection:
FA
EIA
PCR

Vaginal discharge syndrome

Cervicitis:
Trichomonas vaginalis
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Vaginitis:
Bacterial vaginosis Trichomoniasis
Candidiasis

Bacterial vaginosis

A polymicrobial clinical syndrome resulting from replacement of normal H2O2 producing
Lactobacillus sp in the vagina with high concentrations of:
Anerobic bacteria(Prevotella sp, Mobilincus sp),
Gardnerella vaginalis
Mycoplasma hominis
Few or no WBC

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Candidiasis

Agent:
Candida albicans (monilia)

Specimens
High vaginal swab
Endocervical swab

Identification of Candidiasis

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Identification of Candida albicans

Trichomoniasis

Agent:
Trichomonas vaginalis - a flagellated protozoan
Specimens:
High vaginal swab (HVS)

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Lecture 3: Human Immunodeficiency Virus Infection
(demonstration)

Human Immunodeficiency Virus

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HIV Diagnostic Methods

Indirect examination
Viral isolation

Direct examination(virus components)
Antigen detection (p24)

Nucleic acid detection: DNA, RNA
Reverse transcriptase activity (RT)

Serological detection
Screening assays: traditional & rapid
Confirmatory assays


Direct:
Antigen detection (P24)
Nucleic acid detection (DNA, RNA)
Reverse transcriptase activity (RT)

P24 Antigen

HIV1 capsid antigen
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High titre present in acute infection prior to conversion
Undetectable after seroconversion as it becomes complexed with p24 antibody
Confirm: neutralisation test
Use
Detection of infection before antibody appears
Diagnosis of acute HIV syndrome
Newborns
Serology:
Screening assay e.g. ELISA

Confirmatory assay e.g. Western Blot

HIV Rapid Screening tests

ELISA-Ab
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Confirmatory assay
The term confirmatory or supplementary testing refers to the retesting of an antibody
sample by another assay having:
A different test principle
A different method of antigen preparation
Methods include:
Western blot
Other rapid tests
Routine screening assays
Rapid confirmatory assays
Western Blot Results
Positive(WHO/CDC/ARC)
Negative: no bands
Indeterminate: any other
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WESTERN BLOT TEST

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HIV testing : general principles
Every positive test (screening) must be
1. Repeated in duplicate using the same test principle
2. Confirmed by a different test principle
3. Repeated on a second, independently obtained sample
Laboratory quality control policy must be in
place, including participation in external quality assessment

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Lecture 4: Urinary Tract Infection

Lecturer: AM Nicholson
MB BS; DM (Med Micro)

Definition/ Introduction
One of the most commonly encountered acute infections
Bacteria in the urine
Covers spectrum from asymptomatic bacteriuria to severe pyelonephritis
May be of lower or upper urinary tract

Urinary Tract
Upper
Kidney
Ureter
Lower
Bladder
Urethra (Genital tract)

Classification

Upper: Pyelonephritis, ureteritis
Lower: cystitis
Uncomplicated, complicated
Acute, chronic, recurrent
Community or Hospital acquired (HCAI)

Uncomplicated UTI
Uncomplicated UTI: one occurring in a healthy, ambulatory, non-pregnant female without
any underlying structural abnormality or neurologic dysfunction.
Mostly due to E coli
More susceptible organisms
Easy to treat

Complicated UTI
UTIs at sites other than the bladder eg pyelonephritis.
Those in children, most men, pregnant females.
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Those associated with obstruction, urologic dysfunction, catheters, renal transplant
recipients
High risk groups: immunocompromised, pregnancy, diabetes, hypertension
Warrants broader spectrum antimicrobial coverage (MDRO)
Infrequently requires surgery
High incidence of organisms other than E coli.

Recurrent Infection

Recurrent: >2 inf in 6 mths or >3 in 1 yr
Reinfection: new infection with new organisms. Infection cleared for 2 weeks or more after
treatment. Recurrence of symptoms. Isolation of new organism or new strain
Relapse: recrudescence of prior, partially treated infection. Same organism involved.
Occurs shortly after completion of therapy (days - 1mth)

Epidemiology
In patients < 3 months there is increase in boys> girls but ratio is reversed after that
More common in females (long urethra protects males)
Elderly men and women have about same prevalence
90% caused by part of normal flora

Organisms

Gram negs:
Enterobacteriaceae:
E coli
K pneumoniae, Proteus, Enterobacter, Serratia.
Pseudomonas spp

Gram pos:
Enterococcus faecalis
Staph saprophyticus (comm.)
Staph epidermidis (hosp)
Staph aureus
Acid fast: M tb
Yeast: C albicans
Parasite: Schistosoma haematobium

Determinants of Infection
Inoculum size: need large numbers
Virulence: only certain spp. cause upper UTIs
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Urinary tract abnormalities: obstruction, reflux, catheters
Receptor density in uroepithelial cells

Host defense mechanisms:
complete bladder emptying: one of the most important defense mechanisms. Urine is
normally sterile but good culture medium so if high residual volume, bacteria will thrive
High fluid intake & frequent voiding: ? Washout bacteria
Vesicoureteral valve (ureterovesical): prevents reflux of bacteria from bladder
Length of urethra
Vaginal flora eg lactobacillus decreases colonization with E coli

Virulence
UTI: relies on bacteria to adhere & colonize gut, perineum, urethra, bladder, kidney
Adhesion is important esp. in normal U/ tract
Pathophysiology of adhesion is complex
Enterobact: electronegative & too small to overcome repulsion by the net negative charge of
epithelial cells
Bacterial adhesion cannot occur in absence of fimbriae or other nonfimbrial surface adhesion
systems
Fimbriae allow irreversible attachment to uroepithelium via adhesins
Adhesins: found on tip of bacterial fimbriae and/ or on bacterial surface itself (non-fimbrial
adhesins)
Specific adhesion systems exist for orgs. Eg P fimbriae for E coli.

Virulence factors: E coli
Virulence is NOT related to antimicrobial resistance: most adherent strains sens.
Main serotypes: O1, 2, 4, 6, 7, 16, 18 & 75
Present in 28% of normal faecal flora but account for 80% of pyelonephritis, 60% cystitis &
30% asymptomatic bacteriuria
Flagellae:motility
Hemolysin production: induces pore formation in cell membrane
Siderophore: necessary for iron uptake in the iron-poor environment of the U/tract
K antigen: nonfimbrial adhesin, promotes strong biofilm growth. Assoc with persistence in
bladder
Virulence is not related to antimicrobial resistance: most adherent strain:very sensitive

Pathophysiology/ pathogenesis
Normal urinary tract is sterile except for distal urethra which may have Gm pos & Gm neg
bacteria.
Ascending infection: The most important means by which infection occurs (coliforms).
Urethral orgs. spread to bladder
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Hematogenous infection: Acute pyelonephritis secondary to Gm neg bacteremia can occur
but not common.
May lead to descending infection

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Clinical Presentation

From asymptomatic bacteriuria to pyelonephritis

Lower: Cystitis
Include dysuria, urgency, hesistancy, frequency, incomplete voiding, urinary incontinence,
haematuria (gross or microscopic) & suprapubic pain
The elderly may present with confusion and no localizing features
Constitutional symptoms such as fever are mild or absent

Lower: Urethritis

Females: increased frequency & dysuria, afebrile, pyuria without bacteriuria, H/O STI

Males: Dysuria & urethral discharge. H/O STI

Clinical Presentation: Upper

Acute pyelonephritis
(Infection and inflammation of the renal
pa renchyma)
Symptoms of lower UTI may be present: dysuria, frequency, hesitancy, lower abdominal
pain, urgency, haematuria ,
Symptoms of pyelonephritis: flank pain, back pain, high fever, rigors, chills, weakness,
anorexia, nausea, vomiting, diarrhoea, constipation

Renal abscesses: Symptoms identical to pyelonephritis. Suspect in patient with UTI with fever
persisting >48-72 hrs.

Asymptomatic bacteriuria
Isolation of specified amount of bacteria in urine of pr without symptoms.
2 consecutive specimens with >100,000 orgs/ml with same organism
Or
1 CSU with 100 orgs/ml
Treat pregnant women, pts doing urologic procedures.
Do NOT treat non-pregnant females, diabetics, elderly nursing home residents, pts with spinal cord
injury or indwelling catheters

UTI in females
UTI in males
UTI in elderly
UTI I children
UTI in patients with catheters
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Specimen types
URINE: Primary specimen
Blood: Secondary specimen
Urine samples:
MSU
CSU
SPA
Neonatal bagged urine
In & out catheter urine
Other: nephrostomy urine, bladder cystoscopy urine
Specimen Collection
First voided morning urine preferable
Urine more concentrated then: more likely to recover organisms
MSU: distal urethra may have bacteria

Urine Samples: Too much/ Too little!!

Specimen Collection: How To
Wash hands thoroughly with antibacterial soap and hot water; dry them with a paper
towel. Make sure that the soap does not contain any substances (lotion, scent, etc)
that may interfere with the urine sample.

Prepare the specimen cup. Use care when opening the cup and lid, making sure to
keep the cup sterile. For example, be sure to place the lid with the inner part facing
up on a surface and do not put any part of your hands on the inner cup or lid.

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Thoroughly clean the genital area with antiseptic cleansing cloths or antibacterial
soap and water. Males should pull the foreskin of the penis back to assure complete
cleansing of the area. Females should separate and cleanse the folds, or lips, of the
vulva. Care should be used as a female cleanses that wiping occurs from front to back
so that feces do not contaminate the genital area.

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Dipstick
Nitrite
Leukocyte esterase
Blood
Proteins
Other
Rapid
Simple
Convenient
Cheaper

Culture & Sens.

Culture
Urine culture is semi-quantitative; need to know
if more than 100,000 organisms per ml of urine.
Sample plated onto Blood agar & MacConkey
agar and incubated at 37C for 24 hours

Traditional Interpretation

Organism/ colony forming unit per ml (cfu/ml)

10
5 or more
Significant
10
4
-10
5
Doubtful significance
< 10
4
Insignificant
SPA (babies) Any number significant
Increased nos: improper collection, specimen allowed to stand at room temp

Newer Interpretation
Women with dysuria & pyuria: 100 cfu/ml or more of a single predominant uropathogen is
significant
Men with 1,000 cfu/ml or more of above: significant

Contamination?
MSU: >2 organisms
CSU: >3 organisms

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Quantitative culture
Commensal flora from the periurethral area or vagina may cause contamination, leading to
false positive results
Infecting and contaminating bacteria are distinguished by quantifying the number of
organisms growing from the urine
Colony counts of contaminants in voided specimens are low, while infecting organisms
achieve high concentration

Identification & Susceptibility
Biochemical tests
Antibiotics: Cotrimoxazole
Amoxil, Amoxicillin-clavulanic acid (Augmentin) (20-25% resistance UHWI), Quinolones (10%
resistance), Nitrofurantoin, Nalidixic acid
Gentamicin
Ceftriaxone
Other as requested

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E-TEST

Treatment
Acute uncomplicated cystitis in non-pregnant woman
3 day regimen more effective than single dose regimen but 7 day therapy also:
Cotrimoxazole
Fluoroquinolones
Betalactams
Problem of uropathogens resistant to Bactrim
Treat 1
st
UTI in males with no GU abnorm.
If 2
nd
occurs, complete urologic evaluation
Cranberry Juice

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Lecture 5: Urinary Tract Infection (demonstration)

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END OF MICROBOLOGY SECTION

MBBS/DDS 2K16
Lecture 1: Pathology of Female Genitalia I: Vulva, Vagina &
Cervix

Lecturer: Professor C. Escoffery

Vulva
** Vulvitis may be seen in psoriasis, eczema and allergic dermatitis
Prone to skin infections because of constant exposure to moisture and secretions

** Nonspecific vulvitis is common in:
blood dyscrasias
uremia
diabetes mellitus
malnutrition
avitaminoses

Note: Most skin cysts and tumors can also occur in the vulva

** Vulval disease may fall into the following categories:
Cysts
Infections/inflammatory conditions
Non-neoplastic epithelial disorders (Chronic vulvar dystrophies)
Neoplasms

Cysts
** Vulval cysts may be epidermal or dermal in origin
May be developmental or acquired
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** Cysts and abscesses of the Bartholins glands are relatively common
Bartholins cysts result from obstruction of the Bartholin duct, usually by a preceding infection
Cyst is lined by transitional epithelium of the normal duct or squamous metaplasia
Acute inflammation of the gland (adenitis) may result in a Bartholin abscess
Cysts form secondary to duct obstruction often duct chronic inflammation and scarring
Secondary infection leads to abscess formation

Infectious Inflammatory Conditions
Sexually Transmitted Infections
Granuloma inguinale
Lymphogranuloma venereum
Syphilis
Herpes simplex virus
HPV
Non- STIs
Crohns disease
Miscellaneous bacterial and fungal infections

Granuloma Inguinale (Donovanosis)

Chronic inflammatory disease caused by Calymmatobacterium donovani
C. donovani is an encapsulated cocobacillus that is sexually transmitted
Untreated cases are characterized by development of extensive scarring
The scarring is often associated with lymphatic obstruction and lymphedema (elephantiasis - of the
external genitalia)
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The bacteria cause lesions which vary from painless papules to ulcerating, necrotic granulating
lesions
Inflammatory infiltrate is rich in macrophages and plasma cells

Usually begins as a raised, papular lesion involving the moist stratified squamous epithelium of the
genitalia
The lesion eventually undergoes ulceration along with the development of granulation tissue
Appears as a soft, painless mass and as the lesions enlarges its borders become raised and
indurated

Note: Regional lymph nodes are usually spared or show non-specific reactive changes unlike
chancroid
Special staining with Giemsa or silver stains shows the organisms as Donovan bodies and may be
seen extracellular and within macrophages
Donovan bodies are darkly staining, ovoid organisms with/without a capsule
Abscess formation on the groin mimics lymphadenitisis but the lymph nodes are rarely involved

** Described as a chronically progressive, ulcerative disease with no systemic symptoms
Incubation period = 3- 30 days
Present usually with a non-suppurative genital lesion

** Less common presentations include:
Vaginal bleeding or discharge
Hematochezia - the passage of maroon colored stool
Hematuria
Pelvic inflammatory disease
Pelvic mass

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** Left untreated, possible sequelae include:
Genital adhesions
Stenosis of the urethral, vaginal or anal orifices
Rectovaginal fistulas
Lymphatic obstruction with genital pseudoelephantiasis

Treatment:
Bactrim 2 tablets q12h
Doxycycleine 100mg q12h
Tetracycline or erythromycin 500 mg q6h
Choramphenicol 500 mg q8h
Clindamycin, fluoroquinolones and gentamicin are also effective

Note: Antibiotics should be continued until all the lesions have resolved

Lymphogranuloma Venereum (LGV)
** LGV is a STD caused by the 3 serovars of Chlamydia trachomatis (L1, L2, L3)
Causes a chronic, ulcerative disease
Sporadic disease in the US and Western Europe
Endemic in parts of Asia, Africa, Caribbean and South America
Infection initially manifested by a small papule on the genial mucosa or nearby skin

Note: Men are 6 times more likely than women to have a clinically evident infection and are only
infectious until the primary ulcer heals
Women may harbor persistent asymptomatic cervical lesions that serve as reservoirs of infection
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** LGV is acquired sexually through direct contact with infected tissues or fomites
Perinatal infection occurs as infants pass through an infected birth canal
Epithelial abrasions allow the organism to penetrate the mucosal barrier
Replication with the macrophages is followed by spread via the lymphatic system

2-6 weeks after acquisition growth of the organism and the host response in draining lymph nodes
produce swollen, tender lymph nodes
- These nodes may coalesce and rupture
- If left untreated the infection can cause fibrosis and strictures in the anogenital tract
- Rectal strictures are more common in women

** LGV is characterized by inguinal lymph node inflammation and enlargement (buboes). The
disease has three phases giving the following lesions:
Stage I- Small ulcers- usually painless and located at the site of the venereal contact
Appears 3-21 days after inoculation
Women: found on the cervix, posterior vaginal wall, vulva
Men: coronal sulcus

Bartholin gland inflammation- +/- abscess formation
Scarring with fistulae/strictures of urethra, vagina and/or rectum, especially in chronic cases

Note: Scarring may lead to lymphatic obstruction with chronic lymphedema which can cause
elephantiasis of the vulva

** The lesions of LGV contain a mixed granulomatous and neutrophilic inflammatory response
Regional lymphadenopathy is common
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Lymph node involvement is characterized by a granulomatous inflammatory reaction associated
with irregularly shaped foci of necrosis and neutrophilic infiltration (stellate abscesses)
After time the inflammatory reaction is mainly non-specific chronic inflammatory infiltrates and
extensive fibrosis
The histological picture is non-specific and the organisms are not seen histologically
Diagnosis is usually via demonstration of the of the antibodies to the appropriate chlamydial
serotypes

Stage II-
Occurs days to weeks after the primary infection
Characterized by painful regional lymphadenopathy
In women lymph drainage from the rectum and vagina results in pelvic lymphadenopathy
Involvement of these deep nodes causes lower abdominal and back pain
Regional spread of LGV to the pelvis may cause salpingitis, pelvic adhesions and infertility

Stage III- Anorectal stage
- Predominantly seen in women and homosexual men
- Rectal infection may result from anal intercourse, lymphatic spread or spread from vaginal
secretions
- Patients present with fever, rectal pain and mucopurulent or bloody discharge

Note: Conjunctival or oropharyngeal infection may be a result of autoinoculation or orogenital sex
The regional mandibular and cervical lymph node are involved
Subsequent spread to the supraclavicular and mediastinal nodes may cause pericarditis

Syphilis
** Chronic infectious disease transmitted during sexual intercourse and other intimate contact
Vertical transmission in utero or birth
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** Caused by the organism Treponema pallidum
Incubation period averages 21 days with a range of 10-90 days

Primary Syphilis
Characterized by 1 or more ulcerated lesions known as chancres
Chancres are painless papules that usually indurate (become hardened and firmly fixed)
Regional lymphadenopathy develops in the first week

Secondary Syphilis
Begins 2-8 weeks after the appearance of a chancre
Skin rash- maculopapular
Condyloma lata occurs- white, warty skin lesions associated with secondary syphilis
Condyloma lata are plaque-like lesions represented by epithelial proliferation and a plasma cell rich
mononuclear inflammatory infiltrate

Constitutional symptoms: low grade fever, malaise, pharyngitis, laryngitis, anorexia, weight loss,
arthalgias and generalized painless lymphadenopathy

Tertiary Syphilis- rarely affects the vulva

Herpes Simplex Virus (HSV) Infection
Infection caused by HSV type II that results in the formation of painful vesicles
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Secondary ulceration with infection

** Histological examination demonstrates cytopathic effects of the virus that include:
Nuclear homogenization- ground glass appearance
Multinucleation with intranuclear inclusion bodies
Herpes vulvitis- inflammation of the vulva caused by the HSV
Human Papillomavirus (HPV) Infection

Vulva: Neoplasms

Benign Tumors
Include benign skin adnexal tumors, haemangiomas, lipomas
** Benign raised or wart like (verrucous) conditions of the vulva occurs in 3 forms:
Condyloma acuminatum- papillomavirus-induced squamous lesion also known as venereal warts
Mucosal polyps- Benign stromal proliferations covered with squamous epithelium
Syphilitc condyloma latum

Condylomata acuminata
Anogenital warts
Benign sexually transmitted neoplasm (papillomas) caused by HPV (Types 6 + 11)
Have a verrucoous appearance

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Usually multiple and often coalesce
Involve the perineal, vulvar and perianal regions as well as the vagina and sometimes the cervix

** The histological appearance is a branching, tree like proliferation of a stratified squamous
epithelium supported by a fibrous stroma

** Other features include:
Acanthosis
Parakeratosis
Hyperkeratosis
Koilocytosis- nuclear Atypia in the surface cells with perinuclear vacuolization

** The virus life cycle is complete in the mature superficial cells of the epithelium
The dependence of viral growth on squamous maturation produces a distinct cytologic change in
the mature cells known as koilocytotic atypia

Treatment: Local ablation
Surgical removal
Cryosurgery
Electrocoagulation

Malignant Lesions
** Carcinoma of the vulva is an uncommon malignancy. However 85% of these are squamous cell
carcinomas

** Vulvar squamous cell carcinomas can be divided into 2 general groups:
Group 1- Associated with cancer-related (high risk) HPV
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Usually co-exists with or is preceded by a precancerous change called vulvar intraepithelial
neoplasia
VIN (Vulvar intraepithelial neoplasia) is characterized by nuclear atypia in the epithelial cells,
increased mitoses and a lack of surface differentiation

Group II- Associated with squamous cell hyperplasia and lichen sclerosus
This group of carcinomas is not usually associated with HPV
Lichen sclerosus- a condition that creates patchy, white skin that is thinner than normal. Most often
involves skin of the vulva, foreskin (penis) or skin around the anus

** Squamous cell carcinoma may be in situ or invasive. There are 3 types of vulvar intraepithelial
neoplasia that are related to in situ squamous proliferations of the vulva
VIN- (mild dysplasia)- is diagnosed when the lower 1/3 of the epidermis is replaced by the
malignant squamous cells
VIN II (moderate dysplasia)- makes up malignant cells in more than 2/3rds (to the full thickness)
of the epidermis

Note: Features of HPV infection may be superimposed on VIN especially in younger women

** Invasive squamous cell carcinoma accounts for more than 90% of all vulvar malignancies
Over 90% of the patients are post-menopausal and >60 years old
The lesion usually begins on the labia majora and is slow growing
Tends to grow in a destructive, infiltrating manner with ulceration
Inguinal lymph nodes are the commonest site of metastases
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The lesions may be multifocal and may be associated with malignancies elsewhere in the genital
tract, especially the cervix.
There is a strong association with HPV infection and VIN changes may often be seen
adjacent to the frank carcinoma.
Treatment is usually surgical +/- radiotherapy, and prognosis is related to the presence or
absence of lymph node involvement; 5-year survival is 70-80% with negative nodes and 40-50%
with positive nodes.
Mortality increases with the number of lymph nodes involved by tumor, bilateral
involvement of groin nodes and metastases to pelvic lymph nodes

Metastases to the vulva do occur, and are usually seen in advanced carcinoma of the genital tract,
most commonly of the cervix.

Vaginal Pathology

** Most benign vaginal lesions are uncommon. The only clinically significant benign lesion is vaginal
adenosis
Metaplastic foci of endocervical glandular type epithelium in the normal squamous epithelium
These patients have an increased risk of clear cell adenocarcinoma

** Malignancies of the vagina include:
Squamous cell carcinoma
Adenocarcinoma
Rhabdomyosarcoma (sarcoma botryoids)
Malignant melanoma
Metastatic carcinoma

** Squamous cell carcinoma- makes up over 90% of vaginal malignancies
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Most represent extension from cervical cancers
Therefore true primary vaginal squamous cell carcinomas are rare

** Adenocarcinomas are rare. But increased frequency of clear cell adenocarcinoma in young
women whose mothers have been treated with diethylstilbestrol (DES) during pregnancy

** Rhabdomyosarcoma (sarcoma botryoides) is a are malignancy of infants and children ( <5
years old)
The lesion presents as polypoid masses that resemble grapes
Tumor consists mainly of malignant embryonal rhabdomyoblasts
Tumor tends to grow as polypoid, bulky masses that project out of the vagina
Tumor cells in the deeper regions lien in a loose fibromyxomatous stroma that is edematous and
may contain many inflammatory cells
Therefore the lesions may be mistaken for benign inflammatory polyps leading to delays in
diagnosis and treatment
Tumor tends to invade locally and cause death by penetration into the peritoneal cavity or
obstruction of the urinary tract

Note: Prognosis has improved due to treatment with surgery and multi agent chemotherapy

** Metastatic carcinoma- originates from genital and pelvic organs such as the cervix, ovary,
endometrium, rectum and kidney

CERVIX
** The main disease of the cervix uteri include the following:
Inflammation
Polyps
Carcinoma

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Inflammation: Acute
** Acute cervicitis may be caused by non-specific bacterial infection
Can also arise secondary to specific sexually transmitted diseases
EX: gonorrhea, herpes, Trichomonas, Chlamydia

** At the onset of menarche, the production of estrogens by the ovary stimulates maturation
(glycogen uptake) of cervical and vaginal squamous mucosa
As these cells are shed the glycogen provides a substrate for endogenous vaginal aerobes,
anaerobes, streptococci, enterococci, E. coli and staphylococci
The exposed endocervix is sensitive to the changes in the chemical environment and bacterial flora

Chronic Inflammation
** Chronic cervicitis is common in older women. The exposed endocervix is sensitive to the changes
in the chemical environment and bacterial flora
Undergoes a variety of changes that include proliferation of reserve cells that lead to squamous
metaplasia
The process of transformation from columnar to squamous lining is sped up by trauma and other
infections
Therefore squamous metaplasia of the endocervical epithelium (mucin-secreting columnar type)
accompanies chronic inflammation

** The inflammatory process may lead to occlusion of the endocervical glands
Note: These glands are crypts and not true glands
The occlusion leads to retention of secretions, dilatation and formation of cysts
These cysts are known as Nabothian cysts and are seen clinically as Nabothian follicles

Endocervical Polyps
Overgrown folds of endocervical mucosa
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Relative benign inflammatory tumors that occur in 2-5% of adult women
Contain cystically dilated glands in a vascular fibrous stroma
The polyps can result in irregular vaginal bleeding
These polyps are not premalignant

Carcinoma

Cancer of the cervix is thought to begin in a single cell (or clone of cells) at the squamocolumnar
transformation zone (TZ).
Cervical cancer has two phases:
Pre-invasive disease (Cervical Intraepithelial Neoplasia)
Invasive disease.
Note: The lesion may exist in the non-invasive stage for as long as 20 years and ahead abnormal
cells that can be detected on cytologic exam

MBBS/DDS 2K16
Lecture 2: Pathology of Female Genitalia I: Corpus Uteri


Endometrium
Clinical Considerations
Perhaps the commonest reason why women visit doctors worldwide is abnormal uterine bleeding,
whether this is in the form of excessive or prolonged bleeding at the time of the period
(menorrhagia), irregular periods or intermenstrual bleeding.
The conditions described in this lecture may all cause these problems to a lesser or greater extent.
In the investigation of abnormal uterine bleeding, the endometrial biopsy or curettage is a common
diagnostic procedure, and quite often will yield the specimen that is seen by the pathologist and
diagnosed as one of the diseases discussed below.
It must be noted, however, that quite often patients will have uterine bleeding that is not due to a
demonstrable pathological lesion within the female genital tract.
This is known as dysfunctional uterine bleeding (DUB) - uterine bleeding that is not due to a
demonstrable pathological lesion within the female genital tract.
Most often, this is due to endocrine abnormalities usually due to some disturbance of the
hypothalamic-pituitary-ovarian axis). This leads to irregularities of the proliferative and/or
secretory phases of the endometrial cycle often due to anovulation (failure to ovulate or to
ovulate regularly).
DUB will not be discussed in this lecture, and the endometrial diseases that will be discussed will
fall under the following headings:
Inflammation
Polyps
Endometriosis
Hyperplasia
Neoplasms
Inflammation
Endometritis

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** The endometrium and myometrium are relatively resistant to infections
Because the endocervix normally forms a barrier to ascending infection
Inflammation
Acute Endometritis is rare and limited to bacterial infections that arise after delivery and
miscarriage.
Bacterial infection with a variety of organisms including group A hemolytic streptococcus, staph,
E.Coli or pseudomonas.
It most commonly follows an abortion or delivery especially when fragments of placenta or
membranes are retained in the uterus.
The pathological picture is one of typical acute inflammation.
However the inflammatory response is limited mainly to the interstitium and is usually non-specific
Chronic Endometritis may be specific or non-specific.
It is defined as the presence of plasma cells in chronically inflamed endometrial tissue.
** Chronic inflammation of the endometrium occurs in the following settings:
Chronic PID
Post-partal or post-abortal endometrial cavities- usually due to retained gestational tissue
Patients with intrauterine contraceptive devices
Patients with tuberculosis- from military spread or from drainage of tuberculous salpingitis

** Specific inflammation is uncommon and is nearly always secondary to tuberculosis.
It usually is a complication of tuberculous salpingitis
. Other specific inflammatory diseases include actinomycosis, toxoplasmosis and cytomegalovirus.
These diseases are relatively rare.
Note: Chlamydia is commonly associated with both acute and chronic inflammatory cell infiltrates
- Antibiotics is indicated because it may prevent other sequelae such as salpingitis
Polyps
** Endometrial polyps are masses of variable size that project into the endometrial cavity
May be single or multiple
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Usually about 0.5 to 3cm in diameter
They are non-neoplastic lesions that arise from the endometrium
Form as a result of focal overgrowth of the endometrium

** Polyps may be asymptomatic or may cause abnormal bleeding if they ulcerate or undergo
necrosis
** There are two histologic types made up of:
Functional Endometrium- paralleling the adjacent cycling endometrium
Hyperplastic Endometrium- usually of the cystic variety
These polyps develop in association with generalized endometrial hyperplasia
They are responsive to the growth effect of estrogen
BUT display no progesterone response
Rarely: adenocarcinomas may arise within endometrial polyps

Note: Endometrial polyps have been observed in association with the administration of tamoxifen

** Endometrial polyps are relatively common, tend to occur in peri- and post-menopausal women,
Composed of a variable admixture of endometrial glands (sometimes cystic) and stroma, and are
Readily removed by curettage.
Malignancy arising in endometrial polyps is rare.
Endometrial polyp, gross
Endometrial polyp, histology 1
Endometrial polyp, histology 2

Endometriosis
** Endometriosis- describes the presence of endometrial glands or stroma in abnormal (ectopic)
locations outside the uterus
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** Occurs in the following sites in descending order of frequency:
Ovaries
Uterine ligaments
Rectovaginal septum
Pelvic peritoneum
Laparotomy scars
Rare locations: umbilicus, vagina, vulva, appendix

** Endometriosis affects 5-10% of women and regresses after menopause

** These ectopic foci bleed, like normal endometrium, during the menstrual period
Therefore they respond to the extrinsic cyclic (ovarian) and intrinsic hormonal stimulation with
periodic bleeding

** The bleeding may result in hemorrhagic and fibrotic masses
May cause extensive fibrous adhesions between tubes, ovaries and other structures
This may obliterate the pouch of Douglas

Complications: pelvic pain, dysmenorrhoea, infertility and ectopic pregnancy
Pain on defecation indicates rectal wall involvement
Dysuria reflects involvement of the serosa of the bladder

** Three potential explanations exist for the development of the ectopic tissue:
Theory I- Regurgitation/implantation theory- Retrograde menstruation through the fallopian tubes
occurs regularly even in normal women
This could mediate the spread of endometrial tissue to the peritoneal cavity
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Endometriosis is common in the cervical mucosa

Theory II- Metaplastic Theory- Endometrium could arise directly from coelomic epithelium
Theory III- Vascular/lymphatic dissemination theory- Dissemination through pelvic veins and
lymphatics

Endometrial Hyperplasia (Endometrial Intraepithelial Neoplasia)
** Endometrial hyperplasia is another cause of abnormal bleeding
Has a relationship to endometrial carcinoma

This comprises excessive endometrial proliferation and is caused by prolonged, unopposed, relative
or absolute hyperoestrogenism such as is found with:
Persistent failure of ovulation (anovulation)
Polycystic ovaries (including Stein-Leventhal syndrome)
Therapy with exogenous oestrogenic agents- prolonged administration of estrogenic substances
Oestrogen-secreting ovarian tumours
Cortical stroma hyperplasia-

Endometrial hyperplasia is classified as follows:
Simple hyperplasia (formerly called Glandular cystic hyperplasia)-

Complex Hyperplasia- e
Complex hyperplasia (formerly called Adenomatous hyperplasia)
Atypical hyperplasia (formerly called Atypical Adenomatous hyperplasia)

A simple explanation of these processes is as follows:
Oestrogen stimulation causes proliferation of endometrial glands and stroma.
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Glandular proliferation tends to dominate the picture and the glands become elongated and
cystically dilated, but are still separated by relatively abundant stroma.
There is NO cellular atypia.
This type of hyperplasia is known as simple hyperplasia (Histology) and carries a very low risk
(1%) of progression to endometrial adenocarcinoma.

The next phase of hyperplasia is called complex hyperplasia, (Histology) in which:
The glands become markedly tortuous, bud and branch, and become crowded to the point where
they almost touch each other
The lining epithelium of these glands is markedly hyperplastic
Again there is NO significant cellular atypia.
This category of hyperplasia is said to carry a risk of progression to endometrial carcinoma of about
3-10%.

The final stage of hyperplasia is known as atypical hyperplasia (Histology) in which:
There are features of complex hyperplasia with superimposed cytological atypia in the glandular
cells.
There is a high risk of progression to endometrial carcinoma, in the order of about 20 to 30%.
The risk increases with the degree of cellular atypia whether mild, moderate or severe, as well as
with the duration of the disease.
Progression of atypical hyperplasia to carcinoma is a slow and unpredictable process (estimated to
take about 10 years in some studies).

