Condensed Notes

Endocrinology
Lecture 2 & 3
Hormones, hormone transport, measurement and their actions

Fast communication via nervous system = neurotransmitters. Uses electrical

signals
Slow communication via endocrine system = hormones that travel in blood
stream -> regulatory effects. Bind to specific receptor on target cell -> action
changes function of that cell.
Primary glands -> Hypothalamus (production of ADH, oxytocin and
regulatory hormones), pituitary gland (adenohypophysis = ACTH, TSH, GH,
PRL, FSH, LH and MSH, neurohypophysis = release of oxytocin and ADH),
pineal gland (melatonin -> pigmentation of skin), thyroid gland (thyroxine
[T4], triiodothyronine [T3] and calcitonin), suprarenal glands (suprarenal
medulla = epinephrine and norepinephrine, suprarenal cortex = cortisol,
corticosterone, aldosterone and androgens), parathyroid glands (PTH),
pancreatic islets (insulin and glucagon), gonads (testes = androgens (esp.
testosterone) and inhibin, ovaries = oestrogens, progestins and inhibin),
thymus (thymosins, undergoes atrophy during adulthood) and placenta.
Secondary glands -> heart (natriuretic peptides (atrial and brain natriuretic
peptides), kidneys (erythropoietin [EPO] and calcitrol), liver, digestive
tract, adipose tissue (leptin) and skin
Hormones are secreted from specialised cells in endocrine glands into
circulation -> transported throughout body -> target cells respond only to
hormone for which they have appropriate receptors -> modifies the function
of that cell
Regulation of growth, development, metabolism and maintenance of the
internal environment -> longer lasting effects
Can have local actions -> paracrine such as growth factors (transforming
factor beta), fibroblast factors and clotting factors. Autocrine such as
interleukin 1 on monocytes
Measure hormone concentration -> clinical diagnosis. Concentration in
plasma (or other fluids such as urine) depends on -> rate and pattern of
secretion, rate of removal (metabolism/excretion) and degree of binding
(plasma proteins) i.e. free verses bound -> dependent if lipophilic or
hydrophilic. Key that free hormone is the active form
Mostly pulsatile (regulated by control loops). Regulated in various period
lengths regulated by positive and negative feedback loops. Circadian (~24
h)- Cortisol and growth hormone. Cortisol influenced by light dark patterns,
increases in dark, decreases in light. Ultradian (<24h, multiple release peaks
per day) e.g. LH and FSH -> shorter periodicity. Episodic in response to a
particular stimulus e.g. insulin
Hormone types -> 3 main categories -> (1) derived from amino acids (e.g.
tyrosine), (2) protein based hormones (peptide and glycoproteins) and (3)

derived from lipids (cholesterol = steroids and arachidonic acid = eicosanoids

e.g. prostaglandins.)

Catecholamines derived from tyrosine = water soluble

(hydrophilic) and transported in blood (stored in
secretory vesicles). Short half-life (5-10 mins) = quick
acting. Thyroid hormones T3 and T4 derived from
iodinated tyrosine molecules = lipophilic so transported
bound to plasma proteins (protects hormones from

excretion/metabolism) = long half-life, remain in blood for extended period of

time.

Peptide hormones derived from chains of amino acids = largest class, vary in
size -> 2 AA to 200 AA. Requires gene transcription. Protein synthesis and
modification in Golgi apparatus e.g. glycosylation. Pinches off into either
secretory or storage vesicles, released from cell by exocytosis (Ca
dependent), similar mechanism of release for catecholamines. Storing
hormones in this way allows for rapid response to a stimulus.
Rapid response e.g. insulin levels rise quickly initial -> episodic. Prevents
damage. After acute response goes into chronic phase of release of new
hormone as its then synthesised.
Many peptides and protein hormones are synthesised initially in an inactive
form. Post translational processing and extracellular cleavage generates
active forms. Inactive = pre-prohormone. Enzyme activity in Golgi removes
pre part then pro part, then stored in vesicles.
Peptides are water soluble, exist free in solution = short half-lives.

Lipid derivatives. Arachidonic acid = fatty acid.

Steroid hormones synthesised from cholesterol in enzyme complex cascade
that modifies the cyclopentanoperhydrophenanthrene ring -> differences in
carbon structure, cholesterol has 27 carbon molecules, processed into
hormones by reducing the number of carbon molecules. Secreted from
adrenal cortex, gonads and placenta. Examples are oestrogens and cortisol.
Lipid soluble (cross membranes easily), not stored in vesicles, secreted as
they are produced (constitutive secretion). Requires 3-5 min before
detectable in plasma and 10 15 minutes to achieve max. secretion rates.
Effective at very low free concentration due to high receptor affinity (K D of ~
10-10 M)
Secretion and distribution -> Circulate freely in blood or bound to carrier
proteins. Use of binding proteins by many hydrophobic hormones especially
thyroxine (T4) and triiodothyronine (T3), steroid hormones, insulin-like growth
factors I & II and GH. Creates reservoir of hormone in blood, minimising
fluctuations on hormone levels. Extends half-life of hormone, bound T4

circulates for 7-8 days, free T4 only minutes. Binding proteins have a high
affinity for the hormones. Inactivated when leaves bloodstream, absorbed and
broken down by kidney and liver or broken down by enzymes. Cleared from
the circulation much slower than those unbound -> longer lasting effect.
Hydrophilic hormones are transported dissolved in blood
plasma- e.g. epinephrine. Hydrophobic hormones circulate
in blood, bound to plasma proteins e.g. T4 or cortisol. Free
hormone is the active form. It diffuses across capillary
walls to encounter its target cells.
Help transport hormones and regulate the amount that is
biologically active i.e. free. Hormone inactive until it dissociates from
binding protein. Permits delivery to target tissues. Protect hormones from
degradation & excretion. Plasma Albumins transport: thyroid hormones &
steroid hormones. Specific transport globulins: hormone-binding proteins
& steroid-binding proteins -> made at same time hormone is made.
Binding of a hormone to its binding protein is governed by law of mass
action and follows Michaelis-Menten kinetics. Association and
dissociation of hormone protein complex is an equilibrium set by
concentration of free hormone and binding protein. Ka & Kd =
association and dissociation constants. Concentration of free hormone
can be calculated.
Concentration of free hormone -> the fraction available for binding to
receptors - active hormone. Is involved in regulating hormone release (via
feedback control). The fraction that can be cleared from the circulation by the
liver and kidney (metabolism/excretion). Correlates best with clinical states of
hormone excess and deficiency
Inactivation of hormones -> Target tissue uptake. Metabolic degradation
(plasma, liver, kidney). Excretion in urine (those bound to proteins which
cannot cross the
filtration barrier will
be conserved)
Mechanism of action
on target cell ->
receptors on plasma
membrane or inside
cell. Receptors for
Ad, NA and
dopamine, peptide
hormones are in
plasma membrane as
not lipid soluble.
Eicosanoids are lipid
soluble but bind to
receptor on inner
surface of membrane.
Must use a second
messenger.