Treatment depends on the type of hyperplasia and the age of the woman. In younger women (say
less than 40 years) who desire preservation of fertility, treatment options for simple and complex
hyperplasia include
progestin administration (to combat the unopposed oestrogen stimulation)
repeated endometrial curettage
induction of ovulation e.g. wedge biopsy of the ovary in Stein-Leventhal syndrome.
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Sometimes, however, young women with atypical hyperplasia may opt for, or be advised to have a
hysterectomy.
Older women may be managed in the same way as the younger ones, but as preservation of fertility
is not usually a consideration, sometimes they may come to hysterectomy more often. In all cases of
atypical hyperplasia, close follow up, usually by endometrial biopsy every 3 or 6 months, is
advocated.

Neoplasms
Endometrial Carcinoma
** Endometrial carcinoma is the most common invasive cancer of the female genital tract
- Accounts for 7% of all invasive cancer in women excluding skin cancer

** A higher frequency of this form of neoplasia is seen with:
i- Obesity
ii- Diabetes- abnormal glucose tolerance is found in more than 60%
iiii- Hypertension
iv- Infertility- women who develop cancer of the endometrium tend to be single and nulliparous
- Also have a history of functional menstrual irregularities consistent with anovulatory cycles

** There are two general groups of endometrial cancer:
1- Group I- develops on a background of prolonged estrogen stimulation
2- Group II- Endometrial hyperplasia

Note: Both hyperplasia and cancer are also linked with obesity and anovulatory cycles
Women with ovarian estrogen-secreting tumors have a higher risk of endometrial cancer
Endometrial cancer is rare in women with ovarian agenesis and in those castrated early in life
Estrogen replacement therapy is associated with increased risk
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A simple classification of endometrial carcinomas is as follows
Adenocarcinoma
Adenocarcinoma with squamous metaplasia
Adenoacanthoma
Adenosquamous carcinoma
Squamous cell carcinoma
Undifferentiated
Metastatic

The vast majority of endometrial cancers are adenocarcinomas.
In the USA and in most Western first world countries, endometrial carcinoma is the commonest
invasive cancer of the female genital tract. The Jamaican Cancer Registry groups all malignancies of
the corpus uteri under one heading, therefore the figures shown will be higher than those for
endometrial carcinoma alone.
Over the period 1958-1987 malignancies of the corpus were ranked 7th in Jamaican women with a
3.7% prevalence. The incidence figures (crude rate per 100,000 per annum) are 6.3 for the period
1978-82, 5.2 for 1983-87, 7.6 for 1988-92, and 7.2 for 1993-97.
It is therefore obvious that in Jamaica, cervical cancer greatly outnumbers endometrial cancer (see
figures for cervix uteri given in those lecture notes).

Etiology
As endometrial carcinoma almost invariably follows on endometrial hyperplasia, it is not surprising
to find that the etiological factor for hyperplasia is that for carcinoma, i.e. unopposed, prolonged
oestrogenic stimulation.

The underlying pathological causes are as previously mentioned under hyperplasia.
Nulliparity and obesity are associated risk factors but are not independent variables
nulliparity may be a function of the high oestrogen levels
while obesity is thought to act by increasing the oestrogen levels via conversion of certain adrenal
hormones peripherally in body fat stores.
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Diabetes and hypertension are also epidemiologically related. It must be noted, however, that in
many women who develop endometrial carcinoma, no obvious precursor pathological conditions
are identified.

Pathology
Adenocarcinoma of the endometrium occurs most commonly in the postmenopausal age group
especially over 50-60 years of age.
The tumour most commonly grows as an exophytic, polypoid lesion protruding into the
endometrial cavity, but is sometimes nodular or plaque-like.
May also presents as a diffuse tumor involving the entire endometrial surface
Spread usually occurs by direct myometrial invasion
Eventual extension to the periuterine structures by direct continuity
Spread into the broad ligaments may create a clinically palpable mass
They often have a prominent papillary configuration.
Endometrial carcinoma, gross; Endometrial carcinoma, gross 2; Endometrial carcinoma, gross 3
Histological grade may be well, moderate or poorly differentiated.
Most commonly, the neoplastic glands resemble the endometrial glands from which they came, and
are therefore referred to as endometrioid carcinomas.
Endometrial carcinoma, histology 1; Endometrial carcinoma, histology 2; Endometrial carcinoma,
histology 3

Adenocarcinomas may show foci of squamous differentiation:
the adenoacanthoma is an adenocarcinoma in which the squamous element is benign
the adenosquamous carcinoma the squamous component is malignant.

In neither tumour does the squamous component affect the behaviour, which is determined by the
grade of the adenocarcinomatous part of the neoplasm.

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Endometrial carcinoma spreads locally at first to invade the myometrium and will eventually
penetrate to involve the pelvic structures.
Extension into cervix and fallopian tubes also occurs.
Metastases occur via lymphatics to pelvic and para-aortic nodes and by blood stream to liver, lung
and bone.
Hematogenous spread occurs late in the course of the disease.

** Endometrial carcinoma may be asymptomatic for periods of time
But usually produces irregular vaginal bleeding with excessive leucorrhea
Leukorrhea- is a thick white vaginal discharge
Cytologic detection on Pap smear is variable and usually associated with serous carcinomas
Serous carcinomas produce easily detached cells clusters that are sampled in pap smears

Note: Other upper genital tract carcinomas (fallopian tube + ovary) are also associated with
abnormal cytology
- Diagnosis of endometrial cancer should be confirmed by curettage and histologic examination of
the tissue

Treatment/Prognosis
Treatment involves a combination of surgery (hysterectomy +/- pelvic lymphadenectomy) with or
without adjunctive radiotherapy.
- Prognosis varies with age, race, stage, and tumour grade.
Age: Younger patients (less than 50 years) do better than older ones. This might be related to the
fact that younger women tend to have better differentiated, less advanced disease.
Race: Black women are said to do worse than white (USA figures). They tend to have worse
differentiated, more advanced disease. (Do social, cultural or economic factors play a role here?).
STAGE: This is the most important prognostic determinant. The 5-year survival for Stage I is 75-
90% while for stage IV it is 10%. The average 5-year survival for all stages is 60 - 65%.

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A simple staging system is as follows:
Stage I - Carcinoma confined to the corpus
Stage II - Carcinoma involving the cervix
Stage III - Carcinoma that has spread outside the uterus but is confined to the pelvis
Stage IV - Carcinoma that has extended outside the true pelvis +/- involves bladder or rectum

Grade: As would be expected, well-differentiated tumours have a better prognosis (stage for stage)
than poorly differentiated ones.
Endometrial Sarcomas
These are relatively rare and are much less common than carcinomas. In the USA they account for
only 3% of uterine malignancies. They may be classified as follows:
(1) Endometrial Stromal Sarcoma
(2) Carcinosarcoma, including Malignant Mixed Mullerian tumour - A proportion of endometrial
adenocarcinomas undergo stromal differentiation
(3) Unclassified Sarcoma
(4) Adenosarcoma- stromal neoplasias that arise in association with benign glands
Note: These tumors comprise less than 5% of endometrial cancers
What all of these neoplasms have in common is a sarcomatous stroma.
The following definitions are important in the understanding of the nomenclature of these
neoplasms:
- A pure endometrial sarcoma is composed of sarcomatous stromal cells only.
- A mixed endometrial sarcoma is composed of a mixture of an epithelial component and a
sarcomatous component.
- If the epithelial component in a mixed endometrial sarcoma is benign, the neoplasm is
called an adenosarcoma.
- If the epithelial component in a mixed endometrial sarcoma is malignant (usually an
adenocarcinoma), the neoplasm is called a carcinosarcoma.
- A homologous sarcomatous stroma resembles the normal endometrial cells of origin.
- A heterologous sarcomatous stroma shows differentiation into malignant tissue not native
to the endometrium e.g. cartilage (chondrosarcoma), striated muscle (rhabdomyosarcoma),
bone (osteosarcoma), fat (liposarcoma) etc.

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The endometrial stromal sarcoma may be pure or mixed (most of them are pure), and the stroma
is invariably homologous.
A carcinosarcoma may have homologous or heterologous sarcomatous stroma.
The variety of carcinosarcoma known traditionally as a malignant mixed mullerian tumour
(MMMT) has a heterologous sarcomatous stroma.

Name of Tumour Epithelial Component Stromal Component
Endometrial Stromal Sarcoma Usually absent Malignant; homologous
Carcinosarcoma, unqualified
Carcinosarcoma, MMMT
Present; malignant
Present; malignant
Malignant; homologous
Malignant; heterologous
Adenosarcoma Present; benign Malignant; homologous or heterologous

As a rule, these neoplasms affect elderly women and are extremely rare in the pre-menopausal age
group.
Typically they present as a large polypoid mass arising from the fundus of the corpus, which fills
and expands the endometrial cavity.
The lesion may protrude through the external os of the cervix.
The tumour is often hemorrhagic and necrotic.
Prognosis is poor and, depending on whether the tumour is confined to the uterus or has spread
beyond, 5-year survival varies between 20-40% at best.
Tumour spread is along similar lines to that of endometrial carcinoma.
It must be noted that the adenosarcoma has a better prognosis than the carcinosarcoma
probably because if the benign nature of its glandular component.
MYOMETRIUM

The myometrial diseases worth mentioning are:
- Adenomyosis
- Neoplasms
o Leiomyoma (benign)
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o Leiomyosarcoma (malignant).

Adenomyosis
This is defined as the presence of ectopic endometrial glands and stroma within the myometrium.
It is a disease that predominantly affects perimenopausal women, and it may cause abnormal
uterine bleeding and/or dysmenorrhoea.

- The uterus is enlarged and the myometrium has a trabeculated appearance. Adenomyosis
gross;
- Adenomyosis, microscopic
** Adenomyosis remains in continuity with the endometrium
- Occurs in 20% of turei
- Microscopy: shows irregular nests of endometrial stroma with or without glands
- Arranged within the myometrium and separated from the basalis
- Hemorrhage within these small adenomyotic nests results in menorrhagia, colicky
dysmenorrheal, dyspareunia, pelvic pain

Leiomyoma
Leiomyomata (leiomyomas) are benign neoplasms commonly known as fibroids.
They are extremely common, are usually multiple and are more common in blacks over whites.
- Each uterine leiomyoma is a unique clonal neoplasm
- Most have normal karyotypes but about 40% have a simple chromosomal abnormality

They may be found in any of three locations in the uterus:
- Submucosal i.e. just beneath the endometrium (may form pedunculated, polypoid masses
within the endometrial cavity)
- Intramural i.e. within the myometrium proper
- Subserosal i.e. just beneath the serosal covering of the uterus (may also become
pedunculated).
Typically, they are circumscribed, lobulated, firm masses of variable size (they may grow quite
large!) with a white, whorled cut surface.
- Demonstrate whorled bundles of smooth muscle cells that resemble the uninvolved
myometrium
-
They may become infarcted with areas of hemorrhage and cystic degeneration, and with time
may show dystrophic calcification. Leiomyomata, gross 1;
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Leiomyomata, gross 2;
Histologically, they comprise interlacing bundles of smooth muscle fibers arranged in whorls.
Leiomyomata, microscopic
They are thought to be, at least in part, hormonally related because they enlarge during pregnancy
and in women on oral contraceptives, and tend to regress after menopause.

They may be asymptomatic but may cause a wide variety of effects including abnormal uterine
bleeding, dysmenorrhea, compressive symptoms in the pelvis
EX:. constipation (due to pressure on the rectum) and frequency of micturition (due to pressure on
the bladder) and infertility.
Malignant change is RARE (less than 0.5%).

Leiomyosarcoma
These are malignant smooth muscle neoplasms, the vast majority of which arise de novo.
- They occur most commonly in the sixth decade, and the gross appearance is usually that of a
large intramural mass with a necrotic, haemorrhagic cut surface.
- Treatment is surgical (hysterectomy) and the prognosis is poor.

** Unlike leiomyomas, leiomyosarcomas have karyotypes that are complex and more random
relative
- Indulce deltions identified on a number of chromosomes that are not seen in the benign
tumors

** Leiomyosarcomas grow within the uterus in two distinctive patterns:
i- Bulky, fleshy masses- that invade the uterine wall
ii- Polypoid masses- that project into the uterine lumen

** Histologic examination show a wide range of atypia
- Vary from well differentiated tumors to anaplastic lesions that have cytologic
abnormalities of wildly growing sarcomas

** These tumors tend to recur after removal. More than half the cases eventually metastasize
through the bloodstream to distant organs
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- Ex: lungs, bone, brain
- Dissemination throughout the abdominal cavity is also found
Well differentiated lesions have a better prognosis than the anaplastic lesions

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Lecture 3: Pathology of Female Genitalia III: Ovary


** The most common types of lesions found in the ovary are:
- Functional or benign cysts
- Tumors
- Inflammation

Inflammation
Primary inflammation of the ovaries is rare
- Ovarian inflammation is most frequently the result of spread from the fallopian tube
- Usually as part of a tubo-ovarian abscess.
- Other causes of peritonitis e.g. appendicitis, diverticulitis, can lead to ovarian involvement.

Non-neoplastic cysts
The majority of these are formed when normal ovarian structures become cystically dilated. They
include:
- Follicular cysts Extremely common; formed by dilated follicles.
They may be single or multiple and usually have little clinical significance, but multiple follicular
cysts may form part of the polycystic ovarian syndrome (PCOS) amenorrhoea, obesity, hirsutism
and infertility; associated with endometrial hyperplasia. (polycystic ovary, gross); polycystic ovary,
gross 2)
[Polycystic ovarian/Stein-Leventhal syndrome is caused by increased ovarian production of
androgens leading to impaired follicular development, which causes persistent anovulation
with development of follicular cysts. Women with PCOS manifest peripheral insulin
resistance, and the resultant hyperinsulinaemia appears to cause a feedback loop by
stimulating ovarian hypersecretion of androgens.]
- Corpus luteum cysts - formed by cystic enlargement of corpora lutea. Contain fluid and
usually, blood. Sometimes these rupture and cause intraperitoneal haemorrhage (not
usually serious). corpus luteum cyst
- Simple cysts are cysts of variable size with flattened epithelial lining. Most are thought to
represent markedly distended follicular cysts.

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- Endometriotic cysts are formed by repeated haemorrhage within endometriotic
deposits.
- These may be multiple and may become quite large, even replacing the entire ovary in some
cases. The cysts contain dark-brown, altered blood giving rise to the classical name of
"chocolate cysts". endometriosis of the ovary.

Neoplasms
Ovarian neoplasms may be primary or secondary (metastatic).
Primary ovarian neoplasms are best classified according to their anatomical site/cell of origin
within the ovary i.e. from
- Surface (germinal) epithelium (approx. 65%)
- Sex cord-stromal cells (approx. 10%)
- Germ cells (approx. 20%)
- Miscellaneous, i.e. tumours not specific to the ovary (approx. 5%)

Surface (germinal) epithelium
This gives rise to a variety of adenomas/carcinomas which are often totally or partly cystic i.e.
cystadenomas/cystadenocarcinomas. They are classified as:
- Serous
- Mucinous
- Endometrioid
- Brenner
- Clear cell
- Undifferentiated

This classification is histological:
- Serous neoplasms are lined by cells resembling those which line the fallopian
tube
- Mucinous ones are lined by cells resembling those which line the cervix
- Endometrioid tumours have a lining that resembles the endometrium.
- Brenner tumours are a bit different but their lining cells resemble those of
urothelium.

Serous tumours
As a group these are the most common ovarian neoplasms, and account for almost 25% of all
ovarian tumours. Most occur in adults.
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- About 30-50% of them are bilateral.

Most of these neoplasms have a prominent cystic component and are therefore commonly termed
cystadenomas or cystadenocarcinomas.
- The benign tumours tend to be predominantly cystic
- The malignant ones tend to be relatively more solid.
- Papillary projections are usually present within the cysts, which tend to be multilocular.

These neoplasms exhibit a spectrum of behaviour benign, intermediate and malignant. At one end
there is the benign serous cystadenoma and at the other is the malignant serous
cystadenocarcinoma.
Malignancy is characterized by epithelial stratification, cellular pleomorphism, high mitotic activity
and stromal invasion.
The intermediate neoplasms are known as borderline tumours or serous tumours of low
malignant potential.

They show all the histological features of malignancy EXCEPT stromal invasion. These represent
low-grade carcinomas and have a good prognosis, similar to that of benign tumours. serous
borderline tumour, gross; serous cystadenocarcinoma, gross; papillary cystadenoca, histology

Mucinous tumours
The classification and behaviour of these neoplasms are analogous to that of their serous
counterparts. They are less common than the serous type and are bilateral in 10-20% of cases.
They can be sub-divided into the benign mucinous cystadenoma, the malignant mucinous
cystadenocarcinoma and the intermediate borderline or mucinous tumour of low malignant
potential.

Mucinous tumours have a predilection for attaining large size and specimens weighing more than
20kg have been recorded. Mucinous cystadenocarcinomas, when they spread to or rupture into the
peritoneal cavity may cause a condition called pseudomyxoma peritonei.

This results when the neoplastic cells that are released into the peritoneal cavity implant and
continue to secrete mucoid material causing the bowel to become matted together. Some mucinous
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tumours of low malignant potential may also cause pseudomyxoma peritonei. mucinous
cystadenoma, histology;
mucinous cystadenocarcinoma, gross
(N.B. Some mucinous ovarian carcinomas represent metastases from the G.I. Tract, e.g.
appendix and colon. This should be excluded before the diagnosis of primary mucinous
carcinoma is made).

Endometrioid tumours
They may be sub-divided in similar fashion to those above, but the majority tends to be malignant.
These carcinomas resemble endometrial carcinomas histologically, and some patients also have
associated endometrial hyperplasia or endometrial adenocarcinoma.

Clear cell tumours
These are variants of endometrioid carcinoma. These are lined by cells with clear cytoplasm filled
with glycogen. Most are malignant. Benign and borderline counterparts are rare.

Brenner tumours
These are relatively uncommon representing 1 -2% of ovarian tumours. They tend to be
predominantly solid with cystic formations within the tumour. Most Brenner tumours are benign.
Malignant forms are extremely rare.

Sex Cord-Stromal Tumours
These arise from the specialized (hormonally active) cells of the ovary and include:
- Granulosa cell tumour
- Thecoma/Fibroma
- Sertoli-Leydig cell tumour

Granulosa cell tumours
May occur at any age but peak incidence is in the postmenopausal age group. They are usually
unilateral, and between 25 and 75% of these tumours produce excessive amounts of oestrogen,
which may cause:
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Precocious puberty in children
Menstrual irregularities (endometrial hyperplasia) in adults
Postmenopausal bleeding in older women.
They are partly cystic, partly solid masses and are considered to be potentially malignant, even
though many will behave in a relatively benign fashion. Occasionally, high-grade malignant
varieties do occur.

Thecoma/Fibromas
These are related in that they are both thought to originate from the theca cell that forms
hormonally active cells on the one hand and fibrous tissue on the other.

The thecoma is usually solid and firm, and may produce oestrogens with effects similar to those
mentioned above. A few produce androgens. They are nearly always benign.

The fibroma is also solid, invariably benign and is sometimes associated with ascites and a right-
sided pleural effusion (Meigs' syndrome). fibroma, gross

Sertoli-Leydig cell tumour
These tumours are composed of an admixture of cells resembling the Sertoli and Leydig cells of the
testis. They are predominantly solid and are usually found in young adults.
Nearly a half manifests signs of excess androgen secretion,
- Represented by masculinization (virilization) clitoral hypertrophy, deepening of the voice,
hirsutism etc.
- Like the granulosa cell tumours, most of these tumours tend to behave like low-grade
malignancies, but occasional high-grade lesions occur.

Germ Cell Tumours
These constitute about 20% of all ovarian tumours and are the most common ovarian tumour in
girls and young women.
They may be classified as follows:
- Dysgerminoma
- Yolk sac tumour (endodermal sinus tumour; embryonal carcinoma)
- Choriocarcinoma
- Teratoma
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Dysgerminoma
These are the equivalent of the testicular seminoma, i.e. the malignant cell is derived from the
primordial germ cells. They are all malignant, but fortunately, respond well to radiotherapy with up
to 95% 5-year survival rate in those confined to the ovary after treatment with surgery and
radiotherapy.

Yolk sac tumour (endodermal sinus tumour; embryonal carcinoma)
These names are often used interchangeably and represent tumours with a primitive microscopic
appearance recapitulating early yolk sac/placental development. They are highly malignant
tumours. They produce alpha-fetoprotein.

Choriocarcinoma
Primary ovarian choriocarcinomas are rare. Most represent metastases from uterine tumours.

Teratoma
The most common germ cell tumour is the benign cystic teratoma or dermoid cyst (constitute up
to 95% of germ cell tumours). These are multilocular or unilocular cysts containing cheesy or
porridge-like sebaceous material with matted hair. Sometimes cartilage, bone and/or teeth may be
seen in the wall on gross examination. Tissues from all three germ cell layers are represented
histologically though ectodermal components tend to predominate.

The cyst is usually lined by skin with sweat and sebaceous glands; tissues derived from mesoderm
and endoderm e.g. bone, cartilage, smooth muscle, fat etc are usually represented. All of these
tissues are benign or "mature". Sometimes thyroid tissue predominates to the virtual exclusion of
other components - a variant called "struma ovarii". The tissue may be functional and may even
lead to hyperthyroidism in some cases. dermoid cyst, gross;
dermoid cyst, gross 2

Solid teratomas are invariably malignant and are also known as "immature teratomas". Malignancy
is diagnosed not by the classical features of anaplasia as seen in most other malignant neoplasms,
but by the presence of immature tissues in the neoplasm, usually immature neuroepithelium.
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Miscellaneous (Tumours not specific to the ovary)
These include lymphoma, leukaemia, leiomyomas/leiomyosarcomas, miscellaneous sarcomas,
haemangioma etc. These are relatively uncommon compared to the other types of tumours
previously discussed. Lymphomas of the ovary usually represent ovarian involvement by
generalized lymphoma.

Secondary (Metastatic) Tumours
The ovary is a common site of involvement. The most common primary sources in general are the
stomach, large bowel, appendix, breast, lung and corpus and cervix uteri. The eponymous
Krukenberg tumour is a classic type of metastatic ovarian carcinoma that is usually bilateral,
solid, multinodular, and which microscopically shows a diffuse infiltration of mucin-containing
signet ring cells. The usual primary sources for this type of tumour are the stomach, large bowel
and breast. Cancer metastatic to the ovary usually connotes a poor prognosis.
krukenberg tumour, gross; krukenberg tumour, gross 2

General Features of Ovarian Tumours

In the USA, ovarian cancers account for the greatest number of deaths from gynaecological
malignancies and cause more deaths than do cancer of the cervix and corpus combined.
Figures from the Jamaican Cancer Registry (JCR) show a prevalence rate of 4.2% for ovarian cancer
between 1958 and 1987, making it the 6
th
most common female cancer behindin decreasing
order of frequencybreast, cervix (invasive), stomach, skin aand colon over that period.. The latest
report from the JCR, covering the period 1998-2002, shows a crude incidence rate per 100,000 of
3.5 with a rank of 9
th
most common female malignancy.

Ovarian tumours may present as:
- Incidental findings as an abdominal/pelvic mass
- Abdominal enlargement
- Abdominal pain (may be severe if the tumour/cyst has undergone torsion and infarction)
- Symptoms/signs of tumour metastases e.g. ascites, weight loss, lung/pleural metastases etc.
- Symptoms/signs related to hormonal secretion e.g. menstrual irregularities, virilization,
precocious puberty etc.
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Prognosis is related to the type of tumour, the degree of differentiation and the stage.
Tumours of low malignant potential (borderline tumours) have excellent prognosis even when
there is spread beyond the ovary.
In frank carcinomas, tumour grade correlates closely with survival.

Treatment is usually surgical with post-operative radiotherapy and chemotherapy in some cases,
especially for high-grade neoplasms. This type of combination therapy has improved the prognosis
dramatically over the past few years even in some aggressive germ cell tumours.
CTE/cte/June 2009

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Lecture 4: Pregnancy: Fetus & Placenta

Lecturer: Dr. S. Kulikami

** At 30-32 days the embryo has 22 pairs of somites with three pharyngeal arches
** During the 4
th
to 8
th
weeks all major organs an systems of the body form from 3 germ layers
- The 43 day embryo is implanted within the uterus with the thick umbilical cord
- 53 day embryo with a visualized chondroskeleton

** The fetal period is from the 9
th
week of pregnancy to birth
- 13 weeks in the early second trimester the fetus appears human
- Crown to rump length is 45 mm
- 21 weeks fetus- shows obvious human features and weighs about 220 g

Importance of Fetal Development
** Important to know the normal process of fetal development to then appreciate the abnormalities

1- Birth Defects- Causes, prenatal diagnosis, prevention and possible treatment
2- Growth Problems- too small, too large
3- Problems during delivery and after birth

** At the beginning of the 9
th
week, the head makes up half the crown-heel length of the fetus
- Eyes are widely separated and eyelids are fused

** At the end of the 12 weeks primary ossification centers appear in the skeleton, especially in the
skull and long bones

Placenta
** The placenta is the primary site of nutrient and gas exchange between the mother and fetus. The
placenta has two components:
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i- Fetal Part- that develops from the chorionic sac
ii- Maternal Part- that is derived from the endometrium

** The placenta and umbilical cord form a transport system for substances passing between the
mother and fetus
- Nutrients and oxygen pass from the maternal blood through the placenta to the fetal blood
- Waste materials and carbon dioxide pass from the fetal blood through the placenta to the
maternal blood

** The placenta and fetal membranes perform the following functions and activities:
- Protection
- Nutrition
- Respiration- respiratory function
- Excretion
- Hormone production
- Production of enzymes
- Production of pregnancy associated plasma proteins (PAPP)
- Barrier function
- Endocrine function

** The deciduas refers to the endometrium; the functional layer of the endometrium in a pregnant
woman
** The 3 regions of the deciduas are named according to their relation to the implantation site:

1- Decidua basalis- part of the endometrium deep to the conceptus that forms the maternal
part of the placenta
2- Decidua capsularis- superficial part of the deciduas overlying the conceptus
3- Decidua parietalis- all the remaining parts of the deciduas

** Chorionic villi cover the entire chorionic sac until the beginning of the 8
th
week
- As the sac grows, the villi associated with the decidua capsularis are compressed, reducing
the blood supply to them
- These villi degenerate and produce a relatively avascular are the smooth chorion
- The villi associated with the decidua basalis rapidly increase in number and branch to
form the villous chorion

** The fetal part of the placenta is formed by the villous chorion. The chorionic villi project into
the intervillous space containing maternal blood
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** The maternal part of the placenta is formed by the decidua basalis

Placenta Anatomy at Term
- Discoid in shape
- 15-20 cm in diameter
- 500 gm
- Thickness= 2.5 cm at its center and gradually tapers towards the periphery
- Position: In the upper uterine segment (99.5%)
- Usually in the posterior surface (2/3)) or the anterior (1/3) surface

Fetal Surface
- Smooth, glistening surface
- Covered by the amnion which is reflected on the cord
- The umbilical cord is inserted near or at the center of this surface
- Radiating branches can be seen beneath the amnion
- The chorionic vessels radiating to and from the umbilical cord are clearly visible through
the transparent amnion
- The umbilical vessels branch on the fetal surface to form chorionic vessels that enter the
chorionic villi and form the arteriocapillary-venous system

Maternal Surface
- Dull, grey-red in color
- Divided into 15-20 cotyledons
- Each cotyledon is formed of the branches of one main villus stem covered by decisua
basalis

** Cotyledons are bulging villous areas that are separated by grooves that were formly occupied by
placental septa

Umbilical Cord
- Develops from the connecting stalk
- At term the cord is about 50 cm in length
- Diameter is 2 cm
- Consist of mesodermal connective tissue known as Whartons Jelly
- Described as an intercellular ground substance
- Covered by amnion

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** The umbilical cord contains:
1- One umbilical vein- that carries oxygenated blood from the placenta to the fetus
2- Two umbilical arteries that carry deoxygenated blood from the fetus to the placenta
3- Remnants of the yolk sac and allantois

** The umbilical cord is attached to the placenta usually near the center of the fetal surface
- This is known as eccentric insertion (70%)
- Insertion at the center is known as central insertion (30%)
- Battledore Placenta- insertion of the cord at the placental margin

Amniotic Fluid

** The amnion forms a fluid filled membranous amniotic sac that surrounds the embryo and the
fetus
- Amniotic fluid plays a role in fetal growth and development
- Most amniotic fluid is derived from maternal tissue by diffusion across the amniochorionic
membrane from the decidua parietalis
- Before keratinization of the skin occurs the skin acts as a major pathway for the passage of
water and solutes in tissue fluid from the fetus to the amniotic cavity

** In the 11
th
week the fetus contributes to the amniotic fluid by excreting urine into the amniotic
cavity
- The volume of amniotic fluid normally increases slowly reaching about
- 30 ml at 10 weeks
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- 350 ml at 20 weeks
- 700 to 1000 ml by 37 weeks

Circulation of Amniotic Fluid
** The water content of amniotic fluid changes every 3 hours.
- Large amounts of water pass through the amniochorionic membrane into the maternal
tissue fluid and enter the uterine capillaries
- An exchange of fluid with fetal blood also occurs through the umbilical cord and where the
amnion adheres to the chorionic plate on the fetal surface of the placenta
- Therefore amniotic fluid is in balance with the fetal circulation

** Amniotic fluid is swallowed by the fetus and absorbed by the fetuss respiratory and digestive
tracts
- The fluid passes into the fetal blood stream
- The waste products in it cross the placental membrane and enter the maternal blood in
the intervillous space
- Excess water in the fetal blood is excreted by the fetal kidneys and returned to the
amniotic sac through the fetal urinary tract

** Large volumes of amniotic fluid move in both directions between the fetal and maternal
circulations
- Mainly through the placental membrane
- Most fluid passes into the GI tract but some passes into the lungs
- Therefore the fluid is absorbed and enters the fetal circulation
- Then passes into the maternal circulation through the placental membrane

Fetal Circulation
** Oxygenated blood returns from the placenta in the umbilical vein
- At the liver the blood enters the ductus venosus
- The ductus venosus connects the umbilical vein to the IVC
- Therefore half the oxygenated blood bypasses the liver

** The other half of the blood in the umbilical vein flows into the sinusoids of the liver and enters
the IVC through the hepatic veins
- From the IVC the blood enters the right atrium of the heart
- The IVC contains poorly oxygenated blood from the lower limbs, abdomen and pelvis
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- Most of the blood from the IVC is directed by the inferior border of the septum secundum
through the foramen ovale into the left atrium
- In the left atrium it mixes with the poorly oxygenated blood returning form the lungs
through the pulmonary veins
- From the left atrium the blood passes to the left ventricle and leaves through the ascending
aorta

** The ductus arteriosus

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Lecture 5: The Climacteric

Lecturer: Dr. L. Christie

** The climacteric encompasses the entire change from ovulatory cycles to the cessation of
menses
- Transition from reproductive to non-reproductive state
- Includes immediate pre-menopausal, peri-menopausal and postmenopausal women

** The menopause is one event in the whole range of anatomical, physiological and psychological
events that contribute to the climacteric

** The change that occurs in the transition between fertility and infertility includes a wide variety
of symptoms, signs and metabolic adjustments
- The ultimate cause of which is a major reduction in the level of circulating estrogen

Menopause
** Menopause is the permanent cessation of menstruation
** A natural menopause is considered to have occurred after 6 months of secondary amenorrhea
in a woman aged 45 years and over

** Menopause occurs after 12 consecutive months of amenorrhea for which there is no other
pathologic or physiologic cause
- Due to loss of ovarian follicular activity or follicle depletion

Menstrual Cycle Physiology
** By 16 weeks in utero, 6-7 million primordial follicles exist
- These represent the maximal oocytes in a females lifetime
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** The oocytes grow and undergo atresia in intra + extrauterine life during infancy, pregnancy,
ovulation or anovulation until peri-menopause
- At birth there are 2 million and 300,000 by puberty
- The process is not affected by drugs such as OCPs

** The number of follicles in the ovary determines the age at which the menopause takes place
- The decline continues steadily until approximately age 40
- Thereafter, declines more rapidly until after the menopause

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Physiology of the Climacteric
** The human ovary consists of an outer cortex containing follicles at various stages of
development
- Also contains a central medulla which is heavily vascularized

** Both cortex and medulla contain stroma of mesenchymal origin
- Stromal cells are recruited to form thecal cells which surround the follicles

** The cells of the developing follicles produce the majority of the estrogen circulating in the
plasma of pre-menopausal m=women
- Synthesis of the estrogen is mainly from aromatization of androstenedione and
testosterone in the granulosa cells
- The androgen to estrogen conversion is catalyzed by the aromatase enzyme cascade and
promoted by FSH

** Theca cells also produce estrogen from androgens whose elaboration from cholesterol is
stimulated by LH

** The first sign of approaching menopause is a decline in fertility. The first endocrine change is a
fall in inhibin production by the ovary
- Inhibin inhibits the production of FSH by the anterior pituitary
- Therefore this loss of inhibition causes plasma FSH levels to rise

** With age the ovarian follicle stores are depleted and ovarian function is diminished
- Estrogen decreases
- The pituitary attempts to stimulate the ovary to produce more estrogen by increasing levels
of FSH to stimulate growth
- Anovulation occurs with longer periods and irregular bleeding

** Estrogen receptors are present in many tissues throughout the female body:
- Urogenital tract
- Breasts
- Bones
- Skin
- Connective tissue
- Cardiovascular system
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- Liver
- CNS

** Because of the variety of estrogen receptors, there are wide ranges of climacteric symptoms

** The hormonal changes do not stop suddenly when a woman reaches menopause. There is
instead a gradual change in hormone levels

1- FSH + LH levels increase 2-3 years before menopause

2- E2 levels decline about 6 months before menopause

3- After menopause (total follicular depletion)- FSH and LH levels continue to rise and peak 1-
3 years after menopause
- X 20 increase in FSH
- X 3 increase in LH

4- Androgen levels decrease- because there are decreasing amounts of the theca cells in the
ovary
- Note: in ovulating women, the ovary is the primary source of androgen production
- Adrenal glands, liver, fat, skin also contribute to the production of these androgens
- This androgen decrease contributes to the decreased sexual function in post-menopausal
women

Symptoms & Signs of the Climacteric
** The symptoms of estrogen deficiency (menopausal symptoms) may begin long before the actual
cessation of menstruation

** The symptoms are triggered by a relative fall in circulating E2

1- Menstrual Irregularity- most sensitive clinical indication is the progressively increasing
menstrual irregularities
- Normal Menstrual Cycle- for ovulatory women is 28 +/- 7 days and lasting 5 +/- 2days
- Note: Irregular cycles may occur in 20% of menstruating women
- In the climacteric, there are changes in:
i- Amount or duration of menstrual flow
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ii- Length of the menstrual cycle
iii- Skipped menstrual cycles

** Menstrual irregularity begins several years before menopause. Median age for onset of
climacteric transition is 47.5 years

2- Vasomotor Symptoms- include hot flashes and night sweats
- Occur in at least 70% of perimenopausal women
- Hot flashes are the most common symptoms of menopause (>50% of women)
- Sudden onset of a sensation of heat, sweating and flushing
- Occurs primarily in face and spreads to head, neck and chest
- Lasts 1-5 minutes

- Hot flashes are NOT contemporaneous with LH pulses
- Hot flashes are a vascular response to a central disturbance of the thermoregulatory
center in the hypothalamus
- There is a downshift of the set-point of this center such that there is a frequent central
misapprehension that body temperature is too high
- This leads to activation of the physiological mechanisms: cutaneous flushing + perspiration
- This results in heat loss by radiation and by the loss of the latent heat of vaporization

** The vasomotor symptoms may be associated with chills, clamminess and anxiety
- Night sweats are hot flashes that occur at night usually while a woman is sleeping
- This lack of sleep may correlate with reports of insomnia, fatigue and irritability among
climacteric women
** Increased severities of vasomotor symptoms are associated with:
- Ethnicity- African American + Latin American >> non-Hispanic, Chinese + Japanese women
- Early age of menarche and menopause onset
- History of irregular menses
- Increased BMI
- Social Drugs- alcohol and cigarette use

Note: Vasomotor symptoms usually resolve spontaneously within 5 years
** Theories that decreased estrogen levels alter:
i- CNS Adrenergic Neurotransmission- clonidine is an alpha-adrenergic agonist and
decreases central noradrenaline release. Used to treat vasomotor symptoms
ii- Changes in Serotonergic Neurotransmission- increased sensitivity of hypothalamic
serotonin receptors
- SSRIs that increase central serotonin levels may be effective in the treatment of hot flashes
Note: HRT is the most effective treatment currently available for hot flashes
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- 60-85% average reductions in hot flash frequency

3- Vaginal Dryness- often associated with dyspareunia
- The vaginal skin is dependent on estrogen for the depth and lubrication of its squamous
epithelium
- As estrogen levels decrease, the skin becomes thin and poorly moisturized
- Vaginal dryness leads to urogenital atrophy
- Also changes in the quantity and composition of vaginal secretions

4- Urinary Incontinence- menopausal women often complain of frequency, dysuria + urgency.
These symptoms suggest UTI BUT are not associated with a positive urine culture
- The trigone of the bladder and the proximal urethra both contain estrogen receptors
- Menopause results in atrophy of the urethral mucosa and the trigone (muscles controlling
urination)
- The result is decreased control over bladder function
- Incontinence affects between 26 55% of middle-aged women

5- Psychological Events- the physical symptoms of menopause are partnered by a set of
psychological symptoms
- Depression occurs more frequently in women
- Evidence of a hormonal role exists

i- Development of mood disorders diverge between men and women beginning at
adolescence
ii- Mood disorders linked to the menstrual cycle or pregnancy- post-partum depression or
PMS
iii- E2 + P2 influence levels of CNS neurotransmitters associated with mood- serotonin,
norepinephrine

** In addition significant social events occurring during midlife may also contribute to
psychological symptoms:
- Changing relationships
- Maturing children
- Marital instability or widowhood
- Illness or loss of patients

6- Musculoskeletal Changes- 20% of bone is highly estrogen sensitive and this is mainly
trabecular bone
- These bones are found: vertebrae, distal radius, femoral neck, calcenus
- Estrogen provides a physiological restraint to bone turnover
- Therefore maintains a balance between bone resorption and bone formation
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- The loss of circulating estrogen after menopause results in greater bone resorption than
formation
- Increased risk of bone fractures

** Post-menopausal women are at increased risk for fracture as compared with premenopausal
women and men (of all ages)
- Due to hormone-related bone loss

** Fractures may result in:
- pain
- short term disability
- Hemorrhage
- Thromboemoblic disease
- Shock
- Death

** To prevent fractures, several pharmacologic products are effective:
i- bisphosphanates
ii- parathyroid hormone
iii- Calcium + vitamin D

Note: Non-pharmacologic interventions include: environmental manipulation, and regular exercise
Laboratory Investigations

Serum FSH:
- > 50 IU/ml implies menopause
- Not clinically helpful unless trying to diagnose premature menopause
- Therefore limited clinical value in perimenopausal women
- Levels fluctuate considerably each month depending on whether or not ovulation has
occurred
- Most reliably detected on Day 2 or 3 of the menstrual cycle

Estradiol:
- Can be measured using serum, urine, saliva
- Serum estradiol levels of <50 pg/mL is diagnostic

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Treatment: Hormone Replacement Therapy
- Decreases frequency of hot flashes
- Decreases symptoms associated with vulvo vaginal atrophy
** Therefore HRT effectively relieves the most common menopausal symptoms

Note: The absolute risk for cardiovascular disease and cancer is low when these drugs are used for
short periods of time

** HRT may also be appropriate in the prevention or management of osteoporosis linked directly
to declining serum estrogen levels

** May be administered as:
- Transdermal patch
- Oral
- Topical cream

Note: A topical cream alone may be used if the patient as no hot flashes BUT has vaginal dryness
- In this case there is no need for systemic treatment

** The decision to use HRT depends on:
- Current health status
- Personal health history
- Family health history- of gynecologic cancers and cardiovascular disease

** Benefits are dose related. The lowest dose for the shortest duration should be used
** Women with an intact uterus should be given a progestin combined with estrogen
- Unopposed estrogen would result in unopposed growth, especially of the endometrial lining
- The combination reduces the risk for endometrial cancer and endometrial hyperplasia

Print slide #36 +37 IMPORTANT

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Androgen Levels
** Levels of androgens decrease in menopause. This results in the following:
- Decreased libido
- Decreased sexual response
- Decreased sense of well being
- Poor concentration
- Fatigue

Print Slides #43-44

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Lecture 6: Ovarian Tumours

Lecturer: Dr. S. Mitchell

** Ovarian tumors are common forms of neoplasia in women
- It is the 5
th
most common cancer
- Many of the ovarian neoplasms cannot be detected early in their development
- Therefore ovarian tumors account for a disproportionate number of fatal cancers
- 80% are benign and these occur mostly in younger women (20- 45 years)
- The malignant tumors are more common in older women (40-65 years)

Note: Although only 1 in 8 ovarian tumors are malignant
- Over the age of 55, half the ovarian neoplasms are malignant

** 75% of malignant tumors are epithelial
- The serous type is the most common type of malignant tumor

** 10% of malignant tumors are undifferentiated
** Some are due to rarer causes:
- Sex cord stromal tumors
- Germ cell tumors

** Metastases account for 5% of all ovarian neoplasms. Mets occur from:
- Large intestine
- Stomach- Krukenberg tumor- bilateral ovarian neoplasms usually of gastric origin
- Breast- especially lobular
- Uterus

Risk Factors
1- Nulliparity- because of the incessant ovulation
2- Long fertile period- early menarche and late menopause also sets a stage of continued
ovulation and prolonged exposure to estrogen
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3- Family History- the gene BRCA-1 has been implicated in both breast and ovarian cancers
- Mutations in both BRCA-1 and BRCA-2 increase susceptibility to ovarian cancer
- If a mother had ovarian cancer, her daughters have an increased risk of developing both
breast and ovarian cancers
- If a mother had breast cancer then daughters are at increased risk of developing both breast
and ovarian cancer

4- Gonadal Dysgenesis- in children is associated with ha higher risk of ovarian cancer
- Places the child at risk of the development of ovarian childhood malignancy
- Also the rarely the development of gonadoblastoma

5- Super ovulation Therapy- for infertility may be a predisposing factor **

Protective Factors
1- Anything that interrupts incessant ovulation
i- Pregnancy
ii- Oral contraceptive pill

Clinical
** Most ovarian tumors are benign and non-functional
- Therefore they do not produce clinical effects until they have grown to a large size
- At this time they present with increasing mass or girth
- Because of the length of time take to diagnose, malignant tumors have usually spread
outside the ovary
- Therefore have a poor prognosis

** Abdominal pain and distention, urinary and GI tract symptoms due to compression by tumor
or cancer invasion
- Abdominal and vaginal bleeding are also common symptoms

Types of Ovarian Neoplasm
** All primary neoplasms of the ovary are believed to arise from one of three structures:
i- Surface epithelial cells- derived from either the coelomic epithelium or ectopic
endometrial epithelium
ii- Germ cells
iii- Sex cord stroma

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Surface Epithelium Derived
** Age group affected 20+ years
- Most commonly between 45 and 70
- Often found bilaterally, especially when malignant

** The surface epithelial tumors are derived from wither:
i- Coelomic Epithelium- gives rise to the mullerian epithelium during embryonic
development. From it are derived:
- Fallopian tubes- ciliated columnar serous cells
- Endometrial lining- non-ciliated columnar cells
- Endocervical Glands- mucinous non-ciliated cells

ii- Ectopic endometrial epithelium

Note: Most of the primary neoplasms in the ovary fall are tumors of Mullerian epithelium. There
are 3 major types of these tumors:
i- Serous
ii- Mucinoid
iii- Endometroid- including clear cell

** These neoplasms range in size and composition. Tumors may be small or massive, filling the
pelvis and abdominal cavity

** Components of the tumor may include:
- Cystic areas- cystadenomas
- Cystic + fibrous areas- cystadenofibromas
- Fibrous areas-adenofibromas

Note: On gross examination, the risk of malignancy increases as a function of the amount of
discernable, solid epithelial growth
- Including papillary projections of soft tumor
- Thickened tumor lining the cyst spaces
- Solid, necrotic friable tissue depicting necrosis

Serous Tumors:
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- 30% of all ovarian tumors
- 75% are benign or borderline malignancy
- 25% are malignant- serous cystadenocarcinomas

** Serous tumors are cystic neoplasm lined by tall, columnar, ciliated epithelial cells
- Filled with clear, serous fluid

** The serous cystadenocarcinomas are the most common malignant ovarian tumor
- Tend to occur later in life, than the benign version

** Serous tumors are found on the surface of the ovaries.
- May extend to the peritoneal surface i.e. extension onto the peritoneum

** 25% of benign serous tumors occur bilaterally
- 65% of malignant serous tumors occurs bilaterally
Print slide #20

Histology:
- Cystic neoplasms
- Lined by tall columnar epithelial cells that resemble the lining of the Fallopian tubes
- Tumors of borderline malignancy contain increased complexity of the stromal papillae with
stratification of the epithelium
- Note: Concentric calcifications (psammoma bodies) characterize serous tumors

Mucinous Tumors
** Mucinous tumors resemble serous tumors. However in the gross appearance there are several
differences
** Mucinous tumors are characterized by:
- More cysts of variable size
- Rarity of surface involvement
- Less frequently bilateral
- Tendency to produce larger cystic masses
- Appear grossly as multiloculated tumors filled with sticky, gelatinous fluid rich in
glycoproteins
- Occur principally in middle age

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** Mucinous tumors are cystic tumors consisting of multiple small cysts
- Can grow to large sizes (>25kg)
- Often enlarge without penetrating the capsule
- Therefore they usually present in stage I with torsion, abdominal pain, or mass effect

Histology: Constituent cells are similar to endocervical epithelium
- Most (80%) are benign or borderline
- 10% of benign mucinous tumors occur bilaterally
- 20% of malignant mucinous tumors occur bilaterally
- Lining of tall columnar epithelial cells with apical mucin and NO cilia

Note: A condition associated with mucinous ovarian neoplasms is pseudomyxoma peritonei
** This disorder consists of an ovarian tumor with:
- Extensive mucinous ascites
- Cystic epithelial implants on the peritoneal surfaces
- Adhesions

** Pseudomyxoma peritonei, if extensive, may result in intestinal obstruction and death

Note: Bilateral presentation of mucinous tumors requires exclusion of a non-ovarian origin

Print slide #24

Endometrioid Tumor
- Account for 20% of all ovarian cancers
- Most endometrioid tumors are carcinomas
- Less commonly the benign forms are usually cystadenofibromas

** 25% of endometrioid tumors arise in conjunction with endometrial carcinoma
- BUT not from metastatic spread
- Associated with a relatively good prognoses, which suggests that two tumors have arisen
independently rather than by metastatic spread

** 15% of endometrioid tumors co-exist with endometriosis
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- Possibly a focus of the endometriosis on the ovary precipitates transformation of the
epithelium

** Presents grossly as a combination of solid and cystic areas
- 40% of malignant endometrioid tumors involves bilaterality
- Bilateral involvement usually suggests extension beyond the genital tract in these tumors

Note: Endometrioid tumors are distinguishes from serous

Histology: Resembles endometrial epithelium and contains tubular glands
- The tumor is estrogen-dependent like endometrium

** A sub-type of endometrioid carcinoma is clear cell adenocarcinoma
- Characterized by large epithelial cells with abundant clear cytoplasm
- May occur in association with endometriosis
- Solid Variety- the clear cells are arranged in sheets or tubules
- Cystic Variety- the clear cells line the spaces
- Clear cell adenocarcinoma tends to be aggressive and survival to 5 years is unlikely
- Especially is there is spread beyond the ovary
- > 95% of these tumors are malignant
- The remaining 5% are benign cystadenofibromas

Cystadenofibromas
Variants in which there is more pronounced proliferation of the fibrous stroma that underlies the
columnar lining epithelium
- These benign tumors are usually small and multilocular
- May be composed of mucinous, serous, endometrioid, or transitional epithelium

Brenner Tumor
- Uncommon adenofibromas in which the epithelial components consists of nests of
transitional cells
- Similar to the Wolffian duct epithelium
- These transitional cells resemble the urinary bladder lining
- The nests may contain glandular spaces lined by columnar, mucin-secreting cells
- Benign tumors

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Epithelial Tumors Treatment
** All ovarian epithelial carcinomas produce similar clinical manifestations. Most common
symptoms are:
- Lower abdominal pain
- Abdominal enlargement

Note: GI complains, urinary frequency, dysuria, pelvic pressure and other symptoms may occur

** Benign lesions are easily resected, with cure.
** The malignant forms, tend to cause the progressive weakness, weight loss + cachexia
characteristic of all malignant neoplasms
- If the carcinoma extend through the capsule of the tumor to seed the peritoneal cavity,
massive ascites is common

** The ascitic fluid is filled with diagnostic exfoliated tumor cells
- The peritoneal seeding is distinctive
- Tends to seed all serosal surfaces diffusely
- These surface implants rarely invade deeply into the underlying parenchyma of the organ

** Regional nodes are often involved
- Metastases may be found in liver, lungs, GI tract
- Metastasis across the midline to the opposite ovary is a sign of a worsening prognosis

** Treatment involves the following:
1- Surgery- to remove the tumor bulk
2- Chemotherapy
i- IV cisplatin/carboplatin +/- doxorubicin +/- cyclophosphamide
ii- 6 months treatment

3- Radiotherapy- used in addition to chemotherapy
4- Colloidal Gold- may be used to treat ascites
5- Palliate & Supportive Care- especially debulking, ascites, drainage + pain relief is given if
the tumor extends throughout the peritoneal cavity

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Sex-Cord Stroma Derived
** These tumors are derived from the ovarian stroma. The ovarian stroma is derived from the sex
cords of the embryonic gonad

** The undifferentiated gonadal mesenchyme eventually produces structures of specific cell type
in:
i- Male Gonads- Sertoli + Leydig
ii- Female Gonads- granulosa + theca

** Therefore tumors of all these cell types can be identified in the ovary
** Because some of these cells normally secrete estrogens (theca cells) or androgens (Leydig cells),
their tumors may either be:
- Feminizing- granulosa-theca cell tumors
- Masculinzing- Leydig cell tumors

Clinical Effects
** Clinically the sex-cord stroma derived tumors are hormonally inactive
- Produce abdominal pain and pelvic masses
- 40% are associated with ascites
- Occasionally there is a hydrothorax (usually right sided)

Note: the combination of ovarian tumor, ascites + hydrothorax is known as Meigs Syndrome

Granulosa-Theca Cell Tumors
- Ovarian neoplasms comprised of varying proportions of granulosa and theca cell
differentiation
- These tumors are almost entirely made up of granulosa cells or a mixture of granulosa and
theca cells
- Account for 5% of all ovarian tumors
- They can be discovered at any age
- BUT 66% (2/3rds) occur in post-menopausal women

Note: All the types of granulosa-theca cell tumors have the potential to develop into malignancies

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** Granulosa-theca cells have clinical importance for two reasons:
1- Hormonal production- they have the potential to produce large amounts of estrogen
- May cause precocious puberty in pre-pubertal girls
- May be associated with endometrial hyperplasia and carcinoma and cystic disease of
the breast in adult women
- Occasionally granulosa cell tumors produce androgens and this causes masculinization

2- Risk of Malignancy- in the granulosa cell forms

** Granulosa cell tumors are usually unilateral
- Vary in size from microscopic foci to large, solid and cystic encapsulated masses
- Hormonally active tumors have a yellow coloration produced by lipids

Androblastomas (Sertoli-Leydig Cell Tumors)
- These tumors mimic the cells of the testis at various stages of development
- Found in women of all ages but peak in the 10-30 year age group
- Commonly produce masculinization or at least defeminization
- BUT a few have estrogenic effects
- Tumors are unilateral and resemble granulosa-theca cell neoplasms
- In girls it blocks sexual development

** In women androblastomas:
- Usually produce masculinization
- Breast atrophy
- Amenorrhea
- Sterility
- Hair loss or male distribution of hair
- Clitoral hypertrophy
- Voice changes

Germ-Cell Derived
- Constitute 15-20% of all ovarian tumors
- Most are benign cystic teratomas
- The remainder which are found principally in children and young adults, have a higher
incidence of malignant behavior

** The embryonal carcinoma can be undifferentiated as in dysgerminoma
- OR the carcinoma can differentiate in one of three ways

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** The types of germ cell tumors are:
- Teratoma- produces embryonic tissue
- Dysgerminoma
- Endometrial sinus tumor- produces extra-embryonic tissues
- Choriocarcinoma- produces trophoblastic tissue

** Some rare forms of germ cell tumors are:
i- Embryonal Carcinoma- a highly malignant tumor of primitive embryonal elements
- Histologically similar to tumors arising in the testes

ii- Polyembryoma- a malignant tumor containing embryoid bodies
iii- Mixed Germ Cell Tumors- containing various combinations of dysgerminoma, teratoma,
endodermal sinus tumor and choriocarcinoma

Teratomas
** Teratomas are tumors that contain embryonic tissues from all 3 germ cell layers:
- Ectoderm
- Endoderm
- Mesoderm

** There are 3 categories of teratomas:
i- Mature- benign = dermoid cysts
- Common in women of reproductive years
- Bilateral in 10% and are usually cystic
- Unilocular cysts containing adult-type tissue
- Usually contain hair and sebum (cheesy sebaceous material)
- Other mature tissues such as teeth may be found in the wall of the cyst
- Derived from the ectodermal differentiation of totipotential cells
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- The karyotype of all benign ovarian teratomas is 46, XX and may originate from a meiotic
germ cell
- 1% of cases may undergo a malignant change
- Usually produces a squamous cell carcinoma BUT can produce thyroid carcinoma or
malignant melanoma

ii- Immature- malignant- are rare and usually occur in pre-pubertal or young women
(mean age of 18 years)
- Differs from benign teratomas because it contain fetal/embryonic type tissues instead of
mature, adult tissues
- Grow rapidly and frequently penetrate the capsule with local spread of metastases
- Stage I tumors have excellent prognosis
- Higher grade tumors confined to the ovary are generally treated with chemotherapy
- If there is no recurrence in 2 years the patient is considered cured

iii- Monodermal or highly specialized
- Very rare
- Always unilateral
- Composed of only one tissue type
a- Functional thyroid tissue- struma ovarii
b- Carcinoid- 5HT secretion from intestinal-like tissue

Note: Primary ovarian carcinoid can be distinguished from metastatic intestinal carcinoid because
the metastatic carcinoid is almost always bilateral

Dysgerminoma
- Considered to be the ovarian counterpart of the Seminoma of the testis
- 2% of all ovarian tumors
- All dysgerminomas are malignant
- Tends to occur in adolescents and young women
- Some occur in patients with gonadal dysgenesis, including pseduohermaphrditism

** Dysgerminomas have no endocrine function. Therefore most have no hormonal function
- A few produce elevated levels of HCG

** Dysgerminomas are characterized by a total lack of differentiation
** Although all are malignant only about 1/3 are clinically aggressive
- Tumors tend to be extremely radiosensitive
- Prognosis is excellent if the tumor has not breached the capsule and spread
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- 96% cured following salpingo-oophorectomy

Endodermal Sinus Tumor (Yolk Sac Tumor)
- Rare
- BUT it is the second most common malignant tumor of germ cell origin

** Derived from the differentiation of malignant germ cells toward extra embryonic yolk sac
structure
- Therefore thought to be derived from a multi potential embryonal carcinoma which
differentiates towards yolk sac structure

** The tumor is rich in alpha-fetoprotein and alpha-1 anti-trypsin
- The characteristic histologic feature is a glomerulus-like structure comprised of a central
blood vessel
- Central blood vessel is surrounded by germ cells within a space lined by germ cells
(Schiller-Duval Body)

** Most patients are children or young women presenting with abdominal pain and a rapidly
developing pelvic mass
- Usually appear to involve a single ovary but grow rapidly and aggressively
- Used to be fatal within 2 years
- BUT now combination chemotherapy has improved the outcome

Choriocarcinoma
- More commonly of placental origin
- Similarly to endodermal sinus tumor, it is an example of extra embryonic differentiation
of malignant germ cells
- Forms as a malignant tumor of the ovary

** Contains tissue which has differentiated into trophoblast type
- May occur rarely de novo in prepubertal girls
- In these case it has a poor prognosis and is unresponsive to chemotherapy

** Choriocarcinoma may occurs as malignant change at the implantation site in a ovarian ectopic
pregnancy
- This has a better prognosis
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** Choriocarcinoma has usually metastasized widely by the time of diagnosis to:
- lungs
- liver
- bone

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Lecture 7: Carcinoma of the Cervix & Endometrium

Lecturer: Dr. Rattray

** The impact of cervical screening has been to decreased both incidence and mortality of cervical
cancer

** The decreased mortality of cervical cancer is due in part to the effectiveness of the Pap smear
in detecting cervical pre-cancers
- Also the accessibility of the cervix to colposcopy and biopsy
- Pap smear screening has increased the detection of potentially curable cancers
- It also has increased the detection and eradication of pre-invasive lesions

Note: Although there has been an increase in diagnosis of in situ carcinoma due to screening, there
also has been a decrease in invasive carcinoma

** Cervical cancer incidence demonstrates bimodal peaks
- 26-40 years and 46- 50 years

Cervical Cancer Epidemiology
** The pathogenesis of cervical cancer is multifactorial.
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** Sexual behavior and infectious agents play a large role in the development of cervical cancer
- HPV is considered the most important agent in cervical oncogenesis

** The following risk factors for cervical neoplasia indicate a complex interaction between the
host and the virus
- Early age at first intercourse
- Multiple sexual partners
- Increased parity
- A male partner with multiple previous sexual partners
- Hygiene practices- an uncircumcised male with poor hygiene may increase transmission of
HPV to a female partner more readily
- Presence of a cancer-associated HPV
- Persistent detection of a high-risk HPV- particularly with a high viral load
- Certain HLA + viral subtypes
- Exposure to oral contraceptives and nicotine
- Genital infections (Chlamydia)

Note: Co-factors that increase risk may be in play before HPV can transform the cells in to a
neoplasia.
** Other factors which may contribute to the development of cervical cancer are:
1- Smoking- reduces the laminin cells on the cervix
- These are immune surveillance cells
- Therefore women who smoke are at an increased risk of cancer

2- Parity- increased cancer risk due to the trauma of childbirth
3- Contraception- increases the risk possibly because women who use the pill are less likely
to use barrier methods along with it
4- Socioeconomic Class- lower income women tend to have less screening tests done

Precancerous Lesions
** A precancerous lesion precedes the majority of cancers
- This lesion may exist in the non-invasive stage for as long as 20 years

** The precancerous changes represent a continuum of morphologic change with indistinct
boundaries
- The changes do not invariable progress to cancer and may spontaneously regress
- They are associated with papillomaviruses

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** Cervical pre-cancers are classified in a variety of ways:
1- Dysplasia/Carcinoma in situ System- with mild dysplasia on one end and severe
dysplasia/carcinoma in situ on another end
2- Cervical Intraepithelial Neoplasia (CIN) Classification-
- CIN Grade I- mild dysplasia
- CIN III- carcinoma in situ lesions

** The spectrum of precursor lesions is complex due to its origins in a site (transformation zone)
that supports a wide range of epithelial differentiation
** Postulated steps in the pathogenesis of cervical neoplasia are:
1 Sexual activity
2 HPV exposure
3 Cervical transformation zone- has the potential to undergo squamous cell differentiation
or endocervical columnar differentiation

** Squamous differentiation can lead to the formation of squamous intraepithelial lesions. This
lesion can form either:
i Low grade lesion- rarely transforms into invasive squamous carcinoma
ii High grade lesion- if there are interaction with other co-factors (smoking, OCP, altered
immune status etc) this can lead to invasive squamous carcinoma

** Glandular Intraepithelial Lesion (adenocarcinoma in situ)
- Interaction with other co-facts can lead to the development of invasive adenocarcinoma

Pure Squamous Cell- 85%
Pure Glandular- 10%
Mixed adenosquamous- 5%

Pathology
** Invasive cervical carcinoma manifest in 3 distinct patterns:
1- Exophytic (fungating)- protrudes from the surface of the cervix
- The lesion is friable and bleeds easily and has necrotic tissue

2- Endophytic- grows into the wall of the cervix
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3- Ulcerative

Cervical Cancer Spread
** Advanced cervical carcinoma extends by direct spread to involve contiguous structures
- Ex: peritoneum, urinary bladder, ureters, rectum + vagina
- Local and distant lymphatic permeation also occurs
- Distant metastases occurs via the blood to the liver, lungs, bones etc

Note: Carcinoma of the infravaginal cervix tends to spread to the vagina
- Carcinoma of the supravaginal cervix tends to spread laterally to parametrial tissue
- Or anteriorly to the bladder or posteriorly to the rectum

Note: Lymphatic permeation is usually in an orderly fashion to subsequent nodes in a line
- Can also occur via embolization in which it skips a group of nodes in the line
- Lymphatic spread requires radical surgery and lymphadectomy

Note: If the para-aortic nodes are involved, the tumor has left the pelvis
- Therefore surgical treatment at this time is not indicated and would be suboptimal
- Evaluate the para-aortic first when surgery is done and the patient is first opened
- If they are enlarged and evidence of disease is seen on frozen section of the nodes the
surgery is aborted in favor of more systemic treatment

Order of Lymphatic Spread
- Paracervical
- Parametrial
- Ureteric
- Iliacs
- Obturator
- Para-aortics
- Occasionally: sacral, inguinal, supraclavicular nodes

Staging Cervical Cancer
Clinical Staging- determine the spread of the cancer and prognosis based on clinical signs
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Surgical Staging- determining the extent of the cancer by taking out the cervix and endometrium
surgically
- BUT this cannot be done once the cancer has spread beyond the pelvis

Note: Endometrial cancer is staged surgically but cervical cancer staged clinically

** Cervical cancer is staged as follows:

1- Stage 0- Carcinoma in situ (CIN III)

2- Stage I- carcinoma confined to the cervix
- Stage Ia- preclinical carcinoma. Only seen via microscopy. Divided into Ia1
(microinvasive) and Ia2 (no more than 7mm of invasion)
- Stage Ib- histologically invasive carcinoma confined to the cervix

3- Stage II- Carcinoma extends beyond the cervix but not onto the pelvic wall
- Carcinoma involves the vagina but not the lower 1/3 of the vagina

4- Stage III- Carcinoma extends on to the pelvic wall and the tumor involves the lower 1/3 of
the vagina

5- Stage IV- Carcinoma extends beyond the true pelvis
- Or has involved the mucosa of the bladder or rectum
- Also includes cancer with metastatic dissemination

Cervical Cancer: Clinical Symptoms
** May be asymptomatic at first
1- Bleeding- post-coitally or post-menstrual bleeding
2- Abnormal discharge- may be malodorous especially if tumor necrosis is going on
3- Constitutional symptoms- fever, weight loss, night sweats
4- Pelvic Pain- if the tumor has spread to involve the pelvic nerves
5- Urinary symptoms- due to compression or invasion of the urinary tract
6- GI symptoms

Note: The symptomotology depends on the stage of the disease
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Cervical Cancer: Signs
- Anemia
- Cervical mass
- Vaginal mass
- Rectal examination + EUA (exam under anesthesia)- done to determine of the parametrium
is involved and if there is spread to the pelvic wall
- Lymph node enlargements
- Organomegaly, ureteric block

Cervical Cancer: Investigations
1- Cervical smear
2- Biopsy +/- colposcopy
3- IVU- to determine if there is spread to the sidewall. Looking for hydronephrosis and
urinary system obstruction which would suggest stage III cancer
4- CBC, U&E, LFTs- LFTs done to determine is cancer has spread to the liver
5- CXR
6- Barium enema
7- EUA +/- cystoscopy

Lymphangiography- may not be useful because it is relatively non-specific since there are other
causes for enlarged lymph nodes

CT Scan/MRI
Ultrasound

Cervical Cancer: Treatment
** Radiotherapy can be used to treat every stage of cervical cancer

** Surgery is indicated for patients with early stage disease
- That is up to Stage IIa

** The surgical treatment for Stage Ia1 and Ia2
- Cone biopsy- helps to preserve fertility
- Simple hysterectomy
- TAH + Cuff vagina
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** The surgical treatment for Stages Ia2, Ib & IIa:
- Radical hysterectomy and pelvic lymphadenectomy
- Radical hysterectomy removes the cervix BUT leaves the body of the uterus intact
- Therefore it is a fertility sparing option

** Complications of surgery can be divided into immediate/early or late complication.
Immediate/Early:
- Anesthetic reaction
- Bleeding
- Visceral injury
- Nerve injury
- Pulmonary embolism

Late:
- Infection
- Fistula formation
- Lymphocyst- is a collection of lymph fluid in the pelvis due to lymphadenectomy
- Urinary retention- due to damage of the autonomic nervous system as a result of
lymphadenectomy
- Cancer recurrence

Radiotherapy Treatment
1- External Beam (teletherapy)- done for the pelvic lymphatics
2- Intracavitary (bracytherapy)- tumor and paracervical region. Therefore it is targeted for
cervical and intravaginal therapy

** Complications of radiotherapy include:
- Radiation burns- to contiguous areas and can result in stricture and stenosis
- Ex: vagina, bowel burns (radiation proctitis)

Note: Although radiotherapy can be use for all stages of cervical carcinoma, it is usually reserved
for older women
- Because of in these women ovarian function is less important
- Surgery is given to younger patients to preserve ovarian function
- Also because they are fitter to withstand the associated bleeding of surgery

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** Follow up should be given post-treatment
- 3-4 monthly for 2 years
- 6-monthly for 5 years
- Annually for life
- If there is no recurrence by 5 years consider the patient to be cured

Print slide #34

Cervical Cancer in Pregnancy
- Pregnancy does not worsen the disease prognosis
- Therefore if left untreated for 9 months there will be no change in prognosis
- Maintain the pregnancy to viability (28 weeks) and then deliver by C-section
- Treat according to the stage of the disease