Lipid soluble hormones

can diffuse across the
plasma membrane.
Steroid or thyroid
hormones have receptor
inside cell either in
nucleus or in cytoplasm.

Control of hormone levels -> depends on three factors = rate of

hormone secretion, amount of hormone transported bound to a
carrier protein and rate at which hormone is metabolised.
Hormone secretion result from neuronal or humoral (blood borne)
signals. Can be stimulatory or inhibitory. Released at variable
rates circadian, ultradian or episodic, few released steadily.
Example of neural input -> physiological stress stimulates release
of CRH, eventually leads to release of cortisol. Relieves symptoms
of stress -> decreases HR, blood pressure etc.
Humoral
signals ->
(1) hormones
hormones of
hypothalamus and
anterior pituitary with
negative feedback. Ion
signals- Aldosterone
secretion, control of
release through blood
potassium levels.
Metabolites (such as
glucose) - Insulin
regulation-control of
release through blood
glucose levels

Measurement of hormones = immunological

technique. 1950s Berson & Yalow used anti
insulin Abs. immuno assays in saliva,
plasma, urine. Binding of radiolabelled (e.g.
125
I) hormone to antibodies -> saturation
plot. Labelled hormone can be displaced by
addition of increasing known amounts of
unlabelled hormone, competes for binding of
antibody -> displacement curve -> used as a standard curve.
Degree of displacement used to determine the amount of
unknown hormone.
TSH and TRH= trophic hormone -> stimulates release of
target hormone. TSH and TRH under negative feedback
control from excess T3 and T4.

Low levels of both TSH and T4 indicates a failure of trophic hormone secretion
-> could be a problem with anterior pituitary gland or hypothalamus.
Autonomous secretion could be a result of a tumour in the gland or negative
feedback mechanisms arent working.
Abnormal secretion of hormone -> Hyper or hypo. Hypersecretion
acromegaly excess growth hormone in adult life, jaw elongated, and
extremities enlarged, bones proliferate unexpectedly. Hyposecretion insulin
dependent diabetes mellitus -> increase fails to secrete enough insulin

Lecture 4
Control of Energy Homeostasis and the endocrine pancreas

Energy metabolism -> store and utilise energy. Catabolic and anabolic
metabolism. Energy from what we ingest. Influenced by eating patterns,
stress, period of growth and illness. Catabolic = breakdown of large, complex
molecules into smaller once, generating heat (glucose -> CO 2 and H2O).
Anabolic = synthesis of complex molecules from simpler ones (amino acids ->
proteins)
Metabolism under endocrine control -> alters enzyme activity. Food intake is
intermittent. Brain depends on glucose as primary energy source. Eaten ->
store energy and use when not ingesting food. Break stores down in between
meals -> maintains constant supply of energy glucose.

Food broken down into biomolecules, broken down further inside cells,
releasing energy for muscle contraction, transport, secretion, anabolism,
tissue function, growth repair and storage within large complex molecules.
Diet = carbohydrates, proteins and lipids. Carbohydrates are a very rich
source of energy we tend to utilise it straight away are they are the easiest,

most accessible form of energy

Energy balance -> if equal energy input must equal energy output. Intake =
ingested food, output = basal metabolic rate, activity and thermoregulatory
mechanism. Balance unlikely as it fluctuates, results in change in body
weight. Greater energy input than output = weight gain. If energy balance
positive = increase weight, if negative = decrease weight.
Break down nutrients via oxidation, release
energy as heat or uses it to perform work.
The amount of energy expended per unit
time is the bodys metabolic rate = the rate
at which chemical energy is expended by
the body. Measured by rate of which heat is
produced -> direct measurement.
Influenced by, for example, muscular
activity, age, gender, body SA and env temp.
Basal metabolic rate (BMR) -> Rate of energy
expenditure of a person who is awake, lying down,
physically and mentally relaxed, fasted for 12 hours and in a thermoneutral
environment (20C). Estimate by measuring oxygen consumption correlating
to the nutrients utilising.
Measurement of oxygen consumption -> Rate at which the individual is using
up oxygen (l min-1). Energy equivalent of oxygen for the food being
metabolised (kJ per l of oxygen). Multiply these values by 60 (min) metabolic
rate is obtained (kJh-1)
Spirometer set up -> Node clip used -> measure exactly expiration through
mouth. Mouth piece connected by a hose to drum floating on water. Connects
to a computer. Known quantity of oxygen in drum, can calculate
how much oxygen someone has consumed. Apparatus has
sodalime incorporated to collect carbon dioxide. Oxygen
consumption calculated over a set amount of time at rest.
Measuring energy equivalent of oxygen for the food being metabolised. RQ =
respiratory quotient (cellular level) or RER = respiratory exchange ratio
(whole body), measured in same way. Nature of the food stuffs being
metabolised alters RQ as the composition of carbohydrates, fats and proteins

is very different -> different numbers of oxygen molecules. Carbohydrates RQ

= 1, fat RQ = 0.8 and protein = 0.8. Mixed diet RQ about 0.8. RQ/RER
compared with standard tables -> calculation of BMR for someone on a mixed
diet.
Factors affecting basal metabolic rate -> Body weight, body SA (skin huge
conductor of heat, heat lost so greater SA = higher BMR), lean body mass,
age, sex (males more lean body mass and SA so higher BMR, females more
body fat), pregnancy (baby high metabolic demand). Adult average 20-25
kilocalories per Kg of body weight per day
Physiological factors affect metabolic rate -> rate at which chemical energy is
expended by the body. Mainly determined by activity -> exercise (specific
numbers are known), ingestion of food (high protein meals increase metabolic
rate as increased heat production), fever, fasting and malnutrition (slows MR)
and sleep (decreases MR by 10-15%, not maintaining muscle tone, decrease
in sympathetic activity)
Hormones affecting energy metabolism -> Catecholamines noradrenaline
and noradrenaline. Stimulate metabolic rate 25-100% - fight or flight
response. Thyroid hormones T3 and T4, if lose thyroid function, metabolic
rate decreases by 50%. Growth Hormone. Male sex steroids greater impact
than female sex hormones, males higher MR - increase lean body mass. GH
and male sex steroids have a more mild stimulatory effect
Energy balance -> absorptive state (ANABOLIC), energy is stored in
macromolecules; during the postabsorptive state (CATABOLIC), these energy
stores are mobilised. Maintains plasma glucose
Insulin released in absorptive state. GLUT2 on liver cells, HLUT 4 on fat and
muscle cells. Inside cells = glycogenesis (glucose -> glycogen), glycolysis
(generates acetyl CoA)
Post absorptive state = catabolic. Different transporters moves glucose out of
liver for transportation to muscle. Triglycerides broken down within fat cells
into fatty acids, undergo beta oxidation to acetyl CoA. Free fatty acids ->
circulation to muscle for energy.