Endometrial Cancer
** Endometrial carcinoma is the most common invasive cancer of the female genital tract
- Uncommon in women younger than 40 years
- Median age of 61 years

** A higher frequency is seen in women with:
- obesity
- Diabetes- abnormal glucose tolerance is found in more than 66%
- Hypertension
- Infertility- women tend to be single and nulliparous
- History of functional menstrual irregularities consistent with anovulatory cycle
** Other risk factors include:
1- Menstrual history- menstrual irregularities with anovulatory cycles
2- Endocrine disorders- polycystic ovarian disease, diabetes
3- Unopposed estrogen- endogenous or exogenous sources
4- Radiation exposure
5- Family history- of breast, colon, ovary cancer

** Two general groups of endometrial cancer can be identified:
1- Group that develops on the background of prolonged estrogen stimulation and
endometrial hyperplasia
- Endometrial carcinomas associated with hyperplasia tend to be well differentiated
- Mimic normal endometrial glands (endometrioid appearance)
MBBS/DDS 2K16
- Or may display altered differentiation- mucinous, tubal or squamous differentiation

2- Second group acquires the carcinoma at the older average age and displays less pre-existing
hyperplasia
- Tend to be poorly differentiated
- Have poorer prognoses than estrogen related cancers

Types of Endometrial Carcinoma
** Grossly, endometrial carcinoma presents as either a localized polypoid tumor OR as a diffuse
tumor involving the entire endometrial surface
- Enlarged uterus
- Raised, rough, papillary endometrium
- Tumor occupies at least half the endometrium
- Usually arises in the fundus of the uterus

** Histologically most are adenocarcinomas characterized by gland patterns that closely
resemble normal endometrial epithelium
- Known as endometrioid adenocarcinoma

** Other adenocarcinoma types include:
- Clear cell
- Papillary serous

** 20% of endometrioid carcinoma contains foci of squamous differentiation
- Adenocanthoma
- Adenosquamous

Screening
1- Pap smear- 50% are found on smear
2- Ultrasound
3- Endometrial smaling
4- Hysteroscopy
5- Prostagen Challenge Test- progesterone cause bleeding and this is a positive sign of
endometrial cancer
** Staging for endometrial cancer is done surgically
i- Staging Laparotomy
ii- Saline peritoneal lavage
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iii- TAH + BSO
iv- Node assessment

Clinical Symptoms
** Endometrial carcinoma may be asymptomatic for periods of time
- BUT usually produces irregular vaginal bleeding with excessive leucorrhea
- Uterine enlargement in the early stages may be deceptively absent

Note: Cytologic detection via Pap smear is variable
- Detection associated with serous carcinoma which produce easily detachable clusters of
cells

** Pain is a bad prognostic marker and usually indicates metastases
Diagnosis: must be made ultimately by established curettage and histologic examination of the
tissue
- Examination of the breast and colposcopy also done

Print slide #50, 54
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Treatment
1- TAH- total abdominal hysterectomy
2- BSO- bilateral salpingoopherectomy
3- Radiotherapy- can be given pre-op or post-op
4- Progestagen Therapy- for recurrent and advanced disease
5- Chemotherapy- for failed progestagen therapy- adriamycin or cisplatin or
cyclophosphamide

Print slide #55

MBBS/DDS 2K16
Lecture 8: Contraception: Hormonal & Non-Hormonal

Lecturer: Dr. Dacosta

Oral Contraceptives
- Safe and effective (99%)
- Reversible
- Minor side effects are common
- Require daily use
- Serious complications are rare
- Disadvantage: Does not provide STI/HIV protection

Types of OCPs

1- Combined oral contraceptive (COCP)- is a combination of an estrogen and a progestin.
There are two types:
o Monophasic- usually given as 21 tablets of estrogen and progesterone followed
by 7 days of placebo
However the concentration of the two hormones remains constant
throughout the 21 days
Constant dosage of both components during the cycle
o Triphasic- has different levels of the progestin and sometimes the estrogen
component in each of the 3 weeks of active pills
Available methods: Failure rate:
Abstinence OCPs
Injectables Implants
ECPs Condoms
IUDs
0%
1-3% (5-15%)
0.4%
0.3%
0.5-25%
5-15%
0.5%

Side Effects
- Nausea
- Dizziness
- Breast tenderness
- Headaches
- Mood changes
- Weight gain
- Breakthrough bleeding

Myths- OCPs do not:
- Cause birth defects
- Cause infertility
- Require a rest period

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o The combined pills contain ethinyl estradiol and levonorgestrel

2- Progestin only pills- Contain no estrogen. Useful during breastfeeding
- Ex: Postinor

OCP: Mechanism of Action
** The combinations of estrogens and progestins exert their contraceptive effect mainly through
selective inhibition of pituitary function
- This results in inhibition of ovulation

** The agents also produce a change in the cervical mucus, in the uterine endometrium
- Change in the motility and secretion in the uterine tubes

Note: These changes decrease the likelihood of conception and implantation

** Chronic use of combination agents depresses ovarian function
- Follicular development is minimal

** After prolonged use the cervix may show some hypertrophy and polyp formation
- Endometrial atrophy may also occur

** Stimulation of the breasts occur in most patients receiving estrogen-containing agents
- Therefore breasts tend to enlarge

Initiation
- Anytime once the woman is not pregnant
- Preferably during the first 7 days of menstrual cycle
- If it is initiated after the 7
th
day use back-up method for 7 days

Post-partum- if not breastfeeding delay for 3 weeks
- If breastfeeding- delay for 6 months or until breastfeeding is discontinued
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Note: Do not extend the hormone free interval
- If the hormone-free interval is longer than 7 days, ovarian function may resume and risk
of conception increases

OCPs and Cancer
- Ovarian and endometrial cancers- may have a protective effect
- Breast cancer- no overall increase in risk
- Cervical cancer- small increase in risk
o However possibly due to other factors (high-risk sexual behavior, smoking

OCP: Non-contraceptive Health Benefits
- Reduced risk of ovarian and endometrial cancers
- Reduced risk of ectopic pregnancy
- Reduced risk of benign breast disease
- Reduced menstrual irregularities
- Reduced risk of anemia
- Reduced symptoms of dysmenorrhea, endometriosis and premenstrual syndrome

** Reduces the risk of endometrial cancer by more than 50%
- Protection develops after 12 months of use
- Present for at least 15 years

Relative Contraindications: The following women should not use OCPs
- Pregnant
- Breastfeeding <6weeks postpartum
- Smoke heavily and over 35 years
- Greatly increased risk of CVD
- Current breast cancer
- Liver cancer
- Benign liver tumors
- Thrombo-embolism

Emergency Contraception: Therapy used to prevent pregnancy after an unprotected or
inadequately protected act of sexual intercourse (ACOG)
- Safe to use even by women who cannot use pills as a regular method

** ECP can generally be used by women with:
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- Acute focal migraine
- History of severe cardiovascular or vascular complications
- Severe liver disease

** Types of emergency contraceptive pills:
1- Combined oral contraceptive pills- containing ethinyl estradiol (0.1 mg) and
levonorgestrel (0.5)
2- Progestin-only pills- Each dose should contain 0.75 mg levonogestrel
3- Mifepristone- RU486

** Does not disrupt an established pregnancy. Causes temporary changes in the ovaries,
fallopian tubes and endometrium
- Should be taken within 120 hours of unprotected intercourse
- Not a regular method of contraception

Progestin-only pills have fewer side-effects and more effective than combined pills

Print Slide #28-29

Common Side Effects
- Nausea
- Vomiting
- Headaches
- Dizziness
- Fatigue
- Breast tenderness

Print Slide #31

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Injectable Contraceptives

Types
Progestin-only Combined
(Estrogen & progestin)
Hormones DMPA
(depot medroxyprogesterone acetate)

Mesigyna
Duration of effect 3 months 1 month

MOA:
1- Suppress hormones responsible for ovulation
2- Thicken cervical mucus, blocking sperms

** Depot-medroxyprogesterone acetate- most widely used injectable
- 150 mg every 3 months

Side Effects:
1- Menstrual Changes:
o Irregular bleeding or spotting
o Prolonged or heavy bleeding
o Amenorrhea

2- Weight gain
3- Headaches, dizziness and mood changes

Note: 1/3 of uses discontinue in the first year because of side effects
Advantages: No action required at time of intercourse
o Can be used by breastfeeding women
o Has non-contraceptive health benefits
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** The non-contraceptive health benefits include:
- Reduced risk of endometrial cancer, ectopic pregnancy, virginal yeast infections, acute PID
- Reduced frequency and severity of sickle cell disease painful crises
- Reduced frequency of epileptic seizures
- Reduced symptoms of endometriosis

Disadvantages:
- Effects cannot be stopped immediately
- Delay in return to fertility
- Side effects are common, especially abnormal bleeding
- No STI/HIV protection
- DMPA users have lower bone density than non-users
o Adults regain most lost bone after discontinuing DMPA

Print Slide #41
DMPA and Cancer:
Endometrial cancer: risk reduced by 60%
Ovarian and liver cancer: no effect observed
Cervical cancer
No increase in invasive cancer
Slight increase in precancer lesions, possibly due to detection bias
Breast cancer: no overall increase

Combined Injectables
- Contain progestin and estrogen
- Administered monthly
- Provide more regular bleeding days
- May result in estrogen-related side effects

Advantages:
- Safe and effective
- Reversible and can be discontinued without clinical visit
- No action necessary at time of intercourse

Ex: Mesigyna- 50 mg NET-EN + 5mg estradiol
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- Cyclofem- 25 mg DMPA + 5mg estradiol

Disadvantages:
- Estrogen related side effects
- Effects cannot be stopped immediately
- Monthly injection

Subdermal Implants
- Injected below the skin
- Long-acting but reversible
- Can be used by breast feeding women
- Non contraceptive health benefits

Disadvantages:
- Side effects are common
- Bleeding irregularities are the most common side effects
- Amenorrhea is less common
- Cannot be initiated or discontinued without visit to a provider
- Insertion + removal require minor surgery

Intrauterine Devices
** IUDs are the most commonly used form of reversible contraception
- IUDs are plastic devices which disrupt the normal uterine environment

Types of IUDs

Non-hormonal IUDs
- Copper- T (10 years)
- Lippes Loop
- Stainless steel ring

Hormonal IUDs
- Mirena (levonorgestrel 5years)
- Progestasert (progesterone- 1 year)
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** IUDs work to prevent fertilization and interfere with implantation
- Failure rate is 0.5%

** The failure rate depends on the following factors:
- Skill of provider
- Age of the user
- Unnoticed expulsion of the IUD

Side effects:
- Pain and cramps
- Heavier menstrual bleeding
- Menstrual irregularities

Complications:
- Perforation- 1/1000
- PID- 5%
- Expulsion- 2%

Contraindications:
- Known or suspected pregnancy
- Current or recent STIs or PID
- Cervical, endometrial or ovarian cancer
- Unexplained vaginal bleeding
- Anomalies of the uterus

Barrier Methods
- Male and female condoms
- Diaphragm
- Cervical cap
- Vaginal sponge
- Spermicides

Male Latex Condom
- Effective against pregnancy if used correctly and consistently (97%)
- Less effective in typical use (88%)
- Widely available
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- Proven protection against STIs
- Requires male partner co-operation
- Can be damaged by exposure to oil-based lubricants, heat, humidity or light

Diaphragm & Cervical Cap
- Devices are inserted into the vagina and cover the cervix
- Must be fitted by a trained provider
- Diaphragm can cause irritation and urinary tract infections
- Decreased risk of some STIs when used with spermicides

Spermicides
- Inactivate sperms
- Nonoxynol-9 (N-9) provides some protection against bacterial STIs
- Can increase UTIs in women
- Failure rate of 7-20%
- Should be used with another barrier method

MBBS/DDS 2K16
Lecture 9: Pregnancy: Maternal Adaptations

Lecturer: Dr. S. Kulkarni

Menstrual Age- Dating of pregnancy from the patients last menstrual period (LMP)
Gestational Age- Pregnancy duration from the LMP assuming a 28 day cycle with ovulation on day
14 followed by fertilization

Conceptional Age- weeks from conception

Physiological Changes in Pregnancy
** Maternal adaptation to conception starts early in pregnancy
- Adaptation is progressive and every system is affected
- Rate of change varies in different areas
- Reversal after delivery also variable
- Some changes are permanent

** Factors that influence adaptation are:
- Age
- Parity
- Previous (obstetric) experience
- Body build (BMI)
- Pre-existing disease
- Socio-economic factors
- Ethnic, geographic, climactic variables
- Number and size of conceptus

General Effects of Pregnancy
** The most apparent reaction of the mother to the fetus and to the excessive hormones of
pregnancy is the increased size of the various sexual organs
- The uterus increases from 50g to 1100 grams
- The breasts approximately doubles in size
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Weight Gain in the Pregnant Women
- Average weight gain during pregnancy is about 24 pounds
- Most of the gain occurs during the last 2 trimesters
- Fetus = 7 pounds
- Amniotic fluid, placenta, fetal membranes = 4 pounds
- Extra fluid = 6 pounds
- Fat accumulation = 3 pounds
- During pregnancy a woman has an increased desire for food partly as a result of removal of
food substrates from the mothers blood by the fetus and partly because of hormonal
factors

Gain in Body Water: mean 8.5 kg
- Peripheral edema: 85% by term
- Laxity in connective tissue and joints
- Gingival, corneal and laryngeal edema

** The weight gain results in lordosis
- Lordosis is the inward curvature of a portion of the vertebral column
- The lordosis results in backache, cramps, nerve compression

Print Slide #7-8

Cardiovascular Changes in Pregnancy
- Raised cardiac output by 1/5L/min by 10 weeks
- About 625 mL of blood flows through the maternal circulation of the placenta each minute
during the last month of pregnancy
- This plus the general increase in the mothers metabolism increases the cardiac output to
30-40% above normal by the 27
th
week of pregnancy
- 50% increase from baseline by the third trimester
- Additional 30% increase in labor and delivery

** The maternal blood volume shortly before term is about 30% above normal
- Cause of increased volume is due in part to aldosterone and estrogens
- Also caused by increased fluid retention by the kidneys
- The bone marrow becomes increasingly active and produces extra red blood cells to go
teeth the excess fluid volume

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** The pulse rate is increased by 15 beats per minute
- Raised pulse pressure
- Fall in peripheral resistance (vasodilatation)

** The heart is pushed upwards and rotates forward
- The apex beat is in the 4
th
left intercostals space, mid-clavicular line
- Enlargement due to venous return
- Prominent pulmonary conus
- The 1
st
and 2
nd
heart sound are prominent and split
- The 3
rd
heart sound is frequently heard
- Short ejection systolic (flow) murmur

Blood Pressure Changes
- Systolic blood pressure is normal
- Diastolic pressure falls in the second trimester by 10-15 mmHg
- Venous engorgement is seen
- Increased flow by 50% to uterus, kidneys, and skin
- Uterine-placental bed is an AV-shunt
- Aortocaval compression in late pregnancy

Aortocaval Compression Syndrome- is compression of the abdominal aorta and inferior vena
cava b by the pregnant (gravid) uterus
- Occurs when the pregnant woman lies on her back in the supine position
- The syndrome is a frequent cause of low maternal blood pressure which can lead to loss of
consciousness

** Aortocaval compression may cause supine hypotensive syndrome. This syndrome is
characterized by:
- nausea, hypotension and dizziness
- Occurs when a pregnant woman lies on her back and resolves when she is turned on her
side

Changes in the Respiratory System
** Because of the increased basal metabolic rate of a pregnant woman and her greater size, the
total amount of oxygen increases
- The oxygen use increases by 20% just before the birth of the baby
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- These effects cause the mothers minute ventilation to increase
- High levels of progesterone also increases the minute ventilation
- Progesterone increase the respiratory centers sensitivity to carbon dioxide

Net Result: is an increase in minute ventilation by 50%
- Also a decrease in arterial PCO2

** The growing uterus presses upward against the abdominal contents and these press upward
against the diaphragm
- Therefore the total excursion of the diaphragm is decreased
- As a result the respiratory rate is increased to maintain the extra ventilation

** Changes in the chest shape occur:
- Flaring of the ribs
- Diaphragm raised

** Maternal pCO2 is lowered. Raised maternal ventilation due to resetting of the respiratory center
- Tidal Volume: +200ml
- Vital Capacity +200ml

Hematological Changes
- Red cell mass +20%
- Plasma volume +50%
- Hemodilution- is an increase in the fluid content of blood resulting in lowered
concentration of formed elements
- Red cell volume rises
- Neutrophilia but lymphopenia
- Platelets decreased
- Increased clotting factors and fibrinogen

Endocrine Changes
** In pregnancy, the placenta forms large quantities of several feto-placental hormones
- Human chorionic gonadotrophin
- Estrogens
- Progesterone
- Human chorionic somatomammatropin (human placental lactogen HPL)

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** Menstruation normally occurs in a non-pregnant woman about 14 days after ovulation
- During this time most of the endometrium of the uterus sloughs away from the uterine
wall and is expelled
- If this happens after an ovum has implanted the pregnancy would terminate
- This is prevented by the secretion of HCG by the newly developing embryonic tissue
- HCG is secreted by the syncytial trophoblast cells into the fluids of the mother
- HCG can be first measured in the blood 8-9 days after ovulation
- Rate of secretion rises rapidly to reach a maximum at about 10-12 weeks of pregnancy
- Decreases back to a lower value by 16-20 weeks

** The most important function is to prevent involution of the corpus luteum at the end of the
monthly female sexual cycle
- Causes the corpus luteum to secret larger quantities of its sex hormones (progesterone +
estrogens)
- The sex hormones prevent menstruation and cause the endometrium to continue to grow
and store nutrients

** HCG also exerts an interstitial cell stimulating effect on the testes of the male fetus
- Results in the production of testosterone in male fetuses until the time of birth

Note: The amount of globulins are increased during pregnancy, therefore the amount of bound
hormone in the blood also increases

** The secretion of some anterior pituitary hormones are also increased:
- HGH
- ACTH
- TSH
- Prolactin

** BUT some are suppressed:
- FSH
- LH

** FSH and LH are suppressed as a result of the inhibitory effects of progesterone and estrogens
from the placenta

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** There is also hyperplasia of adrenal, thyroid and parathyroid glands
- The mothers thyroid gland enlarges up to 50% during pregnancy
- Increases its production of thyroxine
- Increased thyroxine production is caused partly by a thyrotropic effect of HCG secreted by
the placenta
- Also by small quantities of a specific thyroid-stimulating hormone (human chorionic
thyrotropin) secreted by the placenta

** The mothers parathyroid glands usually enlarge during pregnancy. Enlargement of these
glands causes calcium absorption from the mothers bones
- This maintains normal calcium ion concentration in the mothers extracellular fluid even
while the fetus removes calcium to ossify its own bones
- Secretion of parathyroid hormone is intensified during lactation because the growing baby
require more calcium than the fetus does

** The beta-cells of the pancreas increase in number. The result is hyperinsulinemia and insulin
resistance

Genital Tract Changes
** Major increase in the size and weight of the uterus (10 x)
- The uterus undergoes both hyperplasia and hypertrophy

** The myometrial syncytium develops more gap junctions and oxytocin receptors
** The cervix becomes less collagenous as term approaches
** The vagina has more glycogen in cells, pH, bacterial and yeast infections develop more readily
Changes in the Kidney and Urinary Tract
** The rate of urine formation by a pregnant woman is usually slightly increased
- Due to increased fluid intake and increased excretory products being formed
- 50% increase in renal perfusion rate and glomerular filtration rate

** The renal tubules reabsorptive capacity for sodium, water, and chloride is increased by as much
as 50%
- Due to increased production of steroid hormones by the placenta and adrenal cortex
** The GFR increases by 50% during pregnancy, which increases the rate of water and electrolyte
excretion in the urine
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** Therefore with these changes the normal pregnant woman accumulates only about 6 pounds of
extra water and salt

** There is extrinsic bladder compression by the enlarging uterus
- This increases the frequency of micturition, Nocturia and stress incontinence
- Ureteric dilation and kinking of the urinary tract may lead to stasis
- The T-max is exceeded leading to glycosuria and proteinuria
- Sodium retention = 500-900 micromols

GI Tract Changes
Mouth: taste changes, ptyalism, pica
Stomach- acid reflux, hyperacidity, reduced emptying
Intestines- better fluid absorption, increased transit time that leads to constipation
Liver + Gallbladder- cholestasis, A/G ratio 1:1
- The A/G ratio is related to the protein level
- It is the ratio of albumin to globulins
- A normal A/G ratio is 1:1 to 1:8
- Alkaline phosphatase is elevated

Skin Changes
i- Increased skin pigmentation (MSH effect)- There is darkening of the nipples and
areola
- Linea nigra- a dark vertical line that appears on the abdomen
- Approximately 1 cm in width
- Line runs vertically along the midline of the abdomen from the pubis to the xiphoid
process
- This line is a type of hyperpigmentation resulting from the increased production of
melanin
- Increased melanin production is related to the release of estrogen during pregnancy

ii- Facial chloasma- Facial pigmentation due to increased production of melanin
iii- Striae-
iv- Vasodilation- resulting in warmth and sweating
v- Spider Nevi- due to the increased amounts of estrogen
vi- Post-natal shedding- loss of hair and nails
vii- Pregnancy prurigo- itchy skin

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Immunologic Changes
** The fetus is accepted despite the fact that it is foreign allograft
- There are very little HLA antigens in the villous trophoblast
- Maternal blocking antibodies coat the placenta
- Also suppression of B and T-lymphocytes
- Steroid mileau
- Placental barrier

Placenta
** The placenta is embryologically entirely fetal in origin. Trophoblastic invasion of maternal
vessels
- First Phase- 4-6 weeks
- Second Phase- completed by 14 weeks

** The result is maternal spiral arterioles that convert to passive distensible vessels
** The basic feto-placental unit is the terminal villus
- Syncitiotrophoblast is the intervening layer
- Transfer area established 3.4 m2 at 28 weeks and 11 months at term

** Patterns of transfer:
- Passive- lipophilic substances
- Active- lipophobic
Print slide #22

Glucose Transfer
- Facilitated diffusion of glucose across the placenta
- Saturation at 20 mmol/L
- Membrane vesicles used as special carriers
- Insulin does not cross
- Fetal hyperinsulinemia promotes transfer
- Maternal hyperglycemia may exaggerate fetal insulin response leading to fetopathy

Fetal Physiology
- Sustain life in utero
- Growth
- Preparation for post-natal life
MBBS/DDS 2K16

Print slide #27

** Insulin is the primary fetal growth hormone. Very little placental transport of insulin
- The fetus starts its own production at 12 weeks

Thyroid
- TSH does not cross the placenta
- Low levels of T3 and T4
- Iodine deficiency can cause low thyroid function in the fetus
- Brain development can be affected resulting in cretinism

Print slide #30, 32
Adrenal Cortex
- Very large until 6 months after birth
- Produces DHEAS which becomes estriol
- These boost maternal estrogen levels
- Partially responsible for labor trigger

Fetal Circulation
- 60% of cardiac output goes to the umbilical arteries
- This returns oxygenate blood through the umbilical veins
- The pulmonary vascular resistance remains high
- Most of the right ventricular output goes through the ductus arteriosus
- Net result is that the brain gets the best oxygenated blood
- The left ventricle has a small preload reserve
- Vagal tone increases with gestation

Print slide #34
Fetal Blood
- Circulation begins at 5 weeks
- Erythropoiesis begins by 6 weeks
- Hb F is most dominant by 8 weeks
- From 26 weeks to term the Hb A rises to 30%
- PO2 20-25% in the fetus
- Higher Hb concentration
- 2-3 DPG higher- related to increased oxygen affinity
MBBS/DDS 2K16

Fetal Lungs
- The lungs are under high pressure and therefore there is low flow through the lungs

Print slide #36
Fetal Urinary Tract
- High GFR
- Low osmolality
- Main source of amniotic fluid
- Obstruction leads to oligohydramnios

Print slide #41-42

MBBS/DDS 2K16
Lecture 10: Trophoblastic Disease: Hydatidiform Mole &
Choriocarcinoma

Lecturer: Dr. I. Bambury

Gestational trophoblastic disease constitutes a spectrum of tumors and tumor-like conditions
- Characterized by the proliferation of pregnancy-associated trophoblastic tissue of
progressive malignant potential

** GTD is the abnormal growth of placental tissue. The lesions of GTD include:
- Complete hydatidiform mole
- Partial hydatidiform mole
- Invasive mole
- Choriocarcinoma

** By monitoring the circulating levels of hCG it is possible to determine the early development of
persistent trophoblastic disease

Note: Any histological type of trophoblastic disease can lead to persistent trophoblastic disease
- Follow up of all patients with this diagnosis is mandatory
- Invasion and metastases can occur in normal pregnancies

Incidences
Hydaditidiorm mole
- USA 1: 1000
- Asia 1:200
- Orient 1:20
- Jamaica 1:1000

Choriocarcinoma
- USA 1:20000
- Asia/Africa 1:1000
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- Jamaica 1:7384

Note: There is increased incidence of h. mole and Choriocarcinoma in Asian/oriental countries
- May be more relevant as an environmental factor rather than a genetic factor
- This is because the incidence in Asian women decreases if they leave Asia
- Therefore change in environment changes incidence

- Increased maternal age
- Incidence increases with age (>40 years) and in the very young (<20 years)
- Risk at ages 45-49 is 24x more than with ages 25-29
- Having a previous mole increase risk by 0.5 2%

Print slide #7

Hydatidiform Mole
** H. mole is characterized by cystic swelling of the chorionic villi
- Swelling is accompanied by variable trophoblastic proliferation

** Most patients present in the 4
th
or 5
th
month of pregnancy with vaginal bleeding
- Also with a uterus that is larger than expected for the duration of pregnancy

** There are two types of benign, non-invasive moles:
- Complete
- Partial

Complete Mole
** In complete mole, the chorionic villi are edematous
- There is diffuse trophoblast hyperplasia

** Cytogenetic studies show that the majority of these moles (>90%) have a 46, XX diploid pattern
- All are derived from sperm (androgenesis)
- Androgenesis- is the development of a zygote that contains only paternal chromosomes
MBBS/DDS 2K16
- This may occur after fertilization of an oocyte whose chromosomes are absent or
inactivated

** The moles may result from fertilization by a single sperm of an egg that has lost its chromosomes
- The remaining 10% are from the fertilization of an empty egg by two sperm
- In both cases, embryonic development does not occur
- Therefore complete moles show no fetal parts

** Complete moles has molar tissue only
- The entire uterus is filled with abnormal tissue
- No membranes or fetal red cells are present

Partial Moles
** Some of the villi are edematous and other villi show only minor changes
- The trophoblastic proliferation is focal
- In these moles the karyotype is triploid (69, XXY) or even occasionally tetraploid (92,
XXXY)

** The moles result from fertilization of an egg with one or 2 sperm
- The embryo is viable for weeks and fetal parts may be present when the resultant mole is
aborted
- In contrast to complete moles, partial moles are rarely followed by Choriocarcinoma

** The partial mole has fetus and molar tissue OR amnion and fetal red blood cells plus molar
tissue
- Partial mole = fetal tissue + abnormal gestational trophoblastic tissue

Gross Pathology

** In most instances, moles develop within the uterus, but they may occur in any site, including
ectopic pregnancies

** Partial moles may be diagnosed in early spontaneous abortion or later following fetal
development
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** Complete moles show hydropic swelling of most chorionic villi
- The chorionic villi are edematous and have a grape-like vesicular appearance
- Absence of vascularization of villi
- Produce large amounts of beta-HcG

Note: Alpha-hCG is similar to TSH and LH

** Early complete moles exhibit subtle conformational changes in the villi
- Accompanied by stromal cell karryorrhexis
- Modest syncytial and cytotrophoblastic hyperplasia

Karyorrhexis- is the destructive fragmentation of the nucleus of a dying cell
- Preceded by pyknosis and is followed by karyolysis

** The most common feature is abnormal vaginal bleeding in 90% of cases
- Most patients present with spontaneous abortion
- Watery fluid and bits of tissue is seen as small, grape-like masses seen in the uterine
contents
- Ultrasound examination confirms the diffuse villous enlargement

** In complete moles quantitative analysis of hCG show levels of hormone exceeding those
produced by a normal pregnancy of similar age
- This results in exaggerated symptoms of pregnancy including
- Hyper-emesis gravidarum
- Early onset pre-eclampsia
- The exaggerate symptoms of pregnancy because of high levels of hcG that are similar to
twin pregnancies

** Hyperthyroidism (thyrotoxicosis) because the alpha-hCG hormone is similar to TSH

** Disseminated intravascular coagulation (DIC) is a pathological activation of blood-clotting
mechanisms
- Occurs in response to a variety of disease
- The clotting factors become used up and the result is uncontrolled bleeding
MBBS/DDS 2K16

Diagnosis
- Made clinically
- Testing levels of blood or urinary beta-hCG
- The beta-hCG should be determined quantitatively (not qualitatively), therefore to see how
much beta-HCG is present
- Note: Levels of beta-hCG are also high in multiple pregnancies

History:
- Very young or very old patient
- Hyperemesis gravidarum
- Previous molar pregnancy

Examination:
- The uterus is larger than normal in 50% of cases
- Oriental/Asian women
- Pre-eclampsia
- Passage of vesicles per vaginum
- Abnormal bleeding

** Ultrasonography- there is a snowstorm appearance with no fetus
- May be a small fetus in partial mole
- In 1/3 of cases there are large cystic ovaries (theca lutein cysts)

Management
** If the diagnosis is made incidentally after spontaneous abortion, follow up hCG levels should be
done
- Follow up levels after mole expulsion because if the levels persists suggests malignancy

** If the diagnosis is made pre-op by ultrasound; the following tests should be done:
- CBC, platelets, PT/PTT, liver function
- Blood type, IDCT
- hCG
- Chest x-ray
- Rh- if they are RH- they should be given anti-D blood to cover the procedure and prevent
sensitization
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- Other tests are done to determine fitness for the evacuation procedure
- Chest X-ray done to find possible metastases

Evacuation
** Evacuation should be done as soon as the patient is stable. Suction curettage is preferred for
trophoblastic disease
- This is because large amounts of blood that needs to be suctioned is produced during the
procedure
- Oxytocin is given to cause uterine contractions

Note: Oxytocin should always be accompanied by suction curettage
- This ensures that trophoblastic tissue does not enter the vasculature
- This may cause increased malignant sequelae

** Suction curettage is performed under general anesthesia.
- Conscious sedation is done if the uterus is small
- Sepsis may occur if complete evacuation is not done
- After dilatation of the cervix the uterus is evacuated with a large suction cannula
- Oxytocin is given during and after for several hours

Complications
- Massive hemorrhage in 7% of cases
- Sepsis
- Pulmonary distress
- Persistent trophoblastic disease- 10%

Follow-up
- 90% of cases will die out after evacuation
- 10% of cases result in persistent trophoblastic disease
- Follow up with the beta-hCG urine or blood
- Quantitative beta-hCG used

Print Slide #24

MBBS/DDS 2K16
Choriocarcinoma
** Gestational Choriocarcinoma is an epithelial malignant neoplasm of trophoblastic cells
- Derived from any form of previously normal or abnormal pregnancy
- Most arise in the uterus
- Ectopic pregnancies may provide extra uterine sites of origin

** Choriocarcinoma is a rare condition
- 50% develop after term pregnancy
- 25% after molar pregnancy
- 25% after other pregnancies

** The choriocarcinoma is a soft, fleshy, yellow-white tumor with a marked tendency to form large
pale areas of ischemic necrosis
- Foci of cystic softening and extensive hemorrhage

Histology: Purely epithelial tumor that does not produce chorionic villi
- Grows by the abnormal proliferation of both cytotrophoblast and syncytiotrophoblast

** The tumor invades the underlying myometrium and frequently penetrates blood vessels and
lymphatics
- Growth spreads quickly to the broad ligament
- Invades locally to the bladder and broad ligament
- Spreads via blood to lungs, vagina and brain
- Rapid growth results in hemorrhage, ischemic necrosis and secondary inflammation

Note: Unlike h.moles, there is no chorionic villi
- Choriocarcinoma also secretes higher levels of beta hCG than h,moles

** In fatal cases, metastases are found in the lungs, brain, bone marrow, liver and other organs
- Sometimes metastatic Choriocarcinoma is found without a detectable primary in the
uterus/ovary
- This is because the primary tumor has undergone total necrosis

** The uterine Choriocarcinoma does not usually produce a large, bulky mass
MBBS/DDS 2K16
- Leading feature is vaginal bleeding
- Bleeding is arterial and is very heavy
- Bleeding comes from the uterus or a vaginal nodule
- Cachexia, pyrexia and offensive vaginal discharge occur as the condition advances

** Widespread metastases are characteristic of these tumors
- Lungs- 50%
- Vagina- 30-40%
- Brain- neurological symptoms and signs
- Liver
- Kidney

** Lung metastases present with the following:
- hemoptysis
- dyspnea
- Chest x-ray demonstrates canon-ball secondaries (coin lesions)

Diagnosis
** The diagnosis is based on hCG levels that are persistently elevated
- Thyrotoxicosis
- Metastases