Transition between absorptive and post

absorptive state by pancreas endocrine and exocrine gland. Acini digestive
juices. Islets of Langerhans different cell types that release different
hormones -> glucagon, insulin & somatostatin

Pancreas = behind stomach, duodenum over the top. Innervated by CNS by

parasympathetic and sympathetic pathways.
Role of insulin -> 51 AA protein hormone derived from proinsulin, synthesis in
rough ER. Converted from precursor to active form in Golgi. Stored in beta
cells. Trigger transition between anabolic and catabolic states. Promotes the
synthesis of energy storage molecules and other processes characteristic of
the anabolic state. Short half-life (5 mins). Liver is the main buffer to regulate
blood sugar levels. Insulin must be present for growth hormone to have its
action (problematic if a child is diabetic)
Glucagon -> peptide hormone, 29 AA long. Secreted from alpha cells from
islets of Langerhans. Short half-life (6 mins). Promotes catabolism. Insulin
more dominant. Low blood glucose, liver releases glucose into blood.

Negative feedback control of blood glucose levels by insulin and glucagon. Set
point for blood glucose. Normal levels -> 70-140 mg dl-1 (4-8 mmol l -1).
Greater than 140 mg dl-1 hyperglycaemia -> diabetes. Less than 60 mg dl -1
hypoglycaemia, affect CNS function.
Other hormones involved in plasma glucose
regulation -> small role. Adrenal corticosteroids
-> glycogen production in the liver and
somewhat in the muscle. GH important in
fasting, depressing glucose uptake, available for
brain. Catecholamines -> action when glucose
falls, mobilises glucose for brain. Thyroid
hormones enhance glucose metabolism

Lecture 5
The Physiology and Pharmacology of Diabetes

Diabetes mellitus -> Impaired insulin secretion (-cell destruction-type 1

or impaired -cell function-type 2). Insulin resistance at target tissue (type
2). It is known that in 2015, 3.5 million of the UK population have been
diagnosed with diabetes (about 5% of the population). Many individuals

remain undiagnosed. Cost to NHS: 10 billion/annum from not only

treating diabetes but also the complications that it includes
Inadequate uptake of glucose -> hyperglycaemia. Dont sequester the
excess glucose for storage. Prevalent disease, 285 million people
worldwide. Many undiagnosed, particularly T2DM, symptoms not
monitored and complications arise.
Type 1 = insulin dependent. Presents in childhood. About 5-10% cases in
western world. Autoimmune destruction of beta cells or absolute insulin
deficiency.
Type 2 = non-insulin dependent. Presents in middle aged, elderly or
overweight. 90-95% cases in western world becoming more prevalent.
Impaired insulin secretion and/or resistance to the action of insulin on
target tissue. More cases of children getting type 2 as overweight
Diagnosis -> symptoms = increased thirst, urination, tired, weight loss. If
undiagnosed for longer period of time, symptoms include
blurred vision, slow wound healing and genital itching. GP
refer to WHO diagnostic criteria. Three tests must be
confirmed in the subsequent days, may have one off
hyperglycaemia. Glucose tests by taking sample of blood
and analysing it to determine glucose concentration.
Fasting for 12 hours, blood analysed after 12 hours. OGTT
= oral glucose tolerance test -> sample of blood taken,
then glucose syrup liquid s ingested which contains 75g
of glucose, a 2 hour period then passes before another
blood sample taken.
Classification -> idiopathic ->
arises spontaneously.
Endocrinopathies = diseases
of the endocrine system, such
as hyperthyroidism, cushings
syndrome, pituitary dwarfism
and polycystic ovary
syndrome -> affects insulin
secretion. Some drugs
negatively affect beta cells.
Cystic fibrosis tend to present
with a pancreas which is not
fully functional. Gestational
diabetes patients whilst
pregnant develop diabetes, present symptoms but disappear after giving
birth or can continue. Usually detected by having a large sized foetus for
the age or excess amniotic fluid. Glucose present in urine tested.
Measurement -> test for hyperglycaemia and how well they are controlling
hyperglycaemia. Patients can test their own glucose levels using a finger
prick test but invasive and painful. Measure glycated haemoglobin ->
formed by haemoglobins exposure to plasma glucose, if plasma glucose
increase, fraction of glycated haemoglobin increases in predictable way.
Three month average plasma glucose concentration measured as lifespan
of RBCs is 3 months. Finger prick test could show normal levels, but
glycated haemoglobin test could show elevated levels. Can also measure

other serum proteins e.g.

fructosamine. Urine ketones
indicates diabetic ketoacidosis.
Management (type 1) ->
Optimised or intensive therapy.
Mimic exogenous insulin,
administer around mealtimes.
Administered subcutaneously.
Need to asses blood glucose
levels e.g. finger prick test and
administer correct dosage so
hypo/hyper glycaemia doesnt
occur. Education includes of both
patients and parents (if child)
Insulin -> short acting -> peak
action 30 min to 3 hrs.
Intermediate acting = delayed
response, peak activity 4-8 hrs.
Long acting last over 12 hrs.
Short/intermediate insulins taken
about 30 mins before eating a
meal. Adjusting dosage is key.
Constantly growing -> affects
dosage. Synthetic form of insulin
most commonly used.

Management (type 2) -> usually middle aged, elderly or overweight.

Initially actions taken to educate
about modifying their lifestyle
-> restrict fat and energy intake,
encourage exercise and stop
smoking. Works for 10-20% of
patients. If symptoms worsen
than oral hyperglycaemic agent
considered.
Oral agents -> sulphonylureas =
main therapy due to action and
low cost. Recently attenuated
slightly, capacity to induce
glucose dependent insulin
release -> hypoglycaemia. Also
may cause weight gain and accelerate beta cell failure. Meglitinide has
shorter duration of action, less hypoglycaemia, more costly.
Thiazolidinediones (TZDs) = PPAR gamma agonist, increase storage of
fatty acids in adipocytes, decreasing amount present in circulation but
increasing weight gain. Causes fluid retention, resulting in congestive
heart failure. -Glucosidase inhibitors affect carbohydrate absorption in
the intestine, limit function of enzymes that aid in carbohydrate
absorption, delay absorption but build-up of carbohydrate in gut, increase