Treatment
** Since all surgical procedures cause dissemination of the cancer, it should be covered with
chemotherapy
- Usually chemotherapy alone is sufficient
- A D/C or biopsying the vaginal nodule can result in profuse bleeding
- Therefore chemotherapy is the treatment of choice

Print Slide #36

** CNS metastases have the worst prognosis. The diagnosis is made clinically and via spinal tap
- The normal blood to CSF hCG ratio is 60: 1
- Therefore an elevated CSF hCG level suggests brain metastases
- A CT scan can be used to confirm the metastases

MBBS/DDS 2K16

** The treatment is based on the risk score (prognostic score)
1- Low Risk- methotrexate with folinic acid rescue
2- Medium Risk- methotrexate, actinomycin + cyclophasphamide (MAC)
3- High Risk- etoposide + MA alternating with cyclophosphmaide and oncovin

Note: If the levels continue to rise, the levels of treatment should be increased to the next level

** Complications of chemotherapy include:
- bone marrow depression
- mucositis
- drug resistance

CNS Treatment:
- Intrathecal methotrexate
- Brain radiotherapy
- Surgery to remove isolated deposits and to control bleeding

Follow Up
- hCG levels are used to monitor treatment and is done every 2 weeks
- Treatment continued until hCG returns to normal and then 2 course given after that
- Pregnancy should be avoided because hCG levels will increase and this would prevent
follow up
- Contraception with OCP needed for 1 year
- IUDs may cause abnormal bleedings
- Pregnancy can be considered one year after remission

** With subsequent pregnancies early ultrasonagraphy should be employed because there is a 1-
2% risk of a second molar pregnancy
- No increased risk of congenital anomaly with previous chemotherapy

MBBS/DDS 2K16
Lecture 11: Bleeding in Early Pregnancy & Ectopic
Pregnancy

Lecturer: Dr. DaCosta

Bleeding in Early Pregnancy
** Bleeding in early pregnancy occurs in 25-30% of all pregnancies
- Approximately 50% go onto abort spontaneously
- Causes range from trivial to life threatening
- Diagnostic techniques are now available that greatly enhance the speed and accuracy of
our diagnosis

** The aetiology of bleeding in early pregnancy may be pregnancy-related or non-pregnancy
related

Pregnancy Related
i- Physiologic bleeding
ii- Spontaneous miscarriage
iii- Ectopic pregnancy
iv- Molar pregnancy

Non-pregnancy Related
i- Cervicitis
ii- Vaginal laceration
iii- Cervical carcinoma

Physiologic Bleeding
** Physiologic bleeding- is bleeding secondary to implantation
- Or bleeding related to a relative deficiency in hormones

Clinical Features:
- Bleeding is usually minimal
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- Bleeding usually occurs within the first 8 weeks of the pregnancy
- No associated pelvic pain
- No cervical dilatation

Diagnosis:
- Made on history and examination
- Special investigations: transvaginal ultrasound scan, serial quantitative beta hCG, +/-
laparoscopy

Management:
- Avoid strenuous activity
- Folic acid 5mg od
- Progesterone

Prognosis:
- Usually good
- Slightly increased risk for low birth weight, premature labor and neonatal mortality

Spontaneous Miscarriage (SM)
** Spontaneous miscarriage is the natural termination of a pregnancy before the fetus is capable
of extra uterine life
- <24/40

Clinical Features:
- Loss of pregnancy symptoms
- Vaginal bleeding
- Pelvic pain
- Passage of products of conception

Incidence:
- 15% of clinical pregnancies
- 30% of chemical pregnancies- lost before implantation

Diagnosis:
- History and examination
- Special investigations- ultrasound
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- +/- quantitative beta hCG
- Should be increased by 66% after 48 hrs

Management: 3 options
1- Expectant Management- Indicated in patients where ultrasound detects little or no tissue in
the uterus with low or falling hCG levels
- Complications: infection, hemorrhage

2- Medical- misoprostol 800 mcg vaginally

3- Surgical- ERPC (evacuation of retained products of conception)
- Indicated in patients with inevitable, incomplete and delayed miscarriages

** Miscarriage is an old term that is now an acceptable alternative to spontaneous abortion. A
series of terms exist to describe the 4 different clinical forms of miscarriages

1- Threatened Miscarriage- defined as painless vaginal bleeding occurring any time between
implantation and 24 weeks gestation
- TM refers to a viable pregnancy presenting with bleeding before 24 weeks of gestation
- of all pregnancies are complicated by threatened miscarriages
- TM is one of the most common indications along with suspected ectopic pregnancy for
emergency referral of young women to A/E
- Bleeding may resolve spontaneously and never recurs
- Bleeding may continue intermittently over weeks
- Only when abdominal cramps supervene that the process may become inevitable
- Bleeding usually occurs between 6 and 9 weeks gestation when the definitive placenta
forms

2- Inevitable Miscarriage (IM)- miscarriage is considered inevitable when the cervical os is
opened in the setting of bleeding and cramps
- Can be complete or incomplete, depending on whether or not all fetal and placental tissues
hae been expelled from the uterus
- The typical features of incomplete abortion are heavy (intermittent) bleeding with passage
of clots and tissues
- Together with lower abdominal cramps
- Note: Ultrasound exam is important in determining the absence or persistence of
conception products inside the uterine cavity

3- Incomplete Miscarriage- is the passage of some but not all the products of conception (POC)
from the uterine cavity through the cervical canal before 24 weeks gestation
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4- Delayed Miscarriage (Missed Abortion)- is a gestational sac containing a dead
embryo/fetus before 20 weeks gestation
- Without clinical symptoms of expulsion
- Diagnosis is usually made by failure to identify a fetal heart beat on ultrasound
- Mother complains of chronic but light bleeding
- Blighted Ovum- Failure or absence of embryo at a very early stage of pregnancy
- This feature is due to the early death and resorption of the embryo with persistence of the
placental tissue rather than a pregnancy originally without an embryo
-
5- Complete Miscarriage- is characterized by resolution of symptoms and the total expulsion
of POC
- On exam the cervical os is closed
- Ultrasonography reveals an empty uterus

Print Slide #18

Immune Disorders & Miscarriages
- Antiphospholipid antibodies- autoimmune
- Antinuclear antibodies= auto immune
- Natural killer cells- autoimmune
- Cytotoxic B-cells- autoimmune
- Blocking (protective) antibodies- alloimmune

** When the immune system is the cause miscarriage:
- The changes of a mother having a successful pregnancy without treatment after 3
miscarriages is 30%
- After 4 miscarriages- 25%
- After 5 miscarriages- 5%

Ectopic Pregnancy
Defn: A pregnancy outside the uterus, usually occurring in the fallopian tube but may also occur
in the ovary, cervix and in the abdomen
- May also occur in an abnormal position within the uterus (cornua, cervix)
- Combine tubal and uterine (heterotopic) pregnancies are uncommon

** More than 50% of tubal pregnancies are situated in the ampulla
MBBS/DDS 2K16
- Approximately 20% occur in the isthmus
- Around 12% are fimbrial and 10% are interstitial

Incidence:
- 1 in 100 pregnancies (USA)
- 1 in 140 pregnancies (Caribbean)

Risk Factors
** The risk of ectopic pregnancy increases with the following factors:
- Number of sexual partners
- use of an intrauterine device
- history of PID
- After pelvic surgery

i- Previous tubal surgery
ii- Intrauterine contraceptive device (IUCD)
iii- Previous ectopic pregnancy

** In theory any mechanical or functional factors that prevent/interfere with the passage of the
fertilized egg to the uterine cavity may be etiological factors for an ectopic pregnancy

** The main cause for a tubal implantation may be a low-grade infection
- 50% of women with ectopic pregnancies have evidence of chronic pelvic inflammatory
disease

** If implantation occurs into a site of the tube that offers a sufficient area for placentation, the
process is very similar to that of an intrauterine pregnancy
- The conceptus penetrates the tubal mucosa and becomes embedded in the tissues of the
tubal wall

** The extravillous trophoblast will penetrate the full thickness of the muscular layer of the tube
to reach the subserosa and the tubo-ovarian circulation
- Due to its limited distensibility, the tube will rupture

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** In an ectopic pregnancy the uterine endometrium usually responds to the hormonal changes of
pregnancy and undergoes focal decidua changes (Arias-Stella reaction)

Clinical Features
** Vaginal bleeding and chronic pelvic pain (iliac fossa sometimes bilateral) are the most commonly
reported symptoms

** Other clinical features include:
i- Vaginal bleeding
ii- Lower abdominal + pelvic pain
iii- Shoulder pain- may occur secondary to blood irritating the diaphragm
iv- Palpitations
v- Syncope- due to vascular instability
vi- Tenderness of the lower abdomen
vii- Adnexal tenderness- is the symptom of pain from the ovary and fallopian tube
viii- Adnexal mass
ix- Tachycardia + hypotension
x- Cullens sign- a bluish discoloration around the umbilicus that is usually a sign of
intraperitoneal hemorrhage

Diagnosis
** Diagnosis of an ectopic pregnancy involves a high index of suspicion
- Ultrasound scan
- Serial quantitative beta hCG
- Laparoscopy

Management
** With earlier diagnosis it is more apparent that spontaneous regression of tubal pregnancies is
more common than previously thought
- Led to non-interventional expectant management
- Based on the assumption that a significant proportion of all tubal pregnancies will resolve
without treatment

** There are 4 management options:
i- Expectant
ii- Medical
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iii- Conservative surgery
iv- Radical Surgery

Expectant Management- 20%- Criteria:
- Beta hCG of <1000 mIU/ml
- Diameter of the mass <3 cm
- No cardiac activity
- No significant abdominal signs
- Patient must be available for follow up

Medical Management: Criteria
- Unruptured
- Diameter <4cm
- No evidence of embryonic heartbeat
- Beta hCG <10,000 mIU/ml
- Reliable for follow up

** Medical management includes:
1- Single dose of methotrexate (50mg.m2)
2- Quantitative beta hCG measured on day 4 and 7
3- If day 7 level is <15% lower than day a repeat dose is given

Note: Weekly hCG levels are performed until the value is zero

Conservative Surgical Management
Salpingostomy- a surgical incision into a fallopian tube
- Quantitative beta hCG performed weekly until the level reaches zero

Radical Surgical Management
Salpingecctomy is the surgical removal of a fallopian tube
- Indicated in cases of ruptured ectopic and in patients requesting sterilization

Hydatidiform Mole (Molar Pregnancy)
** Varying degrees of trophoblastic proliferation and oedema of the villous stroma
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** May be classified as complete or partial
Print Slides 40-49

MBBS/DDS 2K16
Lecture 12: Principles of Antenatal Care

Lecturer: Dr. Mullings

Antenatal Care- is the care of the pregnant woman with the objective of assuring a healthy baby
and mother
** There are two components of antenatal care:
i- Preconception care
ii- Postconception (Antenatal/Prenatal) care

** The needs of the pregnant female include:
- Emotions and attitudes
- Nutrition
- Hazards at the workplace
- Maternity leave
- Patient education programs
- Birth arrangements
- Special needs of the high-risk groups

Terminology

1- Primipara (ous)- has one completed, viable pregnancy (>24 weeks or 500 gm)
2- Multipara (ous)- has complete two or more viable pregnancies
3- Gravida (ity)- previously or currently pregnancy irrespective of the outcome
4- Primigravid (a)- with first pregnancy
5- Multigravid (a)- with at least one previous pregnancy

Trimester- a period of pregnancy roughly equivalent to 3 calendar months
- 1
st
trimester- 0-14
- 2
nd
trimester- 15-28
- 3
rd
trimester- 29-42

Maternal Mortality Ratio- the number of maternal deaths/100,000 live births
MBBS/DDS 2K16

Perinatal Mortality Rate- the number of foetal/neonatal deaths/ 1000 deliveries

Duration of Pregnancy
** From the 1
st
day of the last normal menstrual period for 280 days or 40 weeks

EDD = expected date of delivery

Naegles Rule- is a standard way of calculating the due date of a pregnancy
- The rule estimates the expected date of delivery (EDD) from the first day of the LNMP by:
- Adding a year and then subtracting 3 months and adding 7 days to that date

Term: 37 weeks + 6 days to 41 weeks + 6 days (266-294 days)

Diagnosis of Pregnancy
First trimester symptoms:
- Amenorrhea
- Nausea + vomiting
- Fatigue/lassitude
- Breast tingling and fullness
- Urine frequency/Nocturia
- Constipation

Signs in the last 2 trimesters
- Enlargement of the abdomen
- Uterine contractions
- Palpation of fetal heart
- Auscultation of the fetal heart using the bell of a regular stethoscope

** The overarching goal of antenatal care is risk management. The four components are:
1- Education
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2- Evaluation
3- Monitoring
4- Management

Education
- Begins in the preconception phase
- Aim is to encourage healthy practices

** Healthy practices include:
- Regular health surveillance before pregnancy
- Careful attention to health problems
- Early + regular attendance for care
- Exercise and nutrition
- Avoid smoking/alcohol
- Prepare for labor and delivery
- Preparation for breastfeeding

** Prior to and during pregnancy the woman may
- Eat what she wants
- Eat as much as she wants

BUT watch the pre-pregnancy BMI
- Meals should be balanced with adequate carbohydrates
- Adequate or additional iron and vitamins
- Folate supplementation
- Weight gain should be about 1kg per month

Evaluation
** Assessment for risk categorization and management:
- Initial
- Ongoing

** Components of assessment include:
- history
- examination
- investigations

MBBS/DDS 2K16
**Problems in the delivery of antenatal care include:
- Cost
- Accessibility- distance + timings of institutions
- Crowding and poor attention
- The skills and attitudes of personnel
- Personal beliefs

Response
** Determination of risk:
- to mother
- to fetus
- to pregnancy overall

Low Risk- low risk clinic (midwife/doctor)

High Risk- management in conjunction with a MFM specialist and others as necessary
- Therefore high risk pregnancies require a team approach

Print slide #23

** There are 3 major goals of initial evaluation:
1- Define health status of mother and fetus
2- Determine a gestational age
3- To initiate a plan for continuing care- as for normal or high risk pregnancy

Note: These goals are achieved at booking and at the first medical visit

History
** All the general features of any history plus some specifics:
- planned vs unplanned
- menstrual/contraceptive information to determine EDD (Expected Date of Delivery)
- previous medical, surgical, obstetric history
- History of or family history of- hypertension, diabetes mellitus, multiple pregnancies
- Medications/substance abuse
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- Smoking/alcohol
- Immunizations
- Social history as religion/occupation/smoking
- Living conditions/ support system etc

First Medical Examination
** General physical- complete medical evaluation
Specific:
- Mucus membranes
- Thyroid gland
- Breasts- lumps, nipples
- Oral cavity/teeth- infection etc
- Nutritional status- BMI
- Abdomen + pelvis- size, shape
- Legs- varicosities and swelling

Investigations

Blood:
- Blood group, hemoglobin, Hb electrophoresis
- VDRL, Chlamydia
- HIV, HepB, rubella

Urine:
- Protein
- Sugar/ketone
- Nitrites, pus cells, blood

Specific Investigations:
- Ultrasound- dating, anomaly scan
- Collagen vascular screen
- Diabetes screen
- Thyroid function
- Renal function
- Specialist consultation

METHODS OF TESTING
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Foetal Kick chart
Non Stress Test (NST)
Contraction Stress Test (CST)
Biophysical Profile (BPP)
Doppler flow studies
Specific testing for genetic abnormality e.g.
Chorion villus sampling
Nuchal fold thickness
Targeted ultrasound scanning
Tripple & Quadrupple test on amniotic fluid

Common Complaints
- Nausea + vomiting
- Backache/lower abdominal pain- mainly ligament strain- rest and analgesic
- Vaginal discharge- test + treat
- Varicosities/piles- local treatment
- Heartburn- antacids
- Constipation- stool softeners
- Fatigue
- Ptyalism
- Headache
- Vaginal infections- increased incidence
- Urinary frequency

Foetal Wellbeing Testing
- Decreased fetal movements may suggest:
o Hypertension in pregnancy
o Insulin dependent diabetes
o Oligo or polyhydramnios
o Suspected or proven intrauterine growth restriction
o Post-term pregnancy
o Multiple gestation

** Methods of testing include:
- Fetal kick chart
- Non-stress test
- Contraction stress test
- Biophysical profile
- Doppler flow studies

** Also specific testing for genetic abnormality
- Chorion villus sampling
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- Nuchal fold thickness
- Targeted ultrasound scanning
- Triple + Quadruple test on amniotic fluid

Delivery
Timing: At term (37 +6 to 41 +6) or at any time risk to either mother or fetus exceeds the
benefit to either or both

Mode: Antenatal assessment done to exclude contraindications to vaginal delivery

MBBS/DDS 2K16
Lecture 13: Operative Obstetrics

Lecturer: Dr. N. Johnson

** Operative delivery is performed if a spontaneous birth is judged to pose a greater risk to
mother or child than an assisted one

** Operations are divided into:
1- Abdominal methods- Caesarean section
2- Vaginal assisted deliveries-
iii- Forceps delivery
iv- Vacuum extraction

Preparations for Operative Delivery
** Discuss operative delivery with the woman and her partner

** Follow the womans wishes
- No operative delivery can proceed without her consent even if the doctors think that the
baby will die if it is not done

** Get written consent for elective procedures
- Pediatrician should attend any delivery where problems are anticipated

Indications for Caesarean Sections

1- Cephalopelvic disproportion- may be obvious either antenatally or in the early stages of
labor that the fetus, presenting by the head, is not going to pass through the pelvis
2- Relative cephalopelvic disproportion- fetus descends initially during labor but is then
arrested
- May be due to a malposition such as occipito-posterior
- Occipito-posterior- is the most common malposition. The head is incompletely flexed and
the occipitofrontal diameter presents
MBBS/DDS 2K16
- Therefore a larger diameter is involved

3- Placenta previa- particularly if it is overlapping the internal os
4- Fetal distress- in the first stage of labor
5- Prolapsed cord
6- To avoid fetal hypoxia- when there is poor perfusion of the placental bed
- EX: pre-eclampsia

7- Malpositions
8- Malpresentations- for example transverse lie, breech
9- Bad obstetric history
10- Maternal request

Note: The only absolute indications for Caesarean section are:
- Cephalopelvic disproportion
- Major degrees of placenta previa

** The rest demands a judgment by the obstetrician that the risk of vaginal delivery exceeds the
risk of the operation
- OR that the mothers perception is that it does

** A repeat C-section depends on the indication for the first
- If there is the presence of a recurrent indication, such has a small pelvis, then a repeat is
warranted
- If indication is not recurrent, vaginal delivery can be tried

Print slide #11

** The usual approach is through a transverse lower abdominal incision
- Pfannenstiels incision
- Lower segment operation- a gently curved Phannenstiels incision following the Langers
lines in the skin
- About 3 cm above the pubis in the center

** Classic upper segment operation- a vertical right paramedian incision from the level of the
umbilicus to 3 cm above the symphysis pubis
MBBS/DDS 2K16

C-Section: Procedure
- Drain bladder with an indwelling catheter
- Open abdomen
- Expose lower uterine segment
- Incise visceral peritoneum
- Push bladder down
- Open uterus with a transverse incision
- When the bulge of membranes appears, pricked and open amniotic sac fully with a finger from
each side
- Deliver baby if presentation is by the head
- Sometimes obstetric forceps helpful

Note: Extracting the fetal head through a lower segment C-section with a Wrigleys forceps

** With a breech presentation, the legs are brought down and a modified breech extraction is
performed
- If the lie is transverse, the OB aims to bring down the legs to move the baby into a breech
position
- Being careful to not bring down the arm
- Syntometrine is given and the placenta is delivered by controlled cord traction

Note: Syntometrine injection contains two active ingredients: ergometrine + oxytocin
- Ergometrine is an ergot alkaloid
- Acts on receptors found on the uterus causing it to contract
- The combination of the two drugs is given to manage the 3
rd
stage of labor
- The injection is given just after the birth of the child to stimulate womb contraction and
helps the delivery of the placenta
- May also be given after the placenta has been delivered to prevent excessive bleeding

Note: Manual removal increases the blood loss and should be performed only if the placenta is
adherent
MBBS/DDS 2K16

** Vertical uterine incision was once used and now only used in exceptional circumstances such as:
i- If the lower segment is unapproachable because of fibroids
ii- If the transverse fetal lie with the back inferior
iii- If the lower segment is not formed (EX: before 28 weeks gestation

Note: Future birth will be by C-section because rupture of the vertical scar in the next labor more
common than rupture of the transverse scar
- A rupture in the upper segment bleeds much more

** Most caesarean sections are now performed under a regional block:
i- Spinal- fastest and densest block
ii- Epidural- allows postoperative top ups for continuing pain relief

** General anesthesia is best avoided as incidence of complications post-operatively is
substantially higher:
- Aspiration of stomach contents
- Chest infections
- Thrombosis

** Main indications for general anesthesia include:
- Maternal anxiety
- Operation likely to be complicated
- Emergency, when insufficient time to establish epidural or spinal block

Complications of C-Section
1- Hemorrhage- worst from the angles of the uterine incision or with placenta previa
2- Infection- prophylactic antibiotics usually given
- Particularly if done after the membranes have ruptured
- Studies have shown this to be cost effective

3- Ileus- Treat conservatively with intravenous fluid
- No oral fluids until the mother has passed flatus
- Mild ileus may last for a day after operation

4- Thrombosis- risk is 8x more than after vaginal deliveries
MBBS/DDS 2K16
- Commonly occurs in leg or pelvic veins
- Thrombus may embolise to a pulmonary vessel
- Prophylactic anti-coagulation given particular for those at highest risk
- Age > 35 years, anemia, history of thrombosis, pre-eclampsia, prolonged inactivity, obesity

Post-Operative Care
- Ambulate in the first 24 hours to exercise legs and to go to the bathroom
- Wound commonly closed with clips or subcuticular prolene
- Clips can be removed on the fourth day and this is the peak time for discharge from hospital
- Pain, lack of sleep, and difficulty with establishing breast feeding must be looked for

Forceps
** Forceps are a pair of curved blades, which can be placed on the head
- Allows application of traction to alter the speed of progress
- Usually this is to hasten delivery but occasionally used to slow it down
- This may be used when delivering the after-comign head in a breech delivery

** There are two types of forceps:
- With a pelvic curve
- Without a pelvic curve

Print Slide #26

1- Kiellands Forceps- for rotation and extraction
2- Simpsons Forceps- for mid-cavity assisted delivery without the need for rotation
- When the maximum diameter of the fetal head is about 5-8 cm above the vulva

3- Short Forceps (Wrigleys)- for low extraction when the maximum diameter is about 2.5 cm
above the vulva
- Designed for use by general practioners, obstetricians with the safety feature that they
could not reach high into the pelvis

Print Slide # 28- important

Forceps Functions
Traction: Most important function
MBBS/DDS 2K16
- Pull required in a primigravida is 18 kgs
- Pull required in a multipara is 13 kgs

Rotation of Head- occurs with Keillands forceps
- Also in low forceps cephalic application with the occiput in the 2 or 10 o clock position

Protective Cage
- The premature baby is protected from the pressure of the birth canal

Indications for Forceps Delivery
** Delay in the second stage of delivery:
- Due to uterine inertia
- Failure of labor progression- defined if no progress occurs for more than 20-30 mins wih
the head on the perineum

** Definition of prolonged second stage of labor redefined as:
1- Nullipara-
- <3 hrs with regional anesthesia
- <2 hrs without regional anesthesia

2- Multipara-
- < 2 hrs with regional anesthesia
- < 1hr without regional anesthesia

** Foetal indications for forceps delivery includes:
1- Foetal distress in the second stage when the prospect of vaginal delivery is safe
- Abnormal heart rate pattern
- Passage of meconium
- Abnormal scalp blood pH

2- Cord prolapse in second stage
3- After coming head of breech
4- Low birth weight
5- Post-maturity

** Maternal indications for forceps delivery include:
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- Maternal distress
- Pre-eclampsia
- Post-caesarean pregnancy
- Heart diseases
- Intra partum infection
- Neurological disorders- where voluntary efforts are contraindicated or impossible

Forceps Procedure
- Explain to the patient what is about to happen
- Catherise bladder
- Regional anesthesia is given
- Each blade is slipped beside the fetal head
- The vagina is guarded by the operators hand
- Gentle traction in the correct line of pull will help delivery
- An episiotomy is usually required to achieve a line of pull sufficiently posterior
- Once the head is crowned, the blades can be removed and the rest of the baby is delivered
normally

** The line of pull is the resultant of two lines of forces in mid-cavity
- As the head descends the line of pull needs to become more anterior to negotiate the
pelvic curve

Print slide #36
** There are several prerequisites that should be fulfilled before forceps application:
1- Suitable presentation & position- Vertex, anterior face or after-coming head are the ideal
positions
2- Dilated Cervix- attempts to apply forceps blades to the undilated cervix will lead to
trauma and bleeding without successful delivery
3- Membranes must be ruptured
4- Baby should be living
MBBS/DDS 2K16
5- Uterus should be contracting + relaxing
6- Bladder must be empty- if necessary empty with a catheter. This prevents trauma and
subsequent lack of bladder sensation
7- Episiotomy- should usually be performed to allow space for the posterior pull
8- Analgesia- some form should be used
- Lignocaine pudendal block with infiltration to the vulva is sometimes enough for a mid-
cavity forceps
- More anesthesia (epidural or spinal) usually needed for rotation forceps

Complications/Dangers
** The complications/dangers of forceps delivery are mostly due to faulty technique rather than
instrumentation

** Maternal complications include:
1- Injury- extension of the episiotomy involving anus + rectum or vaginal vault
- Vaginal lacerations and cervical tear if the cervix was not fully dilated

2- Post partum hemorrhage- due to trauma, atonic uterus or anesthesia
3- Shock- due to blood loss, dehydration or prolonged labor
4- Sepsis- due to improper asepsis or devitalisation of local tissues
5- Anesthetic hazards-
6- Delayed or long-term sequel- chronic low backache, genital prolapse and stress
incontinence

** Fetal complications:
1- Asphyxia
2- Trauma-
- Intracranial hemorrhage
- Cephalic hematoma
- Facial/brachial palsy
- Injury to the soft tissues of face and forehead
- Skull fracture

3- Remote cerebral palsy
4- 2% change of fetal death

Vacuum Extraction
** Vacuum extraction is rapidly becoming the method of choice for vaginal assisted delivery
MBBS/DDS 2K16
** Operation for the delivery of the fetal head from the mother by use of vacuum extractor applied
to the fetal scalp on presence of maternal effort

** A negative pressure raises an overhang of soft tissues in the rim of the metal cap
- Therefore the pull is on the overhang of the fetal scalp at this edge
- Silastic caps give more surface area applied to the scalp

Indications for Vacuum Extraction

First Stage of Labor (rarely)
- Fetal distress after the cervix is dilated 8cm in a multiparous woman
- Lack of advance after 8cm dilation in a multiparous woman

Second Stage of Labor (commonly)
- Lack of advance often with occipito-posterior or occipito-transverse position
- After an epidural has relaxed the pelvic floor
- If the mother is tired
- If the head of a second twin is high

Print Slide #47 + 49

Complications
** Damage to the cervix if it not fully dilated
** Hematoma of babys scalp- usually disappears in a week
** Scalp abrasions usually heal readily

Print Slide #52

Episiotomy
- Incisions made during childbirth to the perineum
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- Incision of the muscle between the vagina and rectum to widen the vaginal opening for
delivery

** Indications for episiotomy include:
i- To speed the later part of the second stage of labor in presence of fetal distress
ii- To open up posterior areas to allow correct line of traction at forceps or vacuum
extraction
iii- To over come a rigid perineum that is delaying the last part of delivery
iv- If there is likely to be a major perineal tear and episiotomy may prevent it and this
incision will be easier to repair than a tear

Note: Perineal skin does not stretch as well as the vagina
- May be due to increased fibrous content compared with vaginal epithelium

** Perineal tears are divided into 3 grades according to severity:
1- Stage I- skin of fourchette or vagina only
2- Stage II- skin and superficial perineal muscles involved
3- Stage III- anal muscles and sphincter involved

Note: In the USA, stage III is confined to tears to the anal margin and involvement of the sphincter
and rectal mucosa becomes stage IV

** An episiotomy is performed to limit damage if the perineum seems to be splitting
- Should always done under anesthesia
- With at least 1% Lignocaine infiltration
- Britain and Jamaica the incision is done medio-lateral so that if the incision extends it does
not run into the anus
- Usually repaired by trained midwives

Print slide #60

** Episiotomy repair will occasionally extend at its upper end in the vaginal tissues into one of the
fornices
- Important for hemostasis to put in at least one stitch above highest point of cut or tear to
occlude vessels coming in from above

MBBS/DDS 2K16
** Episiotomies are done to prevent anterior perineal lacerations, which carry minimal
morbidity

BUT the procedure substantially increases:
- Maternal blood loss
- The average depth of posterior perineal injury
- Risk of anal sphincter damage and its attendant long-term morbidity
- Risk of improper perineal wound healing
- Amount of pain in first several post-partum days

Print Slide #64

MBBS/DDS 2K16
Lecture 14: Obstetric Complications of the Antenatal
Period

Lecturer: Dr. D. Stewart- Simms

** The physiological changes of pregnancy mimics signs and symptoms of various pathologies
- Antepartum complications may lead to increased morbidity and mortality in both the
fetus + mother

Note: Each trimester has complications that are NOT specific, but more common to it
- EX: hyperemesis gravidarum in the first and early second trimester

** Vaginal bleeding at any stage of pregnancy needs evaluation. The ability to distinguish between
life-threatening disorders and those that are not life threatening is very important

First Trimester- 0-12 weeks
Second Trimester- 12-28 weeks
Third Trimester- 28-40 weeks

Nausea & Vomiting
** Nausea and vomiting is common in the first and early second trimester (> 16 weeks)
- Affects 75-90% of pregnancies
- Self-limiting
- Usually resolve by 20 weeks of gestation

** Persistent vomiting can result in:
- Dehydration
- Electrolyte imbalance
- Nutritional deficiencies

Hyperemesis gravidarum- protracted vomiting leading to electrolyte imbalance and ketosis
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- The disease is likely to recur in subsequent pregnancies

** The etiology of vomiting is both:
i- Hormonal- increased hCG levels and increased thyroid hormone
ii- Psychological

Note: Must rule out other cause of vomiting:
- Appendicitis
- Pyelonephritis
- Cholecystitis
- Gastroenteritis
- Hydatidiform mole

Treatment: Use of anti-emetics
- Hydrate and correct electrolyte imbalance
- Nutritional supplementation

Vaginal Bleeding
** Vaginal bleeding may be the result of the following:
i- Implantation- a small amount of bleeding occurs as the conceptus implants and may be
associated with the same time frame as a normal period

ii- Ectopic pregnancy- Pregnancy developing in sites other than the uterine cavity
- A ruptured ectopic can result in intraperitoneal hemorrhage and death
- The clinical course of an ectopic pregnancy is punctuated by the onset of severe abdominal
pain about 6 weeks after a previous normal menstrual period
- Common Symptoms: vaginal bleeding, abdominal pain, syncope
- Treat as an emergency
- Diagnostic Methods- Pregnancy test, pelvic ultrasound
- Serial quantitative serum beta-hCG may be needed to make the diagnosis in a stable
patient
- Level is done at once and then in 48 hrs the values should double or increased by 66%
- BUT if levels are not rising as quickly as expected it suggests an ectopic pregnancy

Conservative Management- if there is no evidence of rupture
Expectant Management- observe the patient on the ward
- Can be done if the serum hCG is falling and there are no other symptoms (<2,500)

MBBS/DDS 2K16
iii- Abortion- spontaneous, threatened or inevitable
- Toxoplasmosis, mycoplasma, listeria and viral infections have been implicated as causes of
abortion

iv- Low lying placenta
v- Hydatidiform mole
vi- Genital tract lesion- Vaginitis may cause bleeding during pregnancy

Abdominal Pain
** Abdominal pain in pregnancy may be due to the discomfort of the pregnancy or due to a
pathological problem

** Causes of pregnancy discomfort include:
i- Increasing abdominal distention- e.g. due to multiple pregnancies
ii- Stretching of ligaments
iii- Foetal position- e.g. breech presentation

** The pathological causes of abdominal pain include:
1- Extra uterine causes- urinary tract problems, sickle cell crisis, gastrointestinal
2- Uterine- abortion, degeneration of a fibroid, abruptio placentae, ruptured uterus, labor
3- Adnexal- ectopic pregnancy, ovarian cyst rupture or torsion

Note: Epigastric or right upper quadrant pain in a severely pre-eclamptic woman is an emergency

Placental Abruption (abruptio placentae)- is the separation of the normally located placenta after
the 20
th
week of gestation and prior to birth
- Bleeding into the decidua basalis leads to separation of the placenta
- Hematoma formation further separates the placenta from the uterine wall
- This causes compression of the structures and compromise of blood supply to the fetus
- The severity of fetal distress correlates with the degree of placental separation

Note: In near-complete or complete abruption, fetal death is inevitable unless an immediate C-
section delivery is performed

Hypertensive Disease
MBBS/DDS 2K16
** The definition of hypertension during pregnancy is:
- Systolic BP > 140mmHg
- Diastolic BP >90 mmHg