bacteria and causes severe flatulence. Orlistat reduces fat absorption,

promotes weight loss and reduces symptoms.
Sulphonylureas -> GLUT-2 in beta cell bind glucose and transport it inside
the cell. ATP increases, potassium channel shuts -> depolarises the cell,
opens calcium channels -> insulin released by exocytosis. Sulphonylurea
binds to sulphonylurea receptor on the cell surface and initiates the
normal cascade, releasing insulin.
Thiazolidinediones (TZD) -> insulin sensitizers (reduces insulin resistance
of target cells), stimulate the peroxisome proliferator-activated receptor-
(PPAR- ) in the cell nucleus, mainly in adipocytes (also found in muscle
and liver). Endogenous ligands = free fatty
acids and eicosanoids. In conjunction with
retinoid X receptor, complex binds to DNA,
this promotes transcription of certain insulin
sensitive genes and increase expression of
proteins such as GLUT-4 -> detect glucose
and increases uptake. Enhances lipid
storage by increasing fatty acid uptake.
Decreases amount of fatty acids in
circulation, cells more dependent on
oxidation of carbohydrates (glucose).
Treatment of type 2 -> see diagram.
Pregnancy, ketoacidosis and weight loss
may impact on these treatments.
Hypoglycaemia -> not enough circulating
glucose for brain to function. Glucagon
secreted from alpha cells and other
hormones e.g. cortisol, GH, vasopressin.
Break down glucose stores, inhibits insulin
secretion. Can be induced by too much
insulin. In diabetic = hypoglycaemic shock
in insulin overdose.
Symptoms -> Sweating, pounding heart,
shaking, hunger, confusion, drowsiness,
speech difficulty, in coordination, atypical
behaviour, visual disturbance, nausea and
headache. Oral glucose (or IV if unconscious). Quite often diabetics carry
oral glucose in case this situation arises. Patient should recover in a matter
of minutes
Caused by insulin overdose, insulin secreting tumours, lacking in GH or
cortisol, liver disease or severe exercise without adequate hydration or
food.
Long term complications of diabetes -> complications associated with high
blood glucose for long periods of time. Eyes -> prone to have cataracts
and retinopathy, blindness. Higher risk of heart attack and CVD. Problems
with GI system (bowl problems). Affects nerve conduction (esp.
extremities) = neuropathy. Preventing wound healing. Demyelination of
nerves. Diabetic nephropathy -> increased blood pressure.
When glucose levels elevated -> excess proteins are glycosylated, excess
protein kinase C activated, more advanced glycation end productions ->

contribute to extracellular matrix, not degraded, continues to be

produced, forms scar like tissue around cells.
Diabetic retinopathy -> Alters lens, causing it to degenerate and
degenerate the retina, resulting in blindness. Affects retinal blood vessels
endothelial cells normally joined by tight junctions, constitutes much of
the blood retinal barrier -> separate in diabetes, causing increased
vascular permeability. Proteins leak through intro the retina, causing
macular edema. Accelerates cataract formation. Thickened basement
membrane of retinal blood vessel. Causes maculopathy. Capillaries
become occluded -> haemorrhage and blindness.
Diabetic nephropathy -> most common
cause of end stage renal failure in western
world. More difficult for kidney to filter
blood, works harder and GFR increases.
Extra ECM formation slows down filtering
process -> hypertension. Test urine for
presence of protein albumin. Longer
suffering from diabetes, more likely kidneys
dysfunction. Increased albumin excretion
rate, poor plasma glucose control, genetic
susceptibility and ethnic minorities result in
50% of patients presenting
microalbuminuria (small sustained amounts
of albumin present in the urine). May not
control their blood pressure adequately ->
different proteins may start to appear =
intermittent proteinuria, leading to
proteinuria. Blood pressure control reduced further -> end stage renal
disease. May need kidney transplant (unlikely).
Mechanisms of
diabetic
nephropathy ->
AGE-advanced
glycation end
product; AP-1 =
activator
protein-1
transcription
factor; MAPK =
mitogen
activated
protein kinases;
NFkB = nuclear
factor; PKC protein kinase C. Elevated hyperglycaemia and hypertension
activates signalling pathways, resulting in the activation of growth factors,
cytokines and inflammatory mediators, causing ECM accumulation and
altered vessel permeability in the kidney and therefore results in
proteinuria. Involves positive feedback
Diabetic neuropathy -> Occurs in patients whose diabetes has been
controlled poorly for weeks or months. Symptoms can clear when control

improved. Nerve conduction velocity is slowed at this time. Affects

sensation and pain. Most common type is distal symmetrical neuropathy
-> distal nerves dyeing back slowly -> sensory loss and pain in lower legs.
Results from demyelination, affects nerve conduction -> difficult to
mobilise (problem if overweight)
Future directions in diabetes research and treatment -> Pancreas and islet
cell transplantation -> whole pancreas transplantation successful- up to 10
years in some cases, however, side effects involved with
immunosuppressive drugs for success in transplant. Islet cell
transplantation, again successful but labour intensive, less need for
immunosuppressive drugs. Stem cell therapy -> research in progress in
encouraging embryonic stem cells to develop in to islet cells and then
transplanted. Gene therapy -> still at animal experimentation stage, aim
to transfer DNA to somatic cells to treat or prevent diabetes or its
complications

Lecture 6
Endocrinology of Growth

Prenatal growth has great important for an individuals future wellbeing. Can
be measured by ultrasound -> abdominal circumference, femur length and
bipareital diameter (ear to ear). Greatest 16-20 weeks gestation. Growth
influenced by genetic and environmental factors. Genetic = sets overall
height, patterns and timings of growth spurts. Environmental = diet/nutrition,
illness, trauma and smoking.
Post-natal growth spurt 0-2 years. Growth continues to puberty rate declines
through early childhood. Pubertal growth spurt - between 10.5 and 13 years
old in girls and 12.5 and 15 in boys. End of adolescence growth stops. Growth
refers to height only not weight. Earlier the pubertal growth spurt occurs the
shorter the final stature.
During periods of growth -> Increase in size and number of cells in bodys soft
tissue. Increase in length and thickness of bones
Bone growth -> Reserve of calcium can be moved into bloods stream when
plasma calcium decreases = homeostasis. Strong not brittle received a lot
of mechanical stress. Crystals of calcium phosphate-hydroxyapatite gives
bones strength to withstand force. Dynamic living tissue regenerates in
cases of fracture, will develop when necessary when influenced by hormones.
Full height -> still have fluctuations in calcium and therefore alterations in
bone
Osteoid-organic matrix. 3 cell types -> Osteoblasts-secrete osteoid,
Osteocytes-mature bone cells & Osteoclasts-secrete enzymes that dissolve
bone for remodelling. Skeleton first laid down as a cartilage model ->
replaced by bone (ossification). Growth in stature by increase in length of the
long bones in limbs. Addition of new material at the epiphyseal growth plates
between the diaphysis and epiphyses. Between these plates, stem cells
(chondroblasts) proliferation clones of cartilage cells (chondrocytes) ->
extend into the diaphysis -> mature, enlarge and later degenerate.
Calcification begins at the inner most layer of cells. Osteogenic cells
differentiate into osteoblasts -> secrete osteoid and lay down bone.

Osteoclasts erode bone within the diaphysis -> marrow cavity can increase in
size as the bone grows
Chondroblasts = stem cells. Chondrocytes = proliferating clones of cartilage
cells
Osteoblasts, build up mass of bone tissue, deposition. Osteoclasts, breakdown
bone tissue, resorptiom. Deposition > resorption bone growth occurs. In
adulthood deposition is equal to resorption
Hormones for growth -> Result of multiple interactions of circulating
hormones at different stages of life, tissue responsiveness and supply of
nutrients and energy for growing tissue. Growth hormone, derived from the
pituitary somatotrophs. Peptide hormone secreted by anterior pituitary GHRH stimulates, somatostatin from the pancreas inhibits. Irregular pulsatile
pattern of release, significant increase in rate of secretion in deep sleep, esp.
in children. Influenced by physiological stimuli. Stress & exercise stimulate GH
secretion. Other hormones influence release of GH -> oestrogens stimulate
the earlier adolescent growth spurt in girls, decreased GH secretion by insulin,
but must be present in normal levels for GH to function effectively. GH has a
dominant effect on postnatal & pubertal growth
Effects of growth hormone ->
Metabolic -stimulates lipolysis
(increases availability of FA) and
uptake of AA for protein synthesis.
Growth promoting - rate of
differentiation of chondrocytes
(cartilage formation), exerts a number
of indirect effects through IGFs. Insulin
like growth factors (IGF) - accounts for
growth promoting effects of GH, act on
cartilage, muscle, fat cells, fibroblasts
and tumour cells, has autocrine effects.
Growth hormone stimulates many
tissues, particularly the liver, to
synthesize and secrete IGF-1, which in
turn stimulates hypertrophy (increase
in cell size) and hyperplasia (increase
in cell number) of most tissues,
including bone. Effects oppose those of
insulin. Opposes glucose storage,
maintain energy in plasma, depresses
glucose metabolism, preserving for use
by CNS. Somatomedins = insulin like
growth factors
Dwarfism -> deficient secretion of GH during childhood. Stunting of growth.
70% due to growth disorders, particularly in bone growth, 30% of cases are
called pituitary dwarfism where there is a mutation in the genes or damage to
the pituitary that effects the secretion of GH. Poor muscle development.
Higher than normal body fat. Can be due to defective GH receptors or
deficient secretion
Gigantism -> Excessive secretion of GH before puberty. Could be caused by a
tumour on the pituitary or excess action of IGFs. stature is abnormally large

Acromegaly -> excessive secretion of GH in adulthood. Over growth of soft

tissue and increase in bone circumference. From pituitary tumours causing
increased GH secretion
Other hormones that effect growth -> Thyroid hormone particularly from 1520 weeks gestation, needed for protein synthesis in the brain, normal
development of nerve cells, if T4 secretion affected before puberty ->
abnormal skeletal development. Corticosteriods -> excess hormones of
adrenal gland (cortisol) = inhibitory action on growth/GH -> stress increases
GH secretion, excess stress also causes cortisol release, will have an
inhibitory effect. Insulin normal concentrations for normal growth to occur,
abnormal levels -> stunted growth. Vit D and parathyroid hormone. Hormones
that regulate mineral levels have indirect effects -> actions on development
and maintenance of skeleton.
Using hGH in sport -> people utilise endocrinology and abuse it in sport. May
be an advantage to be tall (basketball) and lean/ muscular (body building).
hGH increasing protein synthesis and therefore muscle, decreases energy
storage -> energy constantly pumped into the blood stream.
WADA regulations -> These substances and substances with similar chemical
structure or effect, and their releasing factors are prohibited -> Erythropoietin
(EPO); Growth Hormone (hGH), Insulin-like Growth Factors (e.g. IGF-1),
Mechano Growth Factors (MGFs); Gonadotrophins (LH, hCG), prohibited in
males only; Insulin; Corticotrophins. Unless concentration due to a
physiological or pathological condition, sample deemed to contain prohibited
substance where concentration or relevant ratio or makers exceeds the
normal range, unlikely to be consistent with normal endogenous production. If
exogenous origin -> report as an adverse analytical finding
hGH -> Orchestrates nutrient partitioning away from fat deposition and
toward protein synthesis to build muscle. Particularly used by body builders
along with testosterone to develop lean muscle. Improves muscle definition
-> anticatabolic effects on muscle protein, simulates anabolic effects.
Elongate bone. Metabolism decreases glucose and fat storage to mobile
glucose and fatty acids for energy during intensive exercise.. Adipose tissue
decreases fat mass. Exercise on hGH- within 20 mins exercise (75-90% VO2
max)- hGH increases, even in adulthood. This makes detection difficult as
athletes doing aerobic exercise are going to have elevated hGH anyway
Administration and supply -> Peptide injected-synthetic NOT human due to
CJD, AIDS etc. Abusers in US spend $30,000/year, usually counterfeit or
bovine (produced by an animal) hGH bought from eBay or amazon. Artificial
stimuli- clonidine, arginine (a food stuff, quite often put into supplement,
insulin induced hypoglycaemia. Decreasing the amount of insulin increases
the effect of hGH. Arginine is a food stuff and difficult to detect
Abuse of hGH in sport -> increase muscle mass and strength, lean body
mass, appearance of musculature and increase final adult height.
16 healthy men 21-34 years old, untrained, administered 0.56 IU/kg/week of
hGH or placebo, during 12 weeks of heavy resistance training. Lean body
mass and total body water increased in hGH group, no difference in muscle
strength. 7 weightlifters took (0.56 IU/kg/week) of GH during a 14 day heavy
session. Muscle protein synthesis did not increase. No change in whole body
protein breakdown. Too shorter studies for too few subjects, different types of
athletes need to be studied, however, difficult to find as illegal.

GH used in children to promote tall offspring -> athletic potential, qualify for
careers where there is minimum height limit. Dose for children 0.6
IU/kg/week, Althletes-10 times more. Side effects -> skeletal changes,
enlargement of fingers and toes, growth of jaw, enlarged internal organs,
cardiomegaly-can lead to death, increase muscle size -> weakness, impaired
glucose regulation, hyperlipidemia, insulin resistance, Diabetes prone in
abuses, Arthritis and Impotence, Skin thickening & Shortened life span
Who abuses -> American footballers and body builders. Co-abuse with
anabolic steroids (GH can prevent some side effects of anabolic steroids). But
impaired detection, Stress?