** Hypertensive disease in pregnancy is classified into:
- Chronic hypertension
- Gestational hypertension
- Pre-eclampsia/ eclampsia
- Chronic hypertension with superimposed pre-eclampsia

Chronic Hypertension
** Chronic hypertension is hypertension that pre-dates pregnancy or is identified before 20 weeks
gestation

** Gestational hypertension- is hypertension that occurs after 20 weeks

Pre-eclampsia/Eclampsia
** Toxemia of pregnancy refers to a symptom complex known as eclampsia, characterized by:
- Hypertension
- Proteinuria- >300mg of protein in a 24 hr urine collection
- Excessive weight gain- predisposes a woman the development of pre-eclampsia
- Edema- was previously used but it is a poor predictive value
Note: Although edema of the feet/ankles may be non-specific, edema of the hands and face may be
suspicious

Note: Occurs in 6% of pregnant women, usually in the last trimester
- More common in primiparas then in multiparas

Note: Both gestational hypertension and pre-eclampsia present with hypertension BUT there is no
proteinuria in gestational hypertension
- Proteinuria is a hallmark of pre-eclampsia

MBBS/DDS 2K16
Chronic hypertension with superimposed pre-eclampsia- is the development of proteinuria in a
patient with chronic hypertension
- Persons with chronic hypertension may have renal disease and related proteinuria
- Therefore although it is associated with pre-eclampsia there be an association with a
confounding factor

** Some patients with pre-eclampsia become more seriously ill and develop convulsions
- This more severe form of toxemia is known as eclampsia

** Patients with eclampsia develop:
- Disseminated intravascular coagulation (DIC)
- Lesions in the liver, kidneys, heart, placenta and sometimes brain

Note: Pre-eclampsia is a multi-organ problem

** Predisposing factors to the development of pre-eclampsia & eclampsia are:
- Nulliparity
- Family history of pre-eclampsia/eclampsia
- Multiple pregnancy- twins, triplets etc.
- Diabetes mellitus
- Hydatidiform mole
- Hydrops fetalis
- Extremes of age
- Lower socio-economic backgrounds

** The cause of pregnancy toxemia is not completely known, however there are several theories.
Three events may be important in the development of the disorder:
i- Placental ischemia
ii- Hypertension
iii- DIC

** The cause of the initial events of toxemia is unknown BUT evidence points to an abnormality of
placentation that leads to placental ischemia
** The placentation abnormality may involve:
i- Defects in trophoblast invasion
MBBS/DDS 2K16
ii- Defects in the development of the physiologic alterations in the placental vessels
required to perfuse the placental bed adequately

** Therefore an intrinsic defect in the invading trophoblast may contribute to the altered vascular
flow

** This abnormality is manifested by the inability of the invading cytotrophoblast to assume the
phenotype of normal endothelial cells
- These defects may further influence remodeling of the uterine vasculature, reducing blood
flow and leading to placental ischemia

** This decreased uteroplacental perfusion induces stimulation of vasoconstrictor substances
- EX: thromboxane, angiotensin, endothelin
- The decreased perfusion also causes the inhibition of vasodilator influences:
- EX: prostaglandin I2, prostaglandin E2, nitric oxide from the ischemic placenta

Note: DIC, hypertension and organ damage is the end-result

** Another cause of pre-eclampsia/eclampsia may be the result of an immunological response
- Inadequate maternal antibody response to the fetal allograft results in vascular damage
from the circulating immune complexes

** Disseminated intravascular coagulation in eclampsia may be a result of the following:
- Endothelial damage
- Abnormalities in the level and activities of coagulation factors
- Primary platelet alteration

** The placental ischemia leads to a higher output of thromboplastic substances and anti-
thrombin III levels are reduced

** The characteristic lesions in eclampsia are mostly due to thrombosis of arterioles and capillaries
throughout the body
- Mainly in the liver, brain, pituitary and placenta

MBBS/DDS 2K16

Pathophysiology Summary:
- CVS- vasospasm = hypertension
- Renal- glomerulo-endothelisosis = proteinuria + oliguria
- CNS- oedema, hemorrhage = convulsion

Clinical Course:
** Pre-eclampsia usually begins after the 32
nd
week of pregnancy
- May begin earlier in patients with hydatidiform mole or pre-existing kidney disease or
hypertension

** The onset is insidious and characterized by hypertension + edema with proteinuria following
within several days
- Headaches and visual disturbances are common

** The onset of eclampsia is signaled by the onset of CNS involvement including convulsions and
eventual coma

** The end result of pre-eclampsia/eclampsia is intrauterine growth restriction (IUGR). This is
because of the decreased circulation of the uteroplacental bed leads to vasoconstriction and
eventual infarcts
- There is retroplacental hematoma and fibrinoid degradation and this can lead to fetal
hypoxia

** The placenta is the site of variable changes, most of which reflect ischemia and vessel injury
i- Placental infarcts- occur more often in normal, full term placentas are larger and more
numerous
ii- Retroplacental hematoma- increased frequency
iii- Increased villous ischemia- thickening of the trophoblastic basement membrane and
villous hypovascularity
iv- Fibrinoid necrosis- is a characteristic finding of the walls of uterine vessels
v- Acute atherosis- intramural lipid deposition

** The liver demonstrates hepatocellular changes. The liver lesions take the form of irregular,
focal, subcapsular and intraparenchymal hemorrhages
MBBS/DDS 2K16
- Histologic examination shows fibrin thrombi in the portal capillaries with foci of
characteristic peripheral hemorrhagic necrosis
- Liver capsule distension
- Risk of hepatic rupture
- Common Symptoms: epigastric pain, nausea, vomiting

** The reticulo-endothelial system demonstrates decreased platelets and increased fibrin
degradation products
- This leads to DIC

Fig 22-61 pg 1109 ROBBINS

** Classification of pre-eclampsia into: mild and severe

Severe Pre-eclampsia:
- Systolic BP > 160 mmHg
- Diastolic BP > 110 mmHg
- Proteinuria- of at least 5g per 24 hrs (in a 24 hr urine collection)
- Oliguria < 500cc/24hrs- oliguria or anuria suggests severe pre-eclampsia
- Cerebral/visual symptoms- cerebral edema due to hemorrhage leasing to blurred vision,
hyperreflexia, and other visual disturbances
- Pulmonary edema/cyanosis

Note: Blood pressure taken on at least 2 occasions and at least 6 hours apart

HELLP Syndrome: - is a presentation of severe pre-eclampsia
- H- hemolysis- increased bilirubin
- E- elevated liver enzymes
- L- low P-platelets

Mild pre-eclampsia- is any pre-eclampsia not considered to be severe

Eclampsia- defined as generalized tonic clonic seizures in a pregnant patient
- Most present with signs of pre-eclampsia prior to onset (80%)

MBBS/DDS 2K16
Management of Pre-eclampsia
** Mild and moderate forms of toxemia can be controlled by:
- Bed rest
- Balanced diet
- Anti-hypertensive agents

BUT induction of delivery is the only definitive treatment of established pre-eclampsia and
eclampsia
- Proteinuria and hypertension usually disappear within 1-2 weeks after delivery except in
patients in whom these findings predate the pregnancy

Note: Dexamethasone may be given to induce fetal lung maturation

Treatment of Eclampsia
- Stabilize the patient and deliver the baby
- Magnesium sulphate given to control seizures in an eclamptic patient
- Can also be given to prevent seizure in a severely pre-eclamptic woman

Route of Delivery:
- Vaginal is the preferred route

** Caesarean section if there are obstetric indications. The indications for C-section include:
- Placenta previa
- Fetal distress
- cepahlopelvic misproportion

** The fetal risks of pre-eclampsia/eclampsia are:
- Growth restriction
- Oligohydramnios
- Placental infarction
- Placental abruption
- Prematurity and its consequences
- Perinatal death

** The maternal risks of pre-eclampsia/eclampsia:
MBBS/DDS 2K16
- Seizures and stroke
- DIC and its complications
- Increased likelihood of C-section
- Renal failure
- Hepatic failure or rupture
- Death

** Pre-eclampsia disappears when the uterus is emptied. The severe form is preventable by early
delivery
- The renal lesions of pre-eclampsia are reversible (glomerulo-endotheliosis)
- There are no known preventative measures for pre-eclampsia

Note: Post-delivery pre-eclampsia may continue after delivery but this is rare

Antepartum Hemorrhage
** Antepartum hemorrhage is bleeding from the genital tract occurring after the 28
th
week of
pregnancy
- Considered an obstetric emergency

** The causes of Antepartum hemorrhage may be due to any of the following:
- Placenta previa
- Placental abruption
- Lower genital tract lesion
- Heavy show
- Vasa previa

Placenta Previa
** Placenta previa is the implantation of the placenta in the lower uterine segment or cervix
- Associated with serious Antepartum bleeding and premature labor

** The types of placenta previa include:
i- Complete- completely covers the internal cervical os
ii- Partial- partially covers the internal cervical os
iii- Marginal- the edge of the placenta lies near but does not cover the internal cervical os

** Other classification of placenta previa is:
MBBS/DDS 2K16
- Type I- the placenta lies mainly in the upper segment but encroaches on the lower
segment
- Type II- marginal
- Type III- partial
- Type IV- complete

** The risk factors of placenta previa include:
- Advanced maternal age
- Multiparity
- Smoking
- Multi-fetal gestation
- Prior history of placenta previa
- Prior history of suction + curettage for abortion- there is increased risk because of the
associated scarring, therefore the placenta may migrate

** Potential maternal complications of placenta previa include:
i- Life threatening maternal hemorrhage
ii- Caesarean delivery

iii- Placenta accreta- caused by partial/complete absence of the decidua with adherence
of the placenta directly to the myometrium
- Therefore the placenta invades the muscle layer of the uterus
- During delivery because it is tightly adherent it will not slough off leading to massive post-
partum hemorrhage
- May necessitate a hysterectomy
- Therefore the post-partum bleeding is life-threatening because of the failure of placental
separation
- In 60% of cases in is also associated with placenta previa

iv- Post-partum hemorrhage

** The potential fetal complications of placenta previa are:
- Fetal distress
- Increased perinatal mortality

** The clinical features of placenta previa include:
1- Vaginal Bleeding- the hallmark of placenta previa is painless vaginal bleeding in the late
2
nd
or 3
rd
trimesters
2- Absence of uterine pain- unless there is pre-term labor

MBBS/DDS 2K16
** The vital signs will reflect the degree of hemorrhage. The abdomen is usually non-tender
- The presenting part of the fetus may be high above the pelvic brim

** Use ultrasound as part of the diagnosis
- Vaginal examination is contraindicated

** The management depends on maternal evaluation and stabilization
- Expectant management if no evidence of maternal or fetal compromise
- This allows for fetal lung maturation

** The optimal time of delivery is at 38 weeks gestation. The optimal mode of delivery is via
caesarean section
Note: Type I anterior placenta previa may be delivered vaginally because the uterine contractions
may facilitate the moving of the placenta in the opposite direction
- However with all other types, once the cervix dilates the contraction will cause
hemorrhage

Placental Abruption
** Placental abruption is the premature separation of a normally implanted placenta before
delivery of the fetus
** There are two types of abruption:
i- Revealed (external)- 90% vaginal bleeding
ii- Concealed (10%)- no vaginal bleeding

MBBS/DDS 2K16
** The risk factors for placental abruption include:
- Cocaine
- Trauma
- Smoking
- Increasing maternal age
- Increasing parity
- Hypertension
- Sudden uterine decompression- a sudden loss of amniotic fluid from the uterus. This can
suck the placenta from the uterus wall
- Causes of uterine decompression include: birth of first twin, rupture of amniotic membranes
when there is excessive amniotic fluid

** The clinical presentation of placental abruption includes:
- Vaginal bleeding- 90%
- Constant abdominal pain- 50%
- Uterine contractions- 90%
- Uterine tenderness
- Shock
- Fetal demise

Note: A difference between placental abruption and placenta previa is in the nature of the pain
- Placenta previa tends to be painless but placental abruption tends to be associated with
constant abdominal pain

Couvaliere Uterus (uteroplacental apoplexy)- develops as a result of placental abruption which
causes retroplacental bleeding that penetrates the thickness of the uterine wall into the
peritoneal cavity
- The myometrium in this area becomes weakened and may rupture with increased
intrauterine pressure during contractions
- The widespread extravasation of blood into the uterine musculature and beaneath the
serosa, gives the uterus a bluish color at the time of laparotomy

** The diagnosis of placental abruption is made clinically
- Ultrasound is useful to exclude cases of placenta previa
- However ultrasound alone is not sensitive enough to diagnose or exclude placental
abruption

Maternal Complications: Placental Abruption
MBBS/DDS 2K16
i- Hemorrhagic shock
ii- DIC- due to entry of thromboplastins in the circulation from the site of placental injury.
- Leading to widespread activation of the clotting cascade

iii- Renal failure- acute tubular necrosis
iv- Post-partum hemorrhage

Fetal Complications
- Hypoxia
- Anemia
- Growth retardation
- Death

Laboratory Studies
- Full blood count
- Blood type and cross match
- Kleihauer-Betke Stain- determine quantity of Rogham for Rh-negative women
- Assess for DIC- PT, PTT, FDP

Management
- Mild cases and term- deliver
- Mild Cases + Pregnancies <37 weeks- conservative management with delivery after 37
weeks if there is no fetal compromise

** The management of moderate to severe cases includes:
- Maintain blood volume
- Prevent DIC
- Deliver fetus

** The route of delivery depends on severity of the abruption and the gestational age of the fetus
- If there is fetal demise or non-viable fetus but maternal condition is stable, attempt a
vaginal delivery
- Other wise deliver via C-section

Disorders of Fetal Growth: Intrauterine Growth Restriction (IUGR)
**IUGR is an important cause of infant mortality and morbidity
MBBS/DDS 2K16
** IUGR is defined as an estimated fetal weight below the 10
th
percentile for gestational age

Note: Important to distinguish between:
a- Constitutionally small fetus
b- Growth-restricted fetus- prone to adverse perinatal outcome

**Maternal co-morbid conditions that can lead to IUGR are:
- Elevated blood pressure
- Pre-gestational diabetes
- Systemic lupus erythematosus
- Sickle cell disease
- Anti-phospholipid syndrome

** Other causes include:
- Structural anomalies
- Exposure to drugs and toxins
- Primary placental disease
- Multiple gestation
- Infections
- Genetic disorders
- Low socioeconomic status
- Maternal age

Note: In over 1/3 of cases the placenta is small for date, implying poor perfusion

** IUGR can increase perinatal morbidity and mortality. This is related to the decrease in
placental reserve.
**Complications of IUGR include:
- Polycythemia
- Hypoglycemia
- Hyperbilirubinemia
- Hypothermia
- Apneic spells
- Seizures
- Sepsis
- Low Apgar scores
- Umbilical artery pH <7
- Neonatal death
MBBS/DDS 2K16
Print slide #93-95

Intervention
- Avoid smoking
- Bed rest, oxygen therapy
- Careful monitoring of fetal and placental development

** Time of delivery is based on when it is felt that the risk of fetal death exceeds the risk of neonatal
death

Fetal Macrosomia
** Fetal macrosomia is a defined as a birth weight more than 2 standard deviations above the
mean
- or more than 4000 grams

** Maternal factors associated with large for date fetuses are:
- Post maturity
- Obesity
- Excessive weight gain in pregnancy
- Family history of diabetes
- Gestational or clinical diabetes
- Previous macrosomic infant

** The maternal risks are:
- Prolonged labor- which can lead to both maternal and fetal distress
- Obstructed labor and uterine rupture
- Maternal soft tissue injury

** The fetal risks include:
- Shoulder dystocia- after delivery of the head, the anterior shoulder cannot pas below the
pubic symphysis or requires significant manipulation to pass
- The chin of the neonate presses against the walls of the perineum. Associated with infant
brachial plexus injury
- Perinatal asphyxia

Disorders of Amniotic Fluid
MBBS/DDS 2K16
** In the first trimester amniotic fluid may originate as:
i- Transudate of maternal plasma through the chorion/amnion
ii- Transudate of fetal plasma through the fetal skin

** In the second and third trimesters, amniotic fluid is a combination of fetal urine and lung liquid
- The volume of fluid is a balance between fluid production and resorption
- Fetal urine is the main source of production and swallowing the main source of resorption

Oligohydramnios- condition characterized by a deficiency of amniotic fluid
- Diagnosis is made by ultrasound measurement of amniotic fluid index (AFI)
- AFI < 5cm OR single deepest pocket < 2cm

** The causes of oligohydramnios include:
- Fetal chromosomal/congenital anomalies
- Chronic fetal hypoxia
- Post-term pregnancy
- Maternal dehydration
- Rupture of membranes

** The fetal consequences of oligohydramnios are:
- Pulmonary hypoplasia
- Limb contracture
- Fetal distress and death secondary to umbilical cord compression

Polyhydramnios
- Diagnosis: AFT >24 cm OR a single pocket > 8cm

** The causes of polyhydramnios are:
- Idiopathic- in most cases (66%)
- Congenital anomalies- eg. Esophageal atresia
- Maternal diabetes
- Twin-twin transfusion syndrome- is the result of an intrauterine blood transfusions from
one twin to the other twin through placental vascular anastomoses
- The donor twin becomes hypovolemic and oliguric/anuric and oligohydramnios develops
in the donor twin
- The recipient twin becomes hypervolemic and polyuric and polyhydramnios develops
- Hydrops fetalis- is a condition in the fetus characterized by an accumulation of fluid
(edema) in at least two fetal compartments
MBBS/DDS 2K16
- EX: subcutaneous tissue, pleura, pericardium, abdomen
- Hydrops fetalis usually is the result of fetal anemia

** The obstetric complications of polyhydramnios are due to over distention of the uterus:
- Preterm premature rupture of membranes
- Preterm labor

Note: Rapid decompression of polyhydramnios can lead to placental abruption

Preterm Labor
Defn: Labor that begins before the 37
th
week of pregnancy
- Preterm labor is the most significant cause of neonatal morbidity and mortality

Risk Factors
- Past history of pre-term delivery- is the most significant risk factor
- Premature rupture of membranes
- Urinary tract infection
- Multiple gestation
- Abdominal or cervical surgery

Management:
- Rest
- Hydration
- Beta-adrenergic drugs- ritrodine
- Magnesium sulfate
- Dexamethasone- for lung maturity

MBBS/DDS 2K16
Lecture 15: Complications of Labour & Delivery

Lecturer: Dr. Mullings

Print Slide #2

Labour- is the process by which the products of conception are expelled from the uterus and
birth canal

Delivery- is the process by which the products of conception pass out through the birth canal
- May be natural or assisted

** Some complications of labor include:
- Prolonged labour
- Precipitate labour
- Obstructed labour
- Ruptured uterus
- Hemorrhage
- Fetal distress
- Maternal distress
- Operative delivery
- Trauma
- Death

Labour and Delivery
** Freidman describes 3 stags of labour:
1- First Stage- Start of labour to full dilatation. Divided into 3 phases:
- Prodromal or latent
- Active
- Deceleration

2- Second Stage- Full dilatation to delivery of foetus
3- Third Stage- Delivery of fetus to delivery of placenta
MBBS/DDS 2K16

Note: Complications may occur at any of the 3 stages of labour

** The factors and complications influencing labour and delivery:
i- Powers- uterine contractions and voluntary forces
ii- Passage- bony and soft pelvis
iii- Passenger- fetus and placenta

Complications due to Powers
First Stage- Contraction patterns resulting in failure to progress, prolonged or precipitate labour
- Precipitate Labour- is a short labour that lasts less than 3 hours

Second Stage- can be complicated due to inadequate expulsive forces

Third Stage- complicated due to retention of placenta

** Prolonged labor may be due to faults in the:
i- Powers- expulsive uterine and voluntary
ii- Passage- bony and soft
iii- Passenger- development, presentation and position

First Stage- Prolonged Latent Phase
- > 20 hrs primipara
- > 14 hrs multipara
- Occurs very early in labour
- Approximately 3-4% of cases

** Prolonged active phase- dilatation less than expected after active phase has begun. Expectation
1.2 1.5 cm/hr
- Protraction and arrest- slow pace of dilatation + descent
- Arrest of dilatation- 2hrs with no change
- Arrest of descent- I hr without descent

MBBS/DDS 2K16
** 25% of those in the prolonged active phase is nulliparous and 15% are multiparous

** The etiology of prolonged active phase is:
- Fetal malposition
- Conduction anesthesia
- Uterine overdistention
- Cephalo-pelvic misproportion

** The risks to mother and fetus with ruptured membranes:
- Prolonged labour
- Risk of amnionitis
- Fetal distress

Prolonged Acceleration Phase
** The prolonged acceleration phase is the failure to reach full dilatation after 8cm. Contributing
factors include:
- cephalo pelvic disproportion
- Uterine exhaustion

Second Stage
Prolonged in primiparas- lasting more than 1 hr
Prolonged in multipara- lasting more than 2 hr

** Contributing factors are:
- Cephalo pelvic disproportion
- Malposition of the fetus
- Maternal exhaustion
- Uterine exhaustion

Risks:
- Non recognition of problem
- Associated with intervention with intent to deliver from below

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Management:
- Rule out obstruction
- Oxytocin augmentation
- Operative vaginal delivery if criteria met
- C-section especially with obstruction/CPD or failure of above measures

Third Stage
** Prolonged for more then 30 minutes. Risk of prolongation of the third stage are:
- Post partum hemorrhage
- Infection

Uterine Dysfunction
** Uterine dysfunction may occur at any stage or phase of labor and delivery
- Usually occurs in the first stage
- Can be a second stage disease

** Uterine dysfunction is marked by:
i- Lack of dilatation
ii- Lack of effacement
iii- Lack of descent

Hypotonic Dysfunction-
Hypertonic Dysfunction- in coordinate uterine dysfunction
- The force of uterine contraction up to 60mmHg
- Unknown cause in more than 50% of patients

Hypotonic Labour
- Contractions of less than normal intensity
- Results in a prolongation of labor

Hypertonic Dysfunction
** Uterine contractions which seem to cause pain out of proportion to their strength or effect

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** Discoordinated uterine contractions with mid-segment dominance
- Results in painful contractions with poor or no cervical dilation and a soft fundus
- More common in latent phase

Inadequate Expulsion Force
** Inadequate expulsion force may be the result of compromised contraction of abdominal muscles.
Role of:
- Heavy sedation
- Pain
- Neurological factor

Retraction & Contraction Rings
- Localized rings of constrictions of the uterus
- Secondary to protracted labour
- Most common is Bandls Ring
- Usually associated with obstructed labour
- Also results in retention of the fetus

Precipitate Labor
- Very rapid delivery and most times are unable to return to clinic

Maternal Effects:
- Injury to birth passage
- Amniotic fluid embolism

Fetal Effects
- Perinatal morbidity and mortality increase
- Intracranial trauma

Dystocia due to:
** Abnormalities of:
- Presentation other than the vertex
- Position other than occipito anterior
- Development

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Complications of Presentation
- Breech
- Compound
- Transverse
- Shoulder
- Face
- Brow

Complications of Position
Persistent occipito:
- Posterior
- Transverse

Complications of Development
- Macrosomia
- Shoulder dystocia
- Fetal abnormalities: hydrocephalus, large fetal abdomen, conjoined twin

Dystocia of Pelvis
- Contracted pelvic inlet
- Contracted mid pelvis
- Contracted pelvic outlet

Dystocia due to Soft Tissue
i- Vulvar abnormalities- warts
ii- Vaginal abnormalities- septa, stricture, tumors
iii- Cervical abnormalities- atresia, stenosis, tumor
iv- Uterine abnormalities- fibroids
v- Other soft tissue tumors

Print slide # 36

MBBS/DDS 2K16
Lecture 16: Puerperium & Complications

Lecturer: Dr. L. Samuels

Puerperium- is the time immediately after the delivery of a child
- Defined as the time from the delivery of the placenta through the first few weeks after the
delivery
- The period is usually considered to be 6 weeks in duration

Note: By 6 weeks after delivery, most of the changes of pregnancy, labor, + delivery have resolved
and the body has reverted to the non-pregnant state

Uterus
** The pregnant term uterus weighs approximately 1000 grams
- This weight does not include baby, placenta, fluids

** The uterus recedes to a non-pregnant state with a weight of 50-100 grams during the
puerperium
- Most of the reduction in size and weight occurs in the first 2 weeks
- At this time the uterus has usually shrunk enough to be located in the true pelvis
- The endometrial lining rapidly regenerates so that by the 16
th
day the endometrium is
restored throughout the uterus except at the placental site

** The placental site undergoes a series of changes in the post-partum period. After deliver the
contraction of the myometrium results in hemostasis
- The size of the placental bed decreases by half as a result of this contraction
- A bloody discharge (lochia) continues to flow from the uterine cavity after childbirth
- The duration of this discharge (lochia rubra) is variable

** The red discharge changes to brownish red with a more watery consistency, which is known as
lochia serosa
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- Over a period of weeks, the discharge continues to decrease in amount and color and
changes to yellow
- Then becomes known as lochia alba

** The period of time the lochia can last varies
- Averages about 5 weeks, with a waxing and waning amount of flow and color

Cervix
** The cervix also begins to rapidly revert to a nonpregnant state BUT it never returns to the
nulliparous state
- By the end of the first week, the internal os is closed

Vagina
** The vagina shrinks to a non-pregnant state but it does not completely return to its pre-pregnant
size
- Resolution of the increased vascularity and edema occurs by 3 weeks
- The rugae of the vagina begin to reappear in women who are not breastfeeding

Perineum
** The perineum has been stretched and traumatized (cut + torn) during the process of labor and
delivery
- Swelling and engorgement of the vulva rapidly resolves and is completely gone within 1-2
weeks
- Most of the muscle tone is regained by 6 weeks

Abdominal Wall
** The abdominal wall remains soft and poorly toned for many weeks
- The return to a pre-pregnant state depends greatly on exercise

Ovaries
** The resumption of normal function by the ovaries is highly variable and is influenced by
breastfeeding the infant
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- A woman who breastfeeds has a longer period of amenorrhea and anovulation than the
mother who bottle feeds
- A non-breastfeeding woman may ovulate as early as 27 days after delivery
- Most women have a menstrual period by 12 weeks

** In the breast feeding woman the resumption of menses is highly variable and depends on many
factors
- How much + how often the baby is fed
- Whether the babys food is supplemented with formula

** The delay in the return to normal ovarian function in the lactating mother is caused by the
suppression of ovulation due to elevation in prolactin levels

Puerperal Complications

Post-Partum Hemorrhage
- Excessive blood loss during or after the third stage of labor
- 500 mL at vaginal delivery
- 1000 mL at caesarean delivery

Note: These measurements are often based on subjective observation, and is often difficult to
define clinically

** Post-partum hemorrhage is defined as any blood loss which results in symptoms
- May result in the need for transfusion after delivery secondary to blood loss

Early post-partum hemorrhage- is described as blood loss occurring within the first 24 hrs after
delivery
- Late postpartum hemorrhage most frequently occurs in the first two weeks after delivery
but may occurs up to 6 weeks post partum

** Postpartum hemorrhage may result from problems with any one (or combination of) the four Ts.
Clinically these refer to:

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i- Uterine Atony- Tone
ii- Retained Products of Conception- Tissue
iii- Coagulopathy- Thrombus
iv- Infections- Toxins

Note: Uterine atony and lower genital tract lacerations are the most common cause of postpartum
hemorrhage

** In uterine atony the lack of closure of the spiral arteries and venous sinuses coupled with the
increased blood flow to the pregnant uterus causes excessive bleeding

** Factors predisposing to uterine atony include overdistension of the uterus secondary to:
- Multiple gestations
- Polyhydramnios
- Macrosomia

** Other factors contributing to uterine atony are:
- Rapid prolonged labor
- Grand multiparity
- Intra-amniotic infection
- Use of uterine relaxing agents- terbutaline, magnesium sulfate, halogenate anesthetics,
nitroglycerin

** Vaginal delivery is associated with a 3.9% incidence of postpartum hemorrhage
- C-section delivery is associated with a 6.4% incidence of postpartum hemorrhage

Note: Delayed postpartum hemorrhage occurs in 1-2% of patients

** Initial therapy of post-partum hemorrhage involves:
- Oxygen delivery
- Bimanual massage
- Removal of any blood clots from the uterus
- Bladder emptying
- Routine administration of dilute oxytocin infusion- 10-40 U in 1000 mL of lactated Ringer
solution or isotonic sodium chloride solution

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** If retained products of conception are noted, perform manual removal or uterine curettage
- Methylergonovine- can also be administered IM
- Contraindicated in patients with hypertensive disease
- Misoprotol- is a prostaglandin E1 analogue given PR also can be used

** The following surgical treatment methods may be necessary if pharmacological therapy fails
- Also if no vaginal or cervical lacerations have been identified

1- Uterine artery ligation- is successful in 80-95% of patients
2- Hypogastric (internal iliac) artery ligation- is an option but the approach is technically
difficult and is only successful in 42-50% of patients
3- Emergency hysterectomy- may be a necessary and life saving procedure done when all
other therapies fail
4- Stepwise Devascularization- of the uterus is now thought to be the next best approach
- With uterine artery ligation followed by ligation of the utero-ovarian vessels

Post-partum Hemorrhage Sheehan Syndrome
** Sheehan syndrome is the result of congestion, ischemia and infarction of the pituitary gland
caused by severe blood loss at the time of delivery
- Results in panhypopituiratism
- Patients have trouble lactating due to increased prolactin
- Develop amenorrhea due to the decrease in FSH and LH
- Symptoms of cortisol +thyroid hormone deficiency- decreased ACTH and TSH respectively

Treatment: With hormone replacement in order to maintain normal metabolism and response to
stress

Infection: Endometritis
** Endometritis is the primary cause of post-partum infection. Endometritis is an ascending
polymicrobial infection
- The causative agents are usually normal vaginal flora or enteric bacteria

** Known risk factors for endometritis include:
- Prolonged labor
- Prolonged rupture of membranes
- Multiple vaginal examinations
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- Pre-existing infection or colonization of the lower genital tract
- Twin delivery
- Manual removal of the placenta

** The incidence of endometritis in patients who undergo cesarean delivery after an extended
period of labor is 30-35%
- This falls to 15-20% if the patients receives prophylactic antibiotics

Clinical signs
- Fever
- Chills
- Lower abdominal pain
- Malodorous lochia
- Increased vaginal bleeding
- Anorexia
- Malaise

Note: A focused physical exam is important
- A patient with endometritis typically has a fever of 38 C or more
- Tachycardia and fundal tenderness

** Some patients may develop mucopurulent vaginal discharge. Others may have scant and
odorless discharge
- Treatment: with intravenous antibiotics
- Parenteral antibiotics are usually stopped once the patient is afebrile for 24-48 hrs,
tolerating a regular diet and ambulating without difficulty
- Oral antibiotics- are then continued to complete at least 7 days of therapy

Infection: Cystitis
- UTIs are common in pregnancy and the puerperium
- The most common pathogen is E. coli
- In and after pregnancy, group B streptococci is another major pathogen

Print slide #23

Infection: Mastitis
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** Mastitis is defined as inflammation of the mammary gland.
- Milk stasis and cracked nipples which contribute to the influx of skin flora are the
underlying factors associated with the development of mastitis

** Mastisits is also associated with:
- Primiparity
- Incomplete emptying other breast
- Improper nursing technique

** The most common causative organism isolated in 50% of cases is staphylococcus aureus

Note: Neglected, resistant or recurrent infections can lead to the development of an abscess
- This requires parenteral antibiotics and surgical drainage

** Abscess development complicates 5-11% of cases of postpartum mastitis
- Should be suspected when antibiotic therapy fails

** The diagnosis of mastisis is based solely on the clinical picture
- Fever, chills, myalgias, erythema, warmth, swelling, breast tenderness

** When the exam revels a tender, hard, possibly fluctuant mass with overlying erythema, a breast
abscess should be considered

Treatment: Penicillinase-resistant penicilins and cephalsporins (cloxacillin or cephalexin) are the
drugs of choice
- Use erythtomycin, clindamycin and vancomycin for patients who are penicillin resistant

Wound Infection
** Wound infections in the postpartum period includes:
1- Infections of the perineum developing at the side of episiotomy or laceration
- Tend to be uncommon
- Become apparent on the 3
rd
or 4
th
day post partum
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- Known risk factors include infected lochia, fecal contamination of the wound and poor
hygiene
- Infections are generally polymicrobial, arising from the vaginal/intestinal flora

2- Infection of the abdominal incision after C-section
- Usually caused by staphylococcus aureus
- Either from the skin or from an exogenous source
- Usually develop around postoperative day 4
- Often preceded by endometritis
- These patients present with persistent fever despite antibiotic treatment

** Wound infects are diagnosed on the basis of erythema, induration, warmth, tenderness and
purulent drainage from the incision site
- With out without fever

** Known risk factors of wound infection include:
- Diabetes
- Obesity
- Corticosteroid therapy
- Immunosupperession
- Anemia
- Hematoma development
- Chorioamnionitis
- Prolonged labor
- Prolonged membrane rupture
- Prolonged operating time
- Abdominal twin delivers
- Excessive blood loss
Print slide # 30

Venous Thromboemobolism (VTE)
** Pregnancy and the puerperium are risk factors for VTE. VTE is the greatest single cause of
maternal mortatliy in most countries in the developed world

**Virchows Triad are three broad categories of factors that are thought to contribute to
thrombosis. All 3 factors from Virchows Triad are present in the puerperium:
1- Hypercoagulabiltiy
2- Hemodynamic Changes- stasis, turbulence
3- Endothelial Injury/Dysfunction
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Stasis
** The lower extremity veins of pregnant patients are subject to increased stasis even before the
uterus has enlarged substantially

** Although blood volume and total venous return are above normal in pregnancy, the linear flow
velocity in the lower extremity veins is decreased
- May be due to a hormonally induced dilation of capitatance veins
- This leads to venous pooling and valvular incompetence

Note: These early changes are amplified by inferior vena caval compression by the gravid uterus

Endothelial Injury
** Delivery is associated with vascular injury and changes at the uteroplacental surface
- This may account for the frequency of VTE in the immediate postpartum period
- Forceps, vacuum extraction or surgical delivery can exaggerate vascular intimal injury and
amplify this phenomenon

Hypercoagulability
** Pregnancy is a hypercoagulable state associated with progressive increases in several
coagulation factors
- EX: Factors I, II, VII, VIII, IX and X
- There is an associated decreased in Protein S
- There is a progressive increased in resistance to activated Protein C
- This is normally observed in the second and third trimesters

Deep Vein Thrombosis
** The risk of DVT is approximately twice as high after cesarean delivery than vaginal birth
- DVT is more common in the left leg than the right leg
- Increased stasis in the left leg related to compression of the iliac vein by the right iliac
artery
- Along with compression of IVC by the gravid uterus

** The clinical diagnosis of DVT and pulmonary embolism (PE) is insensitive and non-specific
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- Problem of diagnosis is heightened in pregnant women since lower extremity swelling and
discomfort are common in advanced pregnancy
- Women with DVT may present with diffuse pain in the lower abdomen or leg

Note: Dyspnea is the most frequent symptom of PE and occurs at some point in up to 70% of
normal pregnancies

Note: Therefore there are no differences in the diagnostic strategies for DVT and PE in the pregnant
and the non-pregnant patient

Diagnosis
** Doppler ultrasound is the most commonly employed study to detect DVT
- Highly sensitive (95%) and specific (>95%) for symptomatic proximal (leg + thigh) vein
thrombosis
- Slightly less sensitive for pelvic vein thromboses

** MRI can detect both thigh + pelvic DVT with a sensitivity that approaches 100% in the non-
pregnant population

** Ventilation/perfusion (V/Q) lung scanning remains the initial diagnostic modality of choice in
both pregnant and non-pregnant patients for pulmonary embolism
- The estimated fetal radiation exposure is 100 to 200 times less than the dose thought to
produce a significant risk of fetal anomalies

Print slide #42

Treatment
** Treatment for DVT or PE must be began immediately on suspicion of the problem
** IV unfractonated heparin can be initiated and irtated to prolong the PTT
- 4 to 6 week course of warfarin should be completed after deliver (safe in breastfeeding)
- Total course of anticoagulation lasting from 3 to 6 months or until the end of the
puerperium, whichever is longer

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Psychiatric Problems
** Three psychiatric disorders may arise in the puerperium:
1- Postpartum blues- is a transient disorder that lasts hours to weeks.
- Characterized by bouts of crying and sadness
- Symptoms: anxiety, irritation, restlessness, mood lability, headache, confusion, forgetfulness,
insomnia
- No pharmacotherapy is indicated
- Providing support and education has been shown to have a positive effect

2- Postpartum depression- is a more prolonged affective disorder that lasts for weeks to
months
- The signs and symptoms do not differ from depression in other settings
- Symptoms: insomnia, lethargy, loss of libido, pessimism, incapacity of familial love,
ambivalence/negative feelings to an infant
- Consult with a psychiatrist especially when PPD is associated with co-morbid drug abuse,
suicidal or homicidal ideations, hallucinations,
- Print slide #50

3- Postpartum psychosis- occurs in the first postpartum year
- Refers to a group of severe and varied disorders that elicit psychotic symptoms
- Usually present with schizophrenia or manic depression
- Often signals the emergence of pre-existing mental illness induced by the physical and
emotional stresses of pregnancy and delivery

** The specific etiology is unknown, and may be multifactorial
- Symptoms may be due to the decrease in the endorphins of labor and the sudden fall of
estrogen and progesterone levels that occur after delivery
- Postpartum thyroid dysfunction has also been correlated with postpartum psychiatric
disorders
-

MBBS/DDS 2K16
Lecture 17: Ultrasound in Obstetrics

Lecturer: Dr. N. Johnson

Obstetric Ultrasound- is the use of ultrasound scans in pregnancy
- Currently used equipment are known as real-time scanners
- A continuous picture of the moving fetus can be depicted on a monitor screen
- Very high frequency sound waves are between 3.5 to 7.0 megahertz are used

** Sound waves are emitted from a transducer placed in contact with the maternal abdomen
- Information obtained from different reflections are recomposed back into a picture on the
monitor screen

** Can assess:
- Movements such as fetal heart beat
- Malformations- in the fetus
- Measurements- based on the image to assess gestational age, size and growth in th fetus

** A full bladder is required for abdominal scanning in early pregnancy

** The main uses of ultrasonagraphy in pregnancy are:
i- Diagnosis and confirmation of early pregnancy
- Gestational sac can be visualized as early as 4 weeks of gestation
- Yolk sac visualized at 5 weeks
- Embryo can be observed and measured by about 5 weeks
- Can be used to confirm the site of pregnancy within the cavity of the uterus

ii- Vaginal bleeding in early pregnancy- viability of the fetus can be noted
- Presence of heartbeat is visible and detectable by pulsed Doppler ultrasound by about 6
weeks
- Missed abortion and blighted ovum- deformed gestational sac and absence of fetal poles or
heart beat
- 5-8 weeks- a bradycardia (<90bpm) is associated with a high risk of miscarriage
- The diagnosis of missed abortion is usually made via serial ultrasound scans demonstrating
lack of gestational development
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- Useful in the early diagnosis of ectopic + molar pregnancies

iii- Determination of gestational age and assessment of fetal size- Fetal body
measurements reflect the gestational age of the fetus
- May be helpful if the woman is uncertain of her last menstrual periods
- In the latter part of pregnancy measuring body parameters allows assessment of size and
growth of fetus
- This assists in the diagnosis and management of intrauterine growth retardation
iv- Diagnosis of fetal malformation
v- Placental localization
vi- Multiple pregnancies
vii- Hydramnios and oligohydramnios

Measurements
** There are 4 standard biometric parameters to estimate gestational age and/or fetal weight
i- Crown rump length (CRL)- Measurement can be made between 7-13 weeks
- Very accurate estimation of the gestational age
- Dating with the CRL +/- 3-4 days of the last menstrual period

ii- Biparietal diameter (BPD)- best studied and highly reproducible biometric parameter
- Can predict gestational age with +/- 7 days when measured 14 and 20 weeks of gestation
- Note: Accuracy diminishes beyond this period
- Measured on a plane of section that intersects the third ventricle and thalami
(transventricular view)
- Helps to ensure reproducibility among examiners

iii- Abdominal circumference (AC)- single most important measurement in late pregnancy
- Reflects more of fetal size and weight rather than age
- Serial measurements useful in monitoring growth
iv- Femur length (FL)- measure of the longest bone in the body reflects the longitudinal
growth of the fetus

Diagnosis of Fetal Malformation
** Structural abnormalities in the fetus can be diagnosed by 20 weeks:
i- Congenital cardiac abnormalities
ii- Fetal Hydrops
iii- Cleft lips/palate
iv- GI Abnormalities
- exomphalis
- gastroschisis
- duodenal atresia
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v- Skeletal abnormalities- achondroplasia and other dwarfism
vi- CNS anomalies
- hydrocephalus
- anencephaly
- myelomeningocoele
- spina bifida

** First trimester ultrasonic soft markers for chromosomal abnormalities
- Absence of fetal nasal bone
- Incrased fetal nuchal transparency
- Used to enable detection of Down Syndrome fetuses

** Ultrasound can be used to assist in diagnostic procedures:
- Amniocentesis
- Chhorionic villus sampling
- Cordocentesis- percutaneous umbilical blood sampling
- Fetal therapy

Placental Localization
** Useful in localization of placental site and determining its lower edges
- Therefore used to make a diagnosis of or exclude placenta previa

** Other placental abnormalities may occur in conditions such as:
- diabetes
- fetal Hydrops
- Rh isoimmunizaiton
- Severe intrauterine growth retardation

Multiple Pregnancies
- Number of fetuses
- Chorionicity
- Fetal presentation
- Growth retardation
- Fetal anomaly
- Placenta previa
- Twin to twin transfusion syndrome (TTTS)
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Note: TTTS affects identical twins or higher multiple gestations who share a common
monochorionic placenta
- The shared placenta contains abnormal blood vessels which connect the umbilical cord
and circulations of the twins

Hydramnios & Oligohydramnios
** Excessive or decreased amount of amniotic fluid. Both can have adverse effects on the fetus
** Careful ultrasound examination to exclude:
i- IUGR
ii- Congenital malformation- intestinal atresia, Hydrops fetalis, renal dysplasia

Transvaginal Scans
** Specially designed probes that are placed in vagina
** Provides better images and gives more information especially in obese patients and in early
pregnancy
- Useful in early diagnosis of ectopic pregnancies
- Increasing number of fetal abnormalities diagnosed in first trimester
- Useful in second trimester in diagnosis of congenital anomalies

Doppler Basic Principles
** Echoes from stationary tissues are the same from pulse to pulse
** Echoes from moving objects exhibit slight differences in the time for the signal to be returned
to the receiver

** These differences can be measured as phase shift from which the Doppler frequency is
obtained
- T1 = time of omitted signal
- T2 = time of returned signal
- T2 T1 = time difference or phase shift

** As the time difference decreases; the Doppler frequency increases
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** Doppler frequency is obtained by measuring the time difference for the signal to be returned
when reflected from moving scatterers

Print slide #48

Umbilical Artery Flow
- Characteristic saw-tooth appearance of arterial flow in one direction and continuous
umbilical venous blood flow in the other

** Volume flow in the umbilical arteries increases with advancing gestation
- High vascular impedence detected in the first trimester gradually decreases
- Attribute to the growth of the placental unit and increase in the number of functioning
vascular channels

Middle Cerebral Artery
** In fetal anemia, blood velocity is increased

Schedule
** Scans may be ordered when an abnormality is suspected on clinical grounds. Otherwise a scan
is generally booked at about 7 weeks to:
1- Confirm pregnancy
2- Exclude ectopic or molar pregnancies
3- Confirm cardiac pulsation
4- Measure crown-rump length for dating

** The second scan is performed at 18-20 weeks to look for:
i- Congenital malformations
ii- Exclude multiple pregnancies
iii- Verify dates and growth
iv- Determine placental position

** A third scan may sometimes be done at around 34 weeks
- Evaluate fetal size
- Assess fetal growth
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- Placental position further verified

Note: Many centers are now performing earlier screening scans at 13-14 weeks to aid in the
diagnosis of Downs Syndrome:
- Measure fetal nuchal transparency
- Evaluate the fetal nasal bone

MBBS/DDS 2K16
Lecture 18: Medical Complications in Pregnancy

Lecturer: Dr. S. Kulkarni

Biochemical Disorder in Diabetes

Print slide #5
Classification of Diabetes in Pregnancy
1- Pre-existing diabetes with or without vasculopathy
2- Gestational diabetes

Pre-Existing Diabetes
TYPE I- insulin dependent
TYPE II- non-insulin dependent
** Whites classification based on:
- age of onset
- duration of disease
- presence of vasculopathy
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Whites Classification
A- chemical abnormality only
B- Age onset > 20 years duration < 10yrs
C- Age 10-19, duration 10-19
D- Age < 10, duration > 20, benign retinopathy

F diabetes with renal disease
H diabetes with heart disease
R diabetes with proliferative retinopathy
T diabetes with renal transplant

Gestational Diabetes
Defn: Diabetes in pregnancy in a person previously documented to be normal both pre-pregnancy
and postpartum
- Onset is generally > 20 weeks gestation

Working Defn: Diabetes diagnosed in pregnancy that remits post-partum

** Risk factors for gestational diabetes include:
1- Family history- especially siblings and co-twins
2- Personal history- obesity, hypertension, steroid use
3- Past pregnancies:
- Macrosomia- birth weight > 4kg
- Recurrent miscarriage
- Unexplained perinatal loss
- Congenital malformations (structural)

4- Current Pregnancy:
- Glycosuria
- Large for dates
- Polyhydramnios
- Multiple pregnancy
- PIH
- Pyelonephritis

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Carbohydrate Metabolism in Pregnancy
** During a normal pregnancy there are a few diabetogenic endocrine changes that occur:
1- Production of feto-placental hormones:
- EX: hCG, hPL, estrogens and progesterone

2- Increased globulins- therefore bound hormones are decreased
3- Anterior pituitary hormones- some are increased and some are suppressed
- Increased- HGH, ACTH, TSH, prolactin
- Suppressed- FSH + LH

4- Hyperplasia- of adrenals, thyroid and parathyroid glands
5- Pancreas- beta cells of the pancreas increase in number and the result is hyperinsulinemia
and insulin resistance

Development of Endocrinopathy

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** Fetal-neonatal consequences of Maternal Diabetes

Maternal Problems in Diabetic Pregnancy

Medical:
- Loss of glycemic control
- Infections- genital, UTI
- Worsening vasculopathy- White Classes F to T

Obstetric:
- Pre-eclampsia
- Antepartum hemorrhage
- Polyhydramnios
- Preterm delivery
- Operative delivery

Print Slide #27 + 30 IMPORTANT

Current Recommendations in Screening for Gestational Diabetes

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All pregnant women > 25 years
- OSullivans screen at 24 weeks
- If positive do 75g GTT
- If positive manage as a diabetic

Risk factors present irrespective of age
- Screen at booking or ASAP
- Redcreen at 24 weeks if negative
- GTT whenever screen is positive

Management
Print slide #34
Pre-Pregnancy Care
** Suitable for known diabetics and those with risk factors
- Schedule 3 months prior to pregnancy
- Educate and monitor the blood glucose + glycosylated Hb
- Diet and exercise
- Review medications and convert to insulin
- Folic acid supplementation

Early Booking (1
st
Trimester)
** Screen for diabetes if risk factors are present.
- Confirm the gestational age via LMP, vaginal exam, TV-ultrasound
- Plan care jointly with endocrinologis

Note: A Type I diabetic may present with hypoglycemic coma as the first sign of pregnancy

Medical Care
** Plan a balanced diet:
- 45-50% CHO
- 25-35% protein
- 20% fats
- High fiber
- 30-35 cal/kg ideal weight

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** Divide calories into 3 meals and 3 snacks
- 2/3 of caloric intake in th daytime
- 1/3 of caloric intake in the evening

Glycemic Targets:
- Fasting < 5.5 mmol/L
- 2hr pp < 6.8 mmol/L
- Avoid extremes of hypoglycemia vs ketoacidosis

** Home glucometer monitoring with cross checks at the lab
** Admit if home monitoring is not effective resulting in loss of control and complications
presenting
Print Slide #40

Oral Hypoglycemic Agents
1- Metformin- experience in patients with PCOS who often have co-existing glucose
intolerance suggests continuation of therapy may lessen the risk of gestational diabetes
mellitus and spontaneous abortions
2- Glyburide- Failure is common in the 3
rd
trimester and requires insulin

Obstetric Care
Second Trimesters- detailed anomaly scan at 18-20 weeks in a known diabetic
24 weeks- first diabetic screen in all women > 25 years
- Second screen in those with risk factors
Third Trimester- Monitor for pre-eclampsia, polyhydramnios and pre-term labor

** Planned delivery at 38 weeks. Can be delivered at 40 weeks if GDM is controlled
- Induce labor if the expected fetal weight is <4kg
- Spontaneous labor in exceptional case up to 40 weeks
- C-section delivery if conditions are unfavorable

Print slide #49 +52
MBBS/DDS 2K16
Lecture 19: Abnormal Uterine Bleeding

Lecturer: Dr. S. Mitchell

** Abnormal uterine bleeding is any deviation in normal frequency, duration or amount of
menstruation in women of reproductive age

Normal Menses:
- Frequency = q 21-35 days
- Duration = 3- 7 days
- Volume = 30-80 ml

Clinical Types
1- Polymenorrhoea- frequent menstruation ( <21 days) at regular intervals
2- Menorrhagia- Excessive ( >80 ml) and/or prolonged menstruation at regular intervals
- May idiopathic or secondary to a cause such as fibroids

3- Metorrhagia- Excessive and/or prolonged menstruation at irregular intervals
4- Menometorrhagia- Both?
5- Intermestrual Bleeding- episodes of uterine bleeding between regular menstruations
6- Hypomenorrhea- scanty menstruation
7- Oligomenorrhea- infrequent menstruation (> 35 day interval)
- Oligomenorrhea can also be defined by the quantity <30 ml

Dysfunctional Uterine Bleeding- is defined as abnormal bleeding without associated pathology in
the uterus
- Therefore it is a diagnosis of exclusion after all other uterine pathology has been ruled out
- Therefore bleeding due to endometrial cancer, fibroids, adenomyosis, etc cannot be
considered dysfunctional bleeding
- Dysfunctional uterine bleeding accounts for 60% of abnormal uterine bleeding

** Other pathological causes of abnormal uterine bleeding include:
1- Pregnancy Complications- abortion, ectopic pregnancy, trophoblastic disease
2- Genital Disease
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3- Tumors- Benign- fibroids, polyps (cervical or endometrial)
- Malignant- estrogen secreting- cervical, endometrial, ovarian

4- Infection- PID- the inflamed endometrium may bleed
5- Endometriosis- especially ovarian endometriosis
6- IUCD- associated mainly with non-hormonal bleeding

** Extra-genital causes of abnormal uterine bleeding include:
i- Endocrine- hypo or hyperthyroidism
ii- Hematological- Idiopathic thrombocytopenic purpura, Von-Willebrands disease
iii- Chronic Systemic Disease- liver failure, renal failure, hypertension with uterine artery
artherosclerosis
iv- Iatrogenic- sex hormones, anticoagulants
v- Emotional- change of country, climate, work, stress, psychosomatic disorders
- A reactive history and the absence of pathology can lead to a diagnosis of emotional causes of
abnormal uterine bleeding
vi- Obesity- excessive weight gain can lead to abnormal periods and infertility
- The obesity may be a part of polycystic ovarian syndrome
- Or may be due to diet and sedentary lifestyle
- Obesity can lead to increased peripheral estrogen conversion

Normal Menstruation
** Normal menstruation periods occur as the endometrium is shed following failure of
implantation or fertilization of the oocyte
- Menstruation is initiated in response to changes in steroids produced by the ovaries
- The ovaries are controlled by the pituitary and hypothalamus

** Within the ovary, the menstrual cycle can be divided into three phases:
i- Follicular phase
ii- Ovulation
iii- Luteal phase

Follicular Phase
** The development of the oocyte is the key event in the follicular phase of the menstrual cycle
- The ovary contains thousands of primordial follicles that are in a continuous state of
development from birth
- The initial stages of follicular development are independent of hormonal stimulation
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- Development beyond the pre-antral stage is stimulated by the pituitary hormones: LH
+FSH

** At the start of the menstrual cycle, FSH levels begin to rise as the pituitary is released from the
negative feedback effects of progesterone, estrogen + inhibin
- Rising FSH levels initiate steroidogenesis

** Stetroidogeneis is compartmentalized in the two cell types within the follicle:
- Theca cells- responsive to LH
- Granulosa cells- responsive to FSH

** In the theca cells, LH stimulates the production of androgens from cholesterol
** In the granulosa cells, FSH stimulates the conversion of thecally derived androgens to
estrogens (aromatization)
- FSH is also responsible for the proliferation of granulosa cells

** The changes in the endometrium that occur during the menstrual cycle are described below

** As the corpus luteum dies at the end of the luteal phase, circulating levels of estrogen and
progesterone fall precipitously

** In an ovulatory cycle, where the endometrium is exposed to estrogen and then progesterone
in an orderly manner, the endometrium becomes decidualized
- This occurs during the second half of the cycle to allow implantation of the embryo
- Decidualization is an irreversible process and if implantation does not occur, apoptosis
follows

** Menstruation is the shedding of the dead endometrium and stops as the endometrium
regenerates
- Menstruation is initated by the withdrawal of estrogen and progesterone

** Withdrawal of progesterone has several main effects:
1- Spiral Artery Vasocontriction- two days before menses spiral artery blood flow stops
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- The effect of progesterone on the spiral arteries are indirect and generated by locally
produced prostaglandins, endothelins, and angiotensin II
- Prostanoids = prostacyclin + thromboxane
- The balance between these two prostanoids determines the level of bleeding at the level of
the endometrium

2- Endometrial Glands- empty and shrink

**The above events lead to ischemia and tissue damage and result in shedding of the functional
endometrium
- Menstruation stops as the damaged spiral arteries vasoconstrict and the endometrium
regenerates

Hemostasis
** Hemostasis in the endometrial vessels differs from hemostasis elsewhere. Normally bleeding
from a damaged vessels is stemmed by platelet accumulation, fibrin deposition and platelet
degranulation
- These events normally lead to scarring
- However in the endometrium scarring would significantly inhibit function as seen in
Ashermans syndrome

** In the endometrium, vasoconstriction is the mechanism by which hemostasis is initially
secured
- Scarring is minimized by enhanced fibrinolysis, which breaks down blood clots
- Later, repair of the endometrium and new blood vessel formation (angiogenesis) lead to the
complete cessation of bleeding within 5-7 days from the start of the menstrual cycle

MBBS/DDS 2K16
Lecture 20: Human Reproduction and Reproductive Issues

Lecturer: Professor Frederick

Conception- is the process of implantation of fertilized gametes leading to pregnancy

Fertility- is the number of live children born to a couple
- A fertile couple has a 20-25% rate of conception per ovum

Natural Conception
** Requirements for natural conception include:
I- Ovulation- production of mature eggs
II- Immunocompatibitliy- the immune system plays an important role in sub-fertility
III- Patency of fallopian tubes
IV- Normal semen analysis

Sub-Fertility- is the condition of being less than normally fertile though still capable of fertilization

Infertility
** Infertility is defined as the inability of a couple to conceive after one year of unprotected sexual
intercourse
- Incidence of 10-15% world wide
- Infertility may be manifested in the form of recurrent abortions

** A history related to infertility includes:
i- Menstrual Irregularity- anovulation
ii- Galactorrhea- milk production outside of pregnancy
iii- Hisutism- facial hair or male type distribution of hair
iv- Excessive weight gain
v- Drugs- such as antidepressants that affect dopamine levels

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** Pelvic factors, which can lead to infertility, include:
i- Chronic pelvic pain
ii- Incapacitating dysmenorrheal- related to endometriosis
iii- Congestive dysmenorrheal- is accompanied by congestion of the uterus.
- Various inflammatory diseases such as inflammation of the ovaries and fallopian tubes or
pelvic adhesions
- This results in increased blood flow to the uterus and ovaries
- Therefore these organs become tense before the onset of menses resulting in pain

iv- Previous myomectomy- with posterior incisions. A myomectomy is a surgery done to
remove fibroids
- Therefore adhesions can develop on the uterus which can then compromise fertility

v- Surgery for endometriosis
vi- Tubal Disease
vii- Genital Abnormalities- abnormal uterus morphology or ovarian dysgenesis

** A history related to male infertility includes:
i- Premature ejaculation
ii- Erectile dysfunction
iii- Diabetes mellitus + related drug therapies
iv- Previous vasectomy
v- Previous prostatectomy
vi- Never having sired children in any previous relationships

1- Azoospermia- absence of spermatozoa
2- Oligospermia- is low semen volume
- Oligozoospermia- is defined as a sample with less than 20 million spermatozoa per ml of
ejaculate

3- Asthernospermia- sluggish sperm motility. Less than 40% motility at 6 hrs
- For normal sperm within 6 hrs of coitus they can move from the vagina to the fallopian tube

4- Teratospermia- presence of sperm with abnormal morphology

Andrology
** Androloigy is a medical specialty that deals with male health, particularly relating to the male
reproductive system
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- According to WHO 1 in 6 males has an infertility factor
- Investigations of semen
- Hormonal assay in cases of abnormal semen analysis
- Imaging of testicles

Infertility Investigations
** The aim of infertility investigations is to identify factor(s) inhibiting ovulation
i. Fallopian and tubal factors- occlusion, hydrosalpinges
- Hydrosalpinges- are dilated and occluded fallopian tubes usually the result of prior pelvic
infection
- The presence of hydrosalpinges implies chronic disease of the fallopian tubes
- Normally the fallopian tubes function as a conduit and an incubator
- Contains secretory cells interspersed between ciliated cells
- Contains intergrins which promote fertilization

** Hydrosalpinges reduces B-intergrins in the fallopian tubes
- This has a hydroscopic effect on embryos
- Reduces implantation and pregnancy rates

ii. Ovarian-peritoneal factors- endometriosis, presence of chocolate cysts
iii. Immunological factors- endometriosis, sperm antibodies

Note: Uterine fibroids do not prevent pregnancy BUT they may be associated with recurrent
abortion

Sonography
** Transvaginal ultrasound can be used to asses:
- Endometrial thickness (>7mm)
- Follicular size >18 mm
- Triple line- seen in ovulation

Hysterosonography (sonohystereography) is a technique that involves the slow infusion of saline
solution into a womans uterus during ultrasound imaging
- Allows the evaluation of abnormal growths inside the tissue
- Abnormalities of the tissue lining the uterus
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- In women with fertility problems may be used to visualize polyps, fibroids or adhesions
inside the uterus (intrauterine adhesions)
- Therefore this techniques allows for the evaluation of uterine cavity and fallopian tubes

Hormonal (Biochemical) Tests
1- Pituitary Profile- FSH, LH, prolactin
- Increased levels of prolactin may be related to anovulation
2- Thyroid function- TSH, T3
3- Ovarian- estradiols, inhibinA, inhibin B, day 21 serum progesterone
4- Serum testosterone
5- Adrenal (DHEA)
6- Fasting insulin- women with polycycstic ovarian syndrome will have insulin
insensitivity
- Therefore the fasting insulin will be elevated

Male Hormonal Profile- FSH, LH, prolactin, testosterone
Print slide #22

Hysterosalpingogram (HSG)
** HSG is a radiologic procedure to investigate the shape of the uterine cavity and the shape and
patency of the fallopian tubes
- Injection of a radio-opaque material into the cervical canal
- Normal result shows the filling of the uterine cavity and bilateral filling of the fallopian
tube with the injection material (T-shaped appearance)
- To demonstrate tubal patency spillage of the material into the peritoneal cavity should be
observed
- No uterine fillage = cornual occlusion
- No dye spillage = fimbrial occlusion

Note: The presence of one blocked tube at the fimbrial end increases fertility problems

Surgery
1- Lysis of adhesions- to remove adhesions
2- Fimbrioplasty
3- Tubal reanastomosis
4- Excision of endrometriotic nodules- peritoneal stripping
5- Excision of hydrosalpinges

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Note: Surgery to address problems related to endometriosis has the best chance of improving
fertility

Endometriosis
** Endometriosis may have an immunological basis that may prevent the sperm and egg from
meeting
- Therefore the condition itself may have a deleterious effect on gametes

** Endometriosis also causes distortion of pelvic anatomy contributing to infertility
- Anatomic destruction secondary to invasive lesions and adhesions
- Peritoneal stripping has a high success rate
- Excision of deep infiltrating nodules has demonstrated pain relief and improved pregnancy
rates

Intrauterine Insemination
- Also known as artificial insemination
- Low success rate
- 16% success with donor sperm
- 11% success using partner sperm
- Sperm is placed directly into the uterine cavity

Treatment Options
1- Endoscopic surgery for endometriosis
2- Endoscopic surgery for deep infiltrating nodules (DIN)
3- Intrauterine insemination- with partner or donor sperm
4- IVF + ET
5- Intracytoplasmic sperm injection- injection of a single spermatozoon directly into an
ooplasm
- Useful for men with oligospermia
- Perform testicular aspiration
- Microepididymal sperm aspiration in azoospermia due to blockage of vas deferens

6- Cryopreservation of sperm and embryos

Print slide #49

MBBS/DDS 2K16
Lecture 21: Management of Infertility

Lecturer: Dr. S. Wynter

Primary Infertility- is the inability to conceive despite regular unprotected sexual intercourse
for 1 year
- RCOG = 2 years

Secondary Infertility- is the inability to conceive, having had at least one pregnancy, despite
regular unprotected sexual intercourse for 1 year
- RCOG = 2 years

** 8-10% of couples are affected by infertility

Sterility- is the inability to conceive

Management
History + Examination:
- Thorough history from both individuals
- If they attend together, examine separately and ask about STIs and undeclared pregnancies
- Look for development of secondary sexual characteristics
- Look for features of endocrine disorders
- Examine the reproductive organs

Infertility Investigations
1- Ovarian Reserve- Find Day 3 levels of FSH, LH, estradiol
- FSH is the most significant indicator of ovarian reserve
- If the gonads are resistance there are increased hormone levels
- Therefore FSH levels increase as a woman ages because there are less follicles
- A young female should have a low- normal FSH level

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** On Day 3 FSH, LH and estradiol are at lowest levels because at Day 4 of cycle the levels begin to
climb
- Note: Inhibin B ovarian peptide hormone being investigated

2- Ovulation- Day 21 progesterone, urinary LH, serial ultrasound follicle scan
- Progesterone levels are increased post-ovulation because the levels peak in the mid-luteal
phase
- Urinary LH surge occurs during ovulation
- Transvaginal ultrasound in mid-cycle done serially
- Basal body temperature chart- body temperature dips in the luteal phase then spikes by
0.5 degrees during ovulation

3- Tubal Patency Tests- hysterosalpingogram (HSG), laparoscopy and dye insufflation
4- Others- hysteroscopy, faloposcopy, fertiloscopy
- Fertiloscopy- is a method of doing multiple tests
- Faloposcopy- small enough to enter the os

Print slide #9
Male Infertility
Semen Analysis- masturbation collection post-3day absentia to determine the quality of the
spermatozoa
Print Slide #10
MBBS/DDS 2K16

Diagnosis
** To make a diagnosis at a primary care level there are 3 tests that need to be done:
i- Test of ovulation
ii- Tubal patency
iii- Semen analysis

** To make a more specific diagnosis secondary + tertiary level testing is required i.e.:
- Laparoscopy
- Hysteroscopy
- Endocrine anovulation work-up
- Chromosomes
- Anti-phospholipid syndrome- related to recurrent pregnancy loss
- APLS is a disorder of coagulation that causes clots in both arteries + veins
- Syndrome occurs due to the autoimmune production of antibodies against phospholipids
(cell membrane substance)
- Connected to pregnancy-related complications such as miscarriage, stillbirth, preterm
delivery, or severe pre-eclampsia

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Treatment
1- Counseling- education on human fertility in general
- Cumulative probability
- Effect of age
- Lifestyle age
- Treatment options, success rates, adoption

Male Treatment:
- Stop smoking
- Limit alcohol intake to <3-4 units of alcohol/week
- Treat infections
- Varicocelectomy- if there are pre-existing varicocoeles
- Erective Dysfunction- treat with Viagra, psychotherapy
- Clomiphene Citrate- causes FSH levels to rise
- Therefore used for low sperm count. Test sperm levels in 3 months after treatment
- Artificial Insemination- with donors sperm or partners sperm
- Intrauterine insemination-
- Assisted conception- GIFT, IVF, ICSI

GIFT- Gamete Intrafallopian Transfer- is an infertility treatment in which eggs are removed
from womans fallopian tubes along with the mans sperm
- This allows fertilization to take place inside the womans body
- Can be done with one normal tube present
- Done via laparoscope or hysteroscope

ZIFT- Zygote Intra-Fallopian Transfer- male infertility

PROST- Pro-nuclear stage oocyte transfer

In vitro IVF- union occurs in the dish
In vivo IVF- union occurs in the ampulla

Female Treatment:
1- Tubal occlusion- surgery or IVF
2- Endometriosis- medical and surgical treatment
3- Amenorrhea- treatment directed at the cause
4- Ovarian failure- oocyte donation
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5- Hyperprolactinemia- use of dopamine agonist (Bromocriptine, dostine) or neurosurgical
ablation

6- Polycystic Ovarian Syndrome- related to insulin resistance therefore treat with
metformin
- Clomiphene
- Ovarian endocoagulation

Note: The pregnancy rate post-tubal surgery are low (< 10%) because the tube is still
diseases/scarred even though it has been opened surgically
IVF Indications- Female
1- Tubal Factors- irreversible tubal damage or failed tubal surgery
2- Endometriosis- if no pregnancy after medial or surgical treatment
- Oocyte recovery rate is lower with persistent stage III or IV disease
- After resection ovarian function may be altered