Lecture 7

Thyroid gland located on ventral surface of the trachea. Secretes 3 hormones

- T3, T4 and calcitonin. T3 = 3, 5, 3 Triiodothyronine, T4 = 3, 5, 3, 5 Tetra
iodothyronine (Thyroxine). T3 has 3 iodines and T4 has 4. Calcitonin
regulates calcium levels. T3 and T4 primary role is to regulate body metabolic
rate for normal growth and development. 4 parathyroid glands on posterior
surface of thyroid gland. Secrete parathyroid hormone, important in calcium
regulation
Each spherical follicle consists of a single layer of follicular cells surrounding a
central protein rich colloid secreted by the follicular cells. Between follicles
are C cells which synthesise and secrete calcitonin. Thyroid hormone levels
show little variation secreted constantly to maintain status quo. Follicles
selectively absorb iodide ions form the blood, storage of iodine in
thyroglobulin -> precursor for synthesis of thyroid hormones. 25% of bodys
iodide ions are in the thyroid glands. Inside follicles = follicular lumen, colloid
serves as a reservoir of materials, rich in protein (thyroglobulin & enzymes).
Follicular cells secrete T3 and T4, when not secreting = low columnar to
cuboidal cells, when active = tall columnar cells
Colloid = thyroglobulin molecules, have tyrosine residues -> become
iodinated (iodide is attached). Results in mono-iodinated tyrosine (MIT - 1
iodine) or di-iodinated tyrosine (DIT - 2 iodines) incorporated into
thyroglobulin backbone. MITs and DITs join together. MIT + DIT -> T3, DIT +
DIT -> T4. MITs cannot covalently bond, cannot make thyroid hormone. T3
and T4 molecules are still joined on the backbone of thyroglobulin, can be
stored in the colloid up to 3 months until release. Signal = thyroid stimulating
hormone from anterior pituitary, binds to TSH receptors on membrane of
follicular cells -> signalling cascade involving protein kinase. Follicular cells
then take up iodinated T3 and T4 molecules bound to thyroglobulin molecules
via phagocytosis. Within cells -> lysosomes containing enzymes -> released
-> remove the thyroglobulin backbone off T3 and T4, recycled back into the
colloid, leaving free T3 & T4. Lipophilic so passively diffuse through
membrane of follicular cells into blood stream -> bound to carrier proteins Thyroxine binding protein, transthyretin and albumin -> transport T3 and T4
to target tissue without being broken down within the blood.
Iodine is mainly from our diet -> food stuffs rich in iodine = kelp, cranberries,
organic yogurts, certain types of beans, organic strawberries and potatoes.
T4 produced at 10 x greater rate than T3. T3 is 4 times more potent than T4.
T4 secreted in plasma eventually converted by liver, kidney or target tissues

to more active T3 by removing an iodide. Conversion from T4 to T3 is called

activation. Mainly T3 that has the action at target tissue
Secretion virtually constant.
Controlled by negative
feedback. Prominently T4 that
causes the feedback (main
role). Extra secretion -> stress,
infants if they are cold. TRH =
thyrotropin.
Thyroid hormones lipophilic ->
receptors located in nucleus of
target, effects mRNA
transcription and protein
synthesis -> Takes time for
action but longer lasting
response. Primary role =
increase BMR, oxygen consumption and energy expenditure at rest.
Generates more heat = calorigenic effect. Increases sodium potassium pump
activity -> more heat. Increase number of mitochondria per cell -> promotes
energy mobilisation and glycogenolysis (glycogen -> glucose) and lipolysis.
Permissive/secondary type effects -> increase of synthesis of beta adrenergic
receptors, tissues response more readily to sympathetic stimulation. Needed
for normal growth. Developmental actions with nervous system. Infants ->
thyroid hormone deficiency (hypothyroidism) results in cretinism -> mental
retardation, treated with T3, given early enough, prevents cretinism. Adult
deficiency -> T3 seems to impair mental function, completely reversible if T3
is given.
Effects -> children dont have a lot of
subcutaneous fat, thyroid hormones can help with
controlling body temperature. Accelerated
turnover of minerals in bone, helps in
development
C cells of thyroid gland -> between follicle cells
and basement membrane. C cells or parafollicular
cells. Produce hormone calcitonin (CT), aids
regulation of Ca2+ concentration in body fluids
HYPOTHYROIDISM (Underactive thyroid, not
secreting enough T3 and T4) -> Myxoedema thickening of skin
(immunological in origin). Hashimoto's thyroiditis most common cause,
bodys immune system mistakenly attacks the thyroid gland. Occasionally
hypothyroidism can be from a pituitary or hypothalamic condition (pituitary
tumour). Symptoms -> Fatigue or lack of energy, Weight gain, and Feeling
cold when its not cold outside, Dry skin and hair, Heavy menstrual periods,
Constipation, Slowed thinking. DIAGNOSIS elevated level of serum TSH
Treatment -> Replacement therapy. Thyroxine-orally as thyroxin sodium, peak
effect 9 days after the treatment started. T3- given orally or IV as liothyronine
sodium, more rapid effect as T3 is the active form, used when in myxedema
coma (state of decompensated hypothyroidism) no energy left. Peak effect
about 1-2 days. Thyroid hormone in pill form on a daily basis. Overdose can
lead to angina, cardiac dysrhythmia or hyperthyroidism. Symptoms tend to

clear in few months, dosage needs to be adjusted depending on function of

thyroid gland. Most -> supplement pill for life
HYPERTHYROIDISM (Overactive Thyroid) -> Graves' disease, due to the
immune system. Symptoms -> Jitteriness, shaking, increased nervousness,
irritability, Rapid heartbeat or palpitations (increases in BMR, O2
consumption, HR), Feeling hot (generation of heat), Weight loss (releasing
energy from stores and using more energy), Fatigue, feeling exhausted, More
frequent bowel movements, Shorter or lighter menstrual periods.
Disorders of thyroid gland -> Graves Ophthalmopathy. Associated with
Graves disease, includes eye symptoms -> intense stare, irritation of eyes,
eyes become very reddened and bulging, loss of vision and double vision.
Diagnosis -> can be confused with cancer and heart problems so
hyperthyroidism isnt always diagnosed straight away, analyse elevated level
of free T4 and low level of TSH in the blood, thyroid scan -> can be quite
swollen.
Treatment -> Surgical- remove the thyroid gland if it is very severe, e.g.
bulging, can restrict the trachea, but opposite effect of hypothyroidism as no
T3 or T4 would be produced, would have to be treated. blockers e.g.
propranolol. Slow down HR, decreases BP. Not a cure, treats the symptoms.
Anti-Thyroid drugs e.g. carbimazole, methimazole, propylthiouracil, will
decrease thyroid hormone synthesis, stop the tyrosine joining with iodide and
stop the MIT and DIT joining together. Carbamizole oral, dose 5 to 20 mg/8h,
90% inhibition of organification of iodine within 12h, half-life of 6 to 15 h.
Affects the way the iodine binds with the thyroglobulin molecules.
Propylthiouracil oral, dose 100mg/8h, 70% inhibition in 7h. Not quite as
effective and unwanted side effects. Unwanted effects include enlarged
thyroid, reduce T3 & T4 output leads to increased TSH production and
increased stimulation of the thyroid, decrease white cell number, rashes,
headache and nausea. Iodine. We need iodine to make thyroid hormone but
actually if we give 30x more than physiological levels it and inhibit this
pathway. It works within 1-2 days and will have its max effect between 10-15
days. Unwanted side effects include rashes, lacrimination (lack of tears),
conjunctivitis, pain in salivary glands etc. Radioiodide can be given orally
and damages the thyroid cells but these leads to hypothyroidism
Disorders of thyroid gland -> thyroid nodules (lumps) -> fairly common and
usually harmless. Enlargement in small nodules around thyroid gland. Only
about 4% nodules are cancerous, detected by fine needle aspiration biopsy.
Get too big, thyroid hormone can be given to decrease size of nodules. If too
big (resisting breathing) or cancerous usually removed

Lecture 8
The Parathyroids and control of calcium and phosphate homeostasis

Calcium -> Important roles in the body. Intracellular free concentration 0.1
mol l-1, achieved by mechanisms such as calcium pump, sequestered by
mitochondria and endoplasmic reticulum. Total intracellular calcium 2.3-2.4
mmol l-1, half bound to inorganic complexes. Free calcium ions in extracellular
fluid is around 1.4 mmol l-1 -> half is free and half is bound to plasma
proteins. 99% of calcium found in bones -> form of calcium phosphate salt,

gives bone strength and rigidity. Skeleton large reserve of calcium, maintains
plasma calcium by mobilising it using a variety of different hormones. Main
components of teeth and connective tissue. Role in blood clotting, main
cellular functions -> muscle contraction, secondary messenger systems.
Calcium balance -> Parathyroid hormone (PTH) secreted by parathyroid
gland. Calcitonin secreted by the thyroid gland. Vitamin D (cholecalciferol). 3
target sites involved i) bones, ii) digestive tract & iii) kidneys. Calcium
balance regulated minute by minute, tightly controlled. Vitamin D is
converted into calcitriol.
8.5 mg/dL is equivalent
to 2.2 mmoles/L and
11 mg/dL is equivalent
to around 2.8 - 3
mmoles/L
Parathyroid glands ->
4 glands, posterior
surface of thyroid
gland. Two different
cell populations ->
chief or principle cells
secrete parathyroid hormone and monitor the levels of calcium and oxyphils
cells (not much known)
3 major effects -> calcium concentrations lower in extracellular fluid and
plasma, secretes PTH to increase calcium concentrations -> mobilises calcium
from bone, inhibits osteoblasts and
decreases calcium disposition by
triggering a certain growth factor
known as RANKL -> increases the
number of osteoclasts. Reabsorption of
Ca2+ at the kidneys, reducing urinary
loss of clacium. Stimulates the
formation and secretion of calcitrol at
the kidneys
Role of PTH in calcium balance ->
under negative feedback control to
maintain a normal level of calcium. No
stimulation from the hypothalamus or
anterior pituitary = direct endocrine
control. Parathyroid glands detect
levels of calcium in the blood.
Effect of calcitonin release -> released
by C cells of thyroid, opposes effects of PTH. Secreted when Ca 2+ levels rise
and stimulates a drop in Ca2+ concentration in body fluids by -> inhibition of
osteoclasts (slows rate of calcium release), stimulation of Ca 2+ excretion at the
kidneys. Again direct endocrine regulation -> C cells respond directly. Most
important during childhood, stimulates bone growth, helps in deposition of
skeleton, esp. during periods of growth. Elevated calcium more often in
children. Calcium levels oscillated within the normal range. Sometimes
calcium levels increases or decreases outside the set normal range.

Calcitriol works with PTH -> steroid

hormone, increase calcium levels ->
stimulates calcium reabsorption in GI tract,
increases calcium absorption in kidneys. Can
absorb Vitamin D3 from diet from
mushrooms, oily fish, eggs, beef, liver and
milk products. In response to low calcium,
PTH regulates the conversion of 25 OHD3 into
calcitriol.
So -> calcitonin reduces calcium levels when
too high, PTH and calcitriol increase calcium
levels when too low.
Hypercalcemia -> serum calcium 2.2-2.6
mmol l-1. Causes: hyperparathyroidism (over
secretion of PTH), can also be caused by
malignant cancers of the breast, lung,
kidney and bone marrow and excess use of
calcium and vitamin D supplements.
Symptoms: Severe hypercalcemia causes fatigue, confusion, cardiac
arrhythmias (calciums role in muscle contraction) and calcification of kidneys
(become hardened) and soft tissues. Treatment: Includes infusion of
hypotonic fluid to lower calcium levels (to draw calcium out of the body),
remove parathyroid gland, administer calcitonin
Hypocalcemia (< 2.1 mmol l-1), less common. Causes: Hypoparathyroidism,
under secretion of PTH, Vit D deficiency (calcitriol therefore not synthesised),
chronic renal failure (less reabsorption of calcium). Symptoms: Muscle
spasms, convulsions, weak heartbeats, cardiac arrhythmias and osteoporosis
(we need calcium for bone growth). Treatments: include calcium supplements,
administer Vit D.
Phosphate balance -> 740g of PO43- is bound in mineral salts of skeleton. Most
important function is in ICF, PO43- concentration of plasma is 2.3 mmol l-1. Not
as closely monitored as calcium.
Calcium and phosphate roles together within
bone -> effective mineralisation. Phosphate
needed to form high energy compounds to
activate enzymes and synthesis of nucleic
acids. Reabsorption in kidneys stimulated by
calcitriol. Take in phosphates in diet -> egg
yolk, milk, nuts, wheat, beans, corn and
mushrooms, processed foods etc. Formation
and reabsorption from bone should be
equal. Movement between bones and soft
tissue.

Hyperphosphatemia (too much circulating phosphate). Symptoms: no

immediate symptoms, chronic elevation leads to calcification of soft tissue
(linked to calcium balance). Causes: high dietary phosphate intake (e.g. too
much processed food etc), hypoparathyroidism. Treatments: dietary reduction
or PTH supplementation.
Hypophosphatemia. Symptoms: anorexia, dizziness, muscle weakness,
cardiomyopathy, osteoporosis (similar to hypocalcaemia). Causes: poor diet,
kidney disease, malabsorption syndrome (not absorbing enough phosphate
from the diet), hyperparathyroidism, Vit D deficiency.
Treatment: dietary improvement, Vit D supplement
(rickets can also result from lack of D3) or calcitrol
supplementation
Interactions between calcium and phosphate -> if
calcium concentration decreases, stimulates PTH
secretion -> increases osteoclast activity, increase
blood calcium concentration but also phosphate
concentration. Kidneys -> retains clacium but increases
phosphate secretion.
Integration ->

Lecture 9
The adrenal Glands

Gross anatomy -> Blood supply: superior, middle and inferior suprarenal
arteries. Blood drains into suprarenal vein (L) and inferior vena cava (R)
Glands are paired. Primary endocrine organs. Lie on superior surface of each
kidney (suprarenal glands). Triangular in shape, rich arterial blood supply.
Each gland weighs around 6 10 g. supplied via inferior suprarenal artery (a
branch of the renal artery), middle (branches directly from the abdominal

aorta), superior suprarenal arteries (which branch from the inferior phrenic
arteries) - may actually have more than one of each due to their branching
nature. Single suprarenal vein on left drains into the renal vein (into the
inferior vena cava), right drains directly into the inferior vena cava. Blood
enters the outer regions of the gland (the cortex) and drains down into
venules which flow through the innermost region the medulla. Specialized
for different types of secretion.
Medulla secretes catecholamines (as in adult). Definitive cortex converts
progesterone to cortisol (especially during the last trimester of pregnancy) ->
production of surfactant- lung development, differentiation of the liver,
triggering role in parturition. Foetal zone secretes oestrogen precursors
Adrenal medulla derived from ectodermal cells of the neural crest. Cells are
modified sympathetic post ganglionic fibres (releases catecholamines adrenaline, noradrenaline and dopamine) = part of the sympathetic division
of the autonomic nervous system. Cortex derived mesoderm, specialised for
secretion of steroid hormones. Development - adrenal gland is much larger in
relation to the foetal body size. Consists of three (rather than two) layers small medullary region, small zoned cortex definitive cortex and a third,
large zone known as the foetal zone. Foetus -> medulla can secrete
catecholamines in response to hypoxic stress and immediately after delivery
in response to cold stress. After birth, foetal zone regresses rapidly, definitive
cortex and medulla enlarge -> adult gland
Glands surrounded by a fibrous capsule. Two separate glands cortex and
innermost medulla. Adrenal cortex has three subdivisions
Outermost zona glomerulosa secretes
steroids -> mineralocorticoid function.
Most importantly aldosterone, regulates
mineral metabolism. Kidneys ->
important in mineral and electrolyte
metabolism. Middle layer - zona
fasciculata secretes glucocorticoid steroids -> affects the metabolism of
carbohydrates, lesser extent, fats and proteins. Innermost - zona reticularis.
Not fully developed until 6-7 years of age. Formed by migration of zona
glomerulosa cells which change their secretory pattern from
mineralocorticoids to principal sex steroids -> are androgenic but are also
converted to testosterone in peripheral tissues. Appears of insignificance in
males, produce a lot of testosterone in testicular tissues, females -> adrenals
secrete the major fraction of androgenic hormones. Medulla there is a small
amount of Dopamine released as well.
All corticosteroids formed from cholesterol -> converted via acetylation into
pregnenolone.

Aldosterone is the most

important mineralocorticoid.
Target cells are = distal
tubule and collecting duct of
the kidney. Increases sodium
reabsortpion and potassium secretion. Also stimulates secretion of hydrogen
ions. Results in salt retention and
alkalosis. Important in the long
term regulation of blood volume
and blood pressure. The
glucocorticoid cortisol metabolic
effects oppose those of insulin.
Facilitate the conversion of
protein to amino acids. Cortisol
also stimulates the appetite and
metabolism of fats. Specific
corticosteroid-binding globulin
(transcortin) binds around 80% of
the circulating cortisol, rest is
bound to serum albumin. Lower
affinity for aldosterone which is
mostly bound to albumin. Cortisol
-> weak mineralocorticoid action concentration of cortisol exceeds that of
aldosterone. Enzymes in the kidney inactivates cortisol, preventing
inappropriate mineralocorticoid stimulation. Also released as a consequence
of stress. Sex steroids such as testosterone contribute to the development of
secondary sexual characteristics such as hair etc.
Regulation of secretion of aldosterone -> controlled by levels of potasssium
acting directly on the adrenal cortex and changes in plasma volume, exerted
via the renin-angiotensin system. Decreased afferent arteriolar pressure and
fall in Na in blood releases Renin from JGA. Renin converts Angiotensinogen to
Ang I in the liver, which is converted to Ang II in lungs. Ang II is potent
vasoconstrictor (increases blood pressure) and releases Aldosterone from
adnrenal glands to increase Na+ reabsorption to help increase plasam
volume. Control via negative feedback responses. Increases in plasma K+
stimualtes the release of aldosterone -> excretion of K+.

imporant to keep extracellular and blood potassium levels constant

-> rise = depolarisation of tissues -> muscle contractions,
depolarisation of nerve cells, firing of action potentials and
potentiall convulsions
Regulation of cortisol secretion ->
Control of corticosteroids =
negative feedback responses.
Secretion of cortisol is under the
control of adrenocorticotropic
hormone (ACTH) released from the
anterior pituitary - trophic effect on
the zona fasiculata. Elevated levels
of circulating cortisol feedback to
inhibit ACTH secretion. Diurnal
rhythm, levels are lowest at
around 3 pm, rises to maximum
values between 6 and 8 am. Half
the daily output of cortisol occurs
in this period. Circadian rhythm of
ACTH secretion -> sleep-wake cycle driven by CRH levels. Disruption of
rhythm of cortisol secretion is caused by any kind of acute stress, direct
stimulation of CRH secretion. Stress causes central effects -> neural
singalling to the hypothalamus.
Over production of cortisol
-> Cushings syndrome.
Can be induced by an
ACTH secreting tumour of
the pituitary gland or
adrenal gland. Induced by
long-term use of synthetic
glucocorticoids used to
treat many different
inflammatory conditions,
including arthritis and
dermatitis. Truncal obesity,
hyperglycaemia,
redistribution of body fat
e.g. moon face and buffalo,
increased proteolysis ->
muscle wasting in proximal
limbs, enhanced actions of catecholamines -> hypertension. Addisons
disease = opposite -> failure of adrenal cortex to secrete both cortisol and
aldosterone. Result of autoimmune disorder or tumours. Hypoglycaemia, loss
of appetite, muscle weakness, increased ACTH and CRH (loss of negative
feedback from cortisol) -> hyperpigmentation (CRH increases release of
melanocyte releasing hormone