3- Cervical Factors- sperm fails to penetrate mucus
4- Immunological Causes- anti-sperm antibodies
5- Offspring of Women treated with DES- diethylstilbestrol (DES) is a drug that is an orally
active synthetic nonsteroidal estrogen
- DES was approved for gonorrheal Vaginitis, atrophic Vaginitis, menopausal symptoms +
postpartum lactation suppression
- DES related to uterine + tubal abnormalities

IVF Indications- Male
1- Male Infertility- Azoospermia is amenable to treatment with ICSI
2- Multifactorial Infertility- male factor is the determining element
3- Unexplained infertility- outcome can be as good as tubal factor

Note: Other indications for IVF include:
- Ovulatory disorder
- Persistent LUF syndrome- Luteinized Unrupted Follicle Syndrome- usually within 38 hours
of the urinary LH surface, the follicle ruptures and releases the egg
- Sometimes due to abnormal follicular development or pelvic adhesions there is failure
of the ovary to release the egg into the peritoneal cavity at the time of ovulation
- Failed artificial insemination

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Oocyte Donation
** Oocyte donation may be needed for:
i- Gonadal dysgenesis- is a reproductive system development disorder
- Characterized by a progressive loss of germ cells on the developing gonads of an embryo
- This loss leads to hypoplastic gonads composed mainly of fibrous tissue (streak gonads)

ii- Autoimmune ovarian failure- oocyte donation after failed steroid treatment
iii- Premature menopause
iv- Physically inaccessible ovaries
v- Autosomal dominant, sex linked disorders
Print Slide #32
Induction of Ovulation
i- Cloiphene citrate- 50-100 mg od x 5 days
- From day 5-9 of the cycle
- Serial ultrasound to track follicle growth
- Check dosing with luteal phase progesterone level
ii- Human menopausal gonadotrophin (hMG)- followed by hCG to mimic LH
iii- Pure FSH- followed by hCG- super physiological doses of FSH are given to stimulate
egg production
- Therefore multiple follicles will mature per cycle instead of one
- The main risk is ovarian hyperstimulation syndrome

iv- GnRH agonists- down-regulate then stimulate as above. Pulsatile stimulation

Print slides #35-36 + 43

MBBS/DDS 2K16
Lecture 22: Common Vaginal & Pelvic Problems

Lecturer: Dr. S. Wynter

Vulva
- Vulvitis, candida
- Bartholins cyst/abscess
- Codyloma accuminata, genital warts
- Herpes simplex

Vulvitis
- Pruritis
- Erythematous rash with satellites
- White discharge
- Microabscesses
- Candia
- Treat with topical antifungal

Bartholins Cyst/Abscess\
** Arise from the duct of Bartholins gland, which lies in the subcutaneous tissue below the lower
1/3 of the labium majora
- Bartholins cysts are swelling of the posterior 1/3 of the vulva
- When the duct becomes blocked, a tense retention cyst forms
- The patient usually presents only after a painful abscess has formed

Treatment: Marsupialization of the abscess, incision and drainage
- Antibiotic therapy
- Marsupialization- opening the cyst walls and stitch the edges open

Condyloma Accuminata (Genital Warts)
** Condylomata acuminata presenting as small papules
- Thee are sometimes sessile and often polypoid
- Due to infection with HPV usually type 6 or 11
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- Raised lesions sometimes associated with pruritis

Herpes Simplex
- Vesicles and blisters followed by ulceration
- Self limiting
- Recurrent
- Treat with an antiviral- acyclovir

VAGINA

Physiological Discharge- normal vaginal discharge is white and becomes yellowish on contact
with air, due to oxidation
- Consists of desquamated epithelial cells from the vagina and cervix
- Also mucus that originates mainly from the cervical glands
- Bacteria + fluid is also present as a Transudate from the vaginal wall
- More than 95% of the bacteria present are lactobacilli
- The acidic pH is maintained by the lactobacilli and through the production of lactic acid by
the vaginal epithelium metabolizing glycogen

** Physiological discharge increases due to increased mucus production from the cervix in mid-
cycle
- Discharge also increases in pregnancy
- Also may be increased when women begin using a combined oral contraceptive pill

** Therefore physiological discharge has a variable quantity, hormonal influence and cyclical
pattern. May be increased during:
- pre-menstrual period
- ovulation
- OCPs
- IUCD

** When progesterone increases the discharge is thicker, cloudy, opaque
- Estrogen makes the discharge thinner, runny + clear

** Normal flora- has 10
8 -9
bacteria per gram of fluid
- Contains both aerobic + anaerobic bacteria
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Lucoria- are increased amounts of discharge/secretion without the presence of a pathogen

Note: Lactobacilli produce lactic acid and therefore self-selects out the other bacteria
- Therefore if there are decreased amounts of lactobacilli then the growth of other bacteria
increases

Pathological Discharge (Non-infective)
1- Ectropion- is cervical erosion in which the central columnar epithelium protrudes out of
the external os of the cervix
- Associated with excessive but non-purulent vaginal discharge due to the increased surface
area of columnar epithelium containing mucus-secreting glands
- May give rise to post-coital bleeding as fine blood vessels present within the columnar
epithelium are easily traumatized
- At menopause the columnar epithelium regresses

2- Polyps
3- Neoplasms
4- Foreign bodies- tampons, condoms
5- Allergy + dermatitis

Pathological Discharge (Infective)
** Infective pathological discharge may be due to various infectious agents:
- Fungal
- Protozoa
- Bacterial
- Viral
- Spirochete
- Mycoplasma

** A history associated with pathological discharge include:
i- Duration
ii- Irritation
iii- Odor
iv- Cyclical pattern- recurrent yeast infections pre-menstruation or recurrent bacterial
vaginosis post-menstrual
v- Abdominal pain + fever- is suggestive of upper tract infections
vi- Fever + rash
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vii- Joint pain
viii- Dyspareunia
ix- Menstrual problems
x- Sexual history
xi- Partners symptoms

Examination
- Inspection
- Palpate Bartholins glands
- Milk the urethra
- Speculum Examination- swab the posterior fornix + endocervical canal

Note: An endocervical canal swab is necessary because gonorrhea and Chlamydia infect glandular
cells not squamous cells
- Therefore doing only a vaginal swab is not adequate

- Test pH
- Bimanual palpation

Bacterial Vaginosis
** Bacterial vaginosis is the commonest cause of abnormal vaginal discharge in women of child-
bearing age
- The underlying cause in 50% of cases
- Commoner in women of Afro-Caribbean origin
- Also in those with an intrauterine device

** Bacterial vaginosis often arises spontaneously around the time of menstruation and may
resolve spontaneously in mid-cycle
- When BV develops the predominantly anaerobic organisms that are usually present in the
vagina in low concentrations increase in concentration up to 1000 fold
- Therefore the anaerobes increase in number BUT do not cause an inflammation
- The increase in organisms is accompanied by an increase in vaginal pH (4.5 -7.0)
- Therefore the lactobacilli ultimately disappear
- These increased population of anaerobes release an odor in the presence of an alkali
(semen, menstrual fluid)
- As a result there tends to be a fishy odor, usually post-coital

** The organisms most commonly associated with BV are:
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- Gardnerella vaginalis
- Bacteroides
- Mobiluncus spp
- Mycoplasma hominis

** The principal symptom is an offensive, fishy smelling discharge
- The discharge is thin, homogenous and adherent to the walls of the vagina
- The smell is particularly noticeable around the time of menstruation or post-coitus

** The diagnosis of BV is made using the composite (Amsel) criteria
i- Vaginal pH > 4.5
ii- Whiff test- release of a fish smell on addition of alkali (10% KOH)
iii- Clue Cells- present under microscopy

Note: Clue cells are vaginal epithelial cells that are so heavily coated with bacteria that the
border is obscured

** Women with BV are at a greater risk of second trimester miscarriage and preterm delivery during
pregnancy
- The preterm delivery may result in perinatal mortality or cerebral palsy

Treatment: Metronidazole 500mg bd x 1/52
Alternative Regimens:
- Metronidazole 2g po stat dose
- Clindamycin cream- one 5g applicator pv nocte x 1/52
- Metronidazole gel- one applicator bd 5/7
- Clindamycin 300 mg bd po 1/52

Vaginitis & Candida
** Candida is an organism that is carried in the gut, under the nails, in the vagina and on the skin
- The yeast Candida albicans is implicated in more than 80% of cases

** Sexual acquisition is not an important factor. However the physical trauma of intercourse may
rigger an attack in a pre-disposed individual
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** The classical presentation of vaginal candidiasis is with:
- pruritis- itching of the vagina and vulva
- Curdy, white vaginal discharge
- In some women there may be inching and redness with a thin, watery discharge
- External dysuria and dyspareunia

** The hyphae of the Candida grow into the skin cells and cause inflammation because the growth
is now adherent to the skin

Note: The pH of vaginal fluid is usually normal (3.5-4.5)

** The predisposing factors to vaginal candidiasis are:
- Immunosuppression
- HIV infection
- Immunosuppressive therapy- steroids, chemotherapy
- Diabetes mellitus
- Vaginal douching, bubble baths, tight clothing
- Increased estrogen
- Pregnancy
- High dose combined OCP
- Underlying dermatosis- eczema
- Broad spectrum antibiotic therapy

Treatment: Use of topical azole drugs is preferred
- 3 and 7 day regimens preferred
- Single dose may be effective for mild-moderate cases

Oral azole drugs
- 1-5 days depending on the agent
- Fluconazole, itroconazole
Trichnomoniasis
** A sexually transmissible infection that may be asymptomatic for several months
MEN: Usually carried asymptomatically but may present as non-gonococcal urethritis
WOMEN: causes a vulvovaginitis that is accompanied by a purulent and sometimes offensive
discharge
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** Examinations shows a frothy, malodorous yellow/green vaginal discharge with inflammation
- The inflammation may extend out onto the vulva and adjacent skin
- Punctuate hemorrhages can occur on the cervix, giving the appearance of a strawberry
cervix

Treatment: Metronidazole 2g po stat
Alternative: Metronidazole 500mg BD x 1/52

CERVIX
Cervicitis

** Mucopurulent cervicitis is a clinical diagnosis based on detecting purulent mucus at the
cervical os
- Usually accompanied by contact bleeding

Note: Cervicitis may be confused with a benign ectropion BUT an ectropion does not bleed heavily
unless swabbed vigorously
- However women with cervicitis may present with post-coital bleeding or complain of a
purulent vaginal discharge

** Cervicitis is often caused by a sexually transmissible agent. Chlamydia is a more common
causative agent than gonorrhea

** The treatment for cervicitis si the same as for Chlamydia infection
- Chronic cervicitis produces scarring
- Nabothian follicles are mucus-containing cysts up to 1 cm in diameter
- These cysts are often present on the cervix following chronic cervicitis

Microbiological Tests
- Wet prep
- Gram stain
- Bacterial culture
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- ELISA or IF
- Viral culture
- Blood serology

Syndromic Approach- clinical algorithms are used in the absence of tests or alongside limited
testng
- Based on the history alone and the physical findings

Print slide #28-29

UTERUS
Dysmenorrhea- is defined as painful menstruation. Usually consists of cramp-like suprapubic pain
which starts at the onset of menstrual flow and lasts 8-72 hour

Can be classified according to two categories:
i- Primary or Spasmodic Dysmenorrhea- no underlying organic pathology is related. The
pain usually begins with the bleeding of menstruation and eventually dissipates
ii- Secondary or Congestive Dysmenorrhea- associated with identifiable organic pathology.
Secondary dysmeonrrhea may be a symptom of:
- Endometriosis
- PID
- Adenomysosis
** Ashermans syndrome- is characterized by fibrosis and adhesion formation
- Occurs when the endometrium has been damaged
- Especially when it has been removed down to or beyond the basal layer
- Therefore normal regeneration does not occur and instead there is fibrosis and adhesion
formation
- Ashermans occurs as an adverse consequence of excessive curettage
- Especially at the time of evacuation of retained placental tissue after miscarriage or
secondary post-partum hemorrhage
- Other cause of Ashermans syndrome are tuberculosis and schistosomiasis
- Cervical stenosis- rare

Note: In secondary dysmenorrheal the pain begins before bleeding and it worsens when bleeding
starts

Abnormal Uterine Bleeding- exclude an endometrial lesion
MBBS/DDS 2K16

Uterine Fibroids- are the commonest pelvic tumor seen causing the above symptoms

Uterine Fibroids
** A fibroid is a benign tumor of uterine smooth muscle, known as a leiomyoma
- Causes abnormal uterine bleeding

** Fibroids can be located in a variety of locations:
- Peduncualted- on a stalk external to the uterus. Attached to the uterus by a narrow pedicle
contains blood vessels
- Intramural- centrally within the myometrium
- Subserosal- at the outer border of the myometrium
- Intracavitary
- Submucosal- bulging into the endometrial cavity

FALLOPIAN TUBES
- Salpingitis
- Tubo-ovarian abscess
- Tubal occlusion
- Hydrosalpinges
- PID
- Tubal ectopic pregnancy

Pelvic Inflammatory Disease
** Pelvic inflammatory disease (PID) is a general term for inflammation of the uterus, fallopian tube
(salpingitis) and/or ovaries
- The inflammation progresses to scar formation with adhesions to nearby tissues and
organs
- This may lead to tissue necrosis and abscess formation (tubo-ovarian abscess)
- Pus can be released into the peritoneum resulting in a peritonitis

** Diagnosis via an endocervical swab

PID Sequelae:
MBBS/DDS 2K16
** The first stage of salpingitis includes mucosal inflammation with swelling, redness and
deciliation
- Polymorphonuclear cells invade the submucosa
- Followed by mononuclear cells and plasma cells
- Inflammatory exudate fills the lumen of the tube and adhesions develop between
mucosal folds

** Inflammation extends to the serosal surface and pus exudes from the fimbriae to the ovaries +
adnexae
- In more severe cases the tubes are fixed to adjacent structures via a fibrin exudate and
adhesions

** With pelvic peritonitis all the organs are congested, with multiple adhesions producing an
inflammatory mass
- The omentum usually confines the infection to the pelvis
- The infection cause tissue destruction, tubo-ovarian abscesses

** Subsequent scarring may lead to the fimbriae being drawn into the ends of the Fallopian tubes
- Causes adhesion and sealing of the ends of the tubes

** The uterus and tubes may be pulled back into the pelvis by adhesions and become fixed and
retroverted
- A hydrosalpinx is caused by the accumulation of fluid within the tube, which then
expands and swells
- A hydrosalpinx contains non-infected fluid in to the tube

Note: However, if this becomes infected, a pyosalpinx is formed

** As the infection ascends, there is chronic pelvic pain and deep dyspareunia. The diagnosis of
PID is based on the following:
i- History- of pelvic pain and dyspareunia
ii- Examination- that demonstrates cervical motion tenderness (cervical excitation) with or
without uterine/Adnexal tenderness
iii- Lower genital tract infection- BV, trichomoniasis or cervicitis
iv- Pyrexia- in severe case along with neutrophilia and raised ESR

MBBS/DDS 2K16
Note: If PID is suspected take endocervical swabs for the detection of N. gonorrhea or C.
trachomatis
- High vaginal swab also done for the detection of T. vaginalis and BV
- Must exclude the possibility of ectopic pregnancy
- Laparoscopy is the gold standard for diagnosis

Print slide #37-40

OVARIES
1- Functional Cyst- are simple cysts formed as part of the normal process of menstruation.
There are 3 types:
i- Follicular (Graafian)
ii- Corpus luteal
iii- Polycystic

2- Dermoid benign teratoma- a mature cystic teratoma containing hair and other structures
characteristic of normal skin and ectodermal-derived tissues

Note: The majority of ovarian cysts are functional cysts. These cyst have a thin wall
- NO septae
- NO excresences
- NO ascites
- Resolves in 6 weeks

Print Slides #44-45

Urogenital Prolapse
** A prolapse is a protrusion of an organ or structure beyond its normal confines
- Prolapses are classified according to their location and the organs contained within them

Classification

Anterior vaginal wall prolapse:
- Urethrocele- urethral descent
MBBS/DDS 2K16
- Cystocoele- bladder descent
- Cystourethrocoele- descent of bladder + urethra

Posterior vaginal wall prolapse:
- Rectocele- rectal descent
- Enterocele- small bowel descent

Apical vaginal prolapse
- Uterovaginal- uterine descent with inversion of vaginal apex
- Vault- post-hysterectomy inversion of vaginal apex

** Three degrees of prolapse are described. The lowest or most dependent portion of the prolapse
is assessed while the patient is straining

FIRST DEGREE- Descent within the vagina
SECOND DEGREE- Descent to the introitus
THIRD DEGREE- descent outside the introitus (space/cavity)

** In the case of uterovaginal prolapse the most dependent portion of the prolapse is the cervix
- Third degree uterine prolapse is termed procidentia
- This is usually accompanied by cystourethrocele + rectocele

** The connective tissue, levator ani + intact nerve supply re vital for the maintenance of poison of
pelvic structure.
- They are influenced by pregnancy, ageing, and childbirth

** Therefore congenital or acquired connective tissue defects are important into the etiology of
prolapse and urinary incontinence

Treatment:
** The choice of treatment depends on:
- The patients wishes
MBBS/DDS 2K16
- Level of fitness
- Desire to preserve coital function

Note: Prior to specific treatments, attempt should be made to correct obesity, chronic cough or
constipation
- If the prolapse is ulcerated, a 7-day course of topical estrogen should be administered

** Treatment is via surgical repair to restore anatomy and function

MBBS/DDS 2K16
Lecture 23: The Management of Uterine Fibroids

Lecturer: Dr. Fletcher

** Uterine fibroids (leiomyomata uteri) are benign smooth muscle tumors arising from the
myometrium of the uterus

** Leimyomas are sharply circumscribed, discrete, round, firm gray-white tumors varying in size
- Range from small barely visible nodules to massive tumors that fill the pelvis
- Usually are found within the myometrium of the corpus

** Infrequently they may involve the uterine ligaments, lower uterine segment of the cervix.
Note: Fibroids can arise separately from the uterus, especially in the broad ligament
** Within the myometrium the fibroids may develop in variable locations:
i- Intramural- centrally within the wall of the myometrium
ii- Submucosal- just beneath the endometrium and bulging into the endometrial cavity
iii- Subserosal- beneath the serosa at the outer border of the myometrium
iv- Pendunculated- attached to the outside of the uterus via a narrow pedicle that contains
blood vessels
v- Intracavity- projecting into the cavity of the uterus and attached by a stalk
vi- Cervical- found in association with the cervix

Incidence
- 20-25% of women clinically
- The most common solid pelvic tumor
- 3-9 x more common in black owmen

Pathophysiology
** The key features of uterine leiomyomata are their:
i- Occurrence during reproductive years where ovarian hormone levels are high
ii- Diverse manifestation as either single or multiple tumors
iii- Existence of racial + familial predispositions

MBBS/DDS 2K16
** Therefore fibroids grow under the influence of sex hormones (mainly estrogen)
Note: If the estrogen is opposed by progesterone, there will be less fibroids

** When patients have a cycle high estrogen in the follicular phase before ovulation. The incessant
ovulation leads to the formation of fibroids.
- The constant ovulation may be due to nulliparity or voluntary/involuntary infertility

Note: Pregnancy prevents the formation of new fibroids but old ones grow bigger due to sex
hormones

Differential Diagnosis of a Pelvic Mass
- Full bladder
- Pregnancy
- Ovarian masses

Gynecological System:
- Uterus: adenomyosis, malignancy, cyesis (pregnancy)
- Ovaries: benign or malignant tumor
- Fallopian tubes: hydrosalpinx or tumor
- Whole system hematocolpos, hematometra, hematosalpinx

Urinary System:
- Neurogenic bladder
- Carcinoma
- Acute retention of urine

Gastrointestinal System:
- Full rectum (with stool)
- Rectosigmoid or cecal carcinoma
- Lower intestinal obstruction

Retroperitoneal Structures:
- Enlarged lymph nodes due to malignancy or infection
MBBS/DDS 2K16
- Aneurysm
- Neuromata

** For the differential diagnosis other cause of an abdominopelvic mass in a woman in
reproductive years need to be considered
** The uterus enlarged with fibroids is typically firm in contrast to a uterus enlarged with a
pregnancy
Note: Leiomyosarcomas (malignant transformation) typically present with a history of a rapidly
enlarging abdominopelvic mass

Management
History:
** Conservative management is appropriate where asymptomatic fibroids are detected
incidentally

** Other aspects of the history include:
- Heavy and/or prolonged regular periods
- Symptoms of anemia
- Spasmodic dysmenorrhea
- Urinary frequency
- Leg swelling- indicative of venous or lymphatic obstruction
- Infertility

** The typical patient is:
- Nulliparious
- Median age of 30 years
- Of African ancestry
- Last child delivered more than 10 years ago

** Common presenting complaints are menstrual disturbance and pressure symptoms
(urinary frequency)
- Menorrhagia (heavy prolonged menses) may occurs coincidentally in a woman with fibroids
- Abdominal mass
- Compression symptoms
- Infertility (sub-fertility)

MBBS/DDS 2K16
** Sub-fertility may result from mechanical distortion or occlusion of the fallopian tubes
- Also in a endometrial cavity distorted by submucosal fibroids may prevent implantation
of a fertilized ovum

Note: In late pregnancy, fibroids may be the cause of an abnormal lie
- After delivery postpartum hemorrhage may occur due to inefficient uterine contraction

** Uncommon complications of fibroids include:
- Ureteric obstruction
- Acute urinary retention
- Deep vein thrombosis + pulmonary embolism
- Sarcomatous change- malignant transformation of the benign tumor to a leiomyosarcoma

** In the management of the patient with fibroids must rule out pregnancy
- Ask about future pregnancy desires because this will influence the method of treatment

** Rule out other possible differential diagnoses:
- Urinary symptoms
- GI symptoms
- Symptoms of malignancy

** Determine the general status of the patient:
- Anemic- rule out heart failure
- Cachectic- suggests malignancy

** Specific examination of the fibroid:
- Assess size, position, mobility
- Usually a nodular, firm mass that moves when the cervix is moved on bimanual exam
through the vagina

Note: If the patient is a virgin do a bimanual exam through the rectum

Investigation
MBBS/DDS 2K16
- Blood studies, CBC, renal function
- Ultrasonography- useful to distinguish a uterine from an ovarian mass
- Imaging of the renal tract may be helpful in the presence of a large fibroid to exclude
hydronephrosis
- ECG, chest X-ray
- Pap smear

** No treatment is recommended for the following patients:
- Asymptomatic patient
- Minor symptoms- and trying to get pregnant
- Perimenopausal mild symptoms
- Severely ill patients

** Conservative medial treatment includes:
i- Analgesics
ii- Iron tablets
iii- Depo-provera or norethisteroneI
iv- GnRh agonists- are effective in shrinking functions but when ovarian functions returns
the fibroids regrow to original dimensions

** If the patient is anemic, ensure that the underlying cause is iron deficiency before giving
supplementary iron
- Severe case with heart failure may need blood transfusion
- Stopping the period may help anemia

** GnRh agonists- decrease the size of fibroids in the first 12 weeks of treatment
- Decreases bleeding and improves hemoglobin

** However the disadvantages include:
- Cannot be used for more than 6 months
- Osteoporosis
- Fibroids will return after one year
- Makes myomectomy more difficult because the fibroids are harder to see

** Radiographic treatment- involves embolization of the uterine arteries
- Decreases the blood supply to the fibroids
- Fibroids shrink and normal tissue is less affected

MBBS/DDS 2K16
** Surgical Treatment- is determine by the presenting complaint and the patients wishes for
menstrual function and fertility
- Menorrhagia associated with a submucus fibroid or fibroid polyp may be treated by
hysteroscopic resection
- A bulky uterine fibroid may result in myomectomy with uterine conservation OR
hysterectomy

Note: Myomectomy is the preferred option where the preservation of fertility is required\
- However extra care must be taken for subsequent pregnancies because the uterus is at
risk for rupture

Hysterectomy- surgical removal of entire uterus
- Laparoscopy
- Laparotomy

** Hysterectomy is reserved for patients who have completed their family
- Also done in patients too ill to risk myomectomy which bleeds more
- If the patient has another problem- bleeding disorder, DVT, cervical neoplasia, PID, severe
endometriosis, ovarian tumors

Note: Hysterectomy is a final but permanent cure for fibroids
- Causes less complications than myomectomy
- Useful if fibroids recur after myomectomy

Total Hysterectomy- includes the cervix
Subtotal Hysterectomy- leaves the cervix behind

Myomectomy- removal of only fibroids
- Hysteroscopy- done for submucus fibroids
- Hysteroscopy uses a thin telescope inserted through the cervix into the uterus
- Involves endometrial ablation via cutting loop, roller ball, laser

- Laparoscopy- takes a longer time but shorter hospitalization
- Laparoscopic myomectomy is done for subserous fibroids and used with hysteroscopy

MBBS/DDS 2K16
- Laparotomy- most commonly done
- Main Problems: bleeding, adhesion formation and recurrence of fibroids

Print Slide #41, 43
** Hemostasis with vasopressin should be used with caution
- Vasopressin cause myocardial ischemia if injected intravascular inadvertently
- Do not use in patients with ischemic heart disease

** Complicated fibroid cases are those, which involve the following:
i- Fibroids + ovarian pathology
ii- Fibroids + tubal pathology
iii- Cervical neoplasia
iv- DVT or pulmonary embolism

Note: In these complicated cases, hysterectomy is recommended over myomectomy
Print slide #59

** Removal of the ovaries may be indicated to:
1- Prevent ovarian cancer- especially in high risk patients- genetic predisposition (BRCA gene),
> age 45
2- To remove pathology- endometriosis, ovarian tumors, tubo-ovarian abscess
3- To remove the source of estrogen- breast or endometrial cancer, endometriosis

** Ovarian removal is contraindicated in the following patients:
1- Young patients- <45 years
2- High risk of fractures or cardiovascular disease
3- Patients who cannot take hormone replacement therapy- DVT, embolism

Hysterectomy vs. Myomectomy
- Hysterectomy treats more than the fibroids alone
- Hysterectomy is curative
- Myomectomy tends to have more bleeding

Uterine Fibroids in Pregnancy
** Uterine fibroids tend to grow in pregnancy and undergo red degeneration
MBBS/DDS 2K16
- Red degeneration follows an acute disruption of the blood supply to the fibroid
- This disruption occurs during active growth
- The middle of the fibroid becomes ischemic
- May present with the sudden onset of pain and tenderness localized to an area of the uterus
- Accompanied by mild pyrexia and leukocytosis

** Myomectomy can be done during pregnancy BUT associated with a danger of abortion
- Myomectomy can be done safely at C-section if the blood loss from the C-section is low
Print slides #67-69, 71

Hemorrhage
1- Primary Hemorrhage- bleeding occurs during the procedure from vessel injury
2- Secondary Hemorrhage- bleeding occurs after the operation from a rise in blood pressure

SF28D- SU 16-07-09- Male Sexual Dysfunction- AIKEN

Sexual Response Cycle
Masters & Johnson- 4 phase model
- Excitement
- Plateau
- Orgasm
- Resolution

Kaplan- 3-phase model with the motivational dimension of desire added
- Desire
- Arousal
- Orgasm

Print Slide #6

** Normal age-associated changes in male sexual function are:
- Gradual decrease in sexual desire
- Gradual decrease in penile sensitivity
- Gradual diminution in rigidity of erection
- Less erectile response to psychic stimuli
MBBS/DDS 2K16
- Increased need for direct simulation
- Reduced duration + intensity of orgasm
- Reduced force of emission and ejaculation
- Decreased ejaculatory volume
- Rapid detumesence post-ejaculation
- Prolonged refractory period

Classification of Male Sexual Dysfunction

Disorders of Desire
- Hyperactivity
- Hypoactivity
- Sexual aversion

Disorders of Erection
- Erectile dysfunction
- Prolonged erection
- Erectile deformity- congenital or acquired

Disorders of Ejaculation
- Premature ejaculation
- Delayed ejaculation
- Anejaculation
- Retrograde ejaculation

Disorders of Orgasm
- Anorgasmia
- Delayed orgasm

Disorders of Sensation
- Hyposensitivity
- Hypersensitivity
- Sexual pain disorders

Penile Erection
Penile Erection is mediated by the elevation of cyclic GMP in smooth muscle cells of the penile
vasculature
MBBS/DDS 2K16
- Levels increase in response to erogenous stimuli
- Erogenous stimuli induces the release of nitric oxide from endothelial cells that line the
blood vessels
- Cyclic GMP interacts with a c-GMP dependent protein kinase that phosphorylates several
proteins
- The phosphorylation leads to a lowering of intracellular calcium through increased
calcium extrusion from the cell
- Also increased sequestration of calcium in intracellular stores
- This calcium related effect decreases contractile tone in the smooth muscle and promotes
vasodilation

** Erections can be classified according to how they develop
i- Psychogenic erection- related to sexual thoughts, fantasies, visual stimuli
ii- Reflexogenic erection- related to direct stimulation of the penis

Sexual Health Care

Note: The two most common male sexual dysfunctions are erectile dysfunction and premature
ejaculation

Erectile Dysfunction (ED)
Defn: The consistent or recurrent inability to attain and/or maintain a penile erection sufficient for
sexual performance

** ED can be classified according the etiology:
i- Psychogenic
ii- Organic
iii- Mixed- organic + psychogenic causes

Organic ED
i- Vasculogenic- arteriogenic or veno-occlusive dysfunction
ii- Neurogenic
iii- Endocrine
iv- End-organ failure- structural or anatomical
v- Drugs- medications

MBBS/DDS 2K16
** Erectile dysfunction is highly prevalent especially in older men. The risk factors of ED include:
- age
- heart disease
- hypertension
- dyslipidemia
- lack of physical exercise
- diabetes
- chronic neurological disorders- Parkinsons
- Radiotherapy or surgery
- Trauma
- Certain prescription medicines
- Depression + anger
- Socioeconomic status and quality of life

Note: Erectile dysfunction = Endothelial dysfunction

Evaluation

History:
- Specific complaint
- Sexual
- General medical
- Social and relational

Examination:
- General physical
- Genitourinary
- Focused neurological exam

Investigations:
- Urinalysis
- FBS, lipid profile, RFTs, PSA
- CBC
- Free + total testosterone levels
- LH and prolactin levels
- Dynamic infusion cavernosometry
- Duplex Doppler ultrasound
- Angiography

MBBS/DDS 2K16
Print slide #25

Treatment
** Standard treatment with the use of phosphodiesterase-5 inhibitors
- Sildenafil- Viagra
- Vardenafil- Levitra
- Tadalafil- Cialis

Ejaculatory Dysfunction
Print slide # 29

Premature Ejaculation- is persistent or recurrent ejaculation with minimal sexual stimulation
before, upon or shortly after penetration
- AND before the person wishes it

** The diagnosis of premature ejaculation (PE) is multifactorial and subjective. Characterized by 4
aspects:
1- Diminished intravaginal ejaculatory latency time (IVELT)
2- Loss of voluntary control
3- Presence of marked distress or interpersonal disturbances
4- Not due to another disorder- eg opiate withdrawal

** There are two types of premature ejaculation:

1- Lifelong (Primary)- has a strong biogenic component
- Inherited hyper/hyposensitivity of central 5-HT receptors
- This interacts with psychosocial factors
- Variable expression of a psychogenic component may be present

2- Acquired (Secondary)- related to psychogenic stressors and is often situational
- Associated with ED, prostatitis, urethritis, medications

Central Areas for Ejaculation
MBBS/DDS 2K16
** Seminal emission, ejection and orgasm are integrated into the complex pattern of copulatory
behavior by several forebrain structures
- Medial preoptic area
- Nucleus paragigantocelluaris
- Stria terminalis, amygdala, thalamus

** Multiple regulatory neurotransmitters are also associated with ejaculation
- Serotonin
- Dopamine
- Oxytocin
- GABA

** Central serotonin (5HT) has an inhibitory role in male sexual behaviours
- Injection of a selective serotonin reuptake inhibitor (SSRI) increase central 5-HT levels and
delays ejaculation
- Animal experiment

Treatment:
1- Self help- by using multiple condoms
- Desensitization ointments
- Masturbating prior to intercourse increase the second ejaculatory latency time
- However the second erection is more difficult to achieve with increasing age
- Mental exercises during sex

2- SSRIs- are an off label use in the treatment of premature ejaculation
- Print slide # 39
- Note: Therapeutic doses of SSRIs can also cause decreased libido and delayed ejaculation

Disadvantages:
- Requires chronic dosing because the effect lasts only when the drug is in the body
- Therapeutic response is unpredictable
- SSRIs have a delayed onset of action and long half-life, therefore not conducive to on-
demand therapy
- Side effects at higher doses
- Chronic dosing can decrease libido and cause erectile dysfunction

3- Psychological Approach (Psycho behavioral)
i- Strict Behavioral Adjustments- stop start technique
- Squeeze technique
MBBS/DDS 2K16
- Sensate focus
- Quiet vagina

ii- Psychodynamic- investigating relationship and individual issues

4- Topical Anesthetics- local anesthetic combination in a metered-dose delivery system
that contains lidocaine and prilocaine

END OF OBSTETRICS AND GYNAECOLOGY SECTION

END OF LECTURE NOTES

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Compiled By: Jordiann A.

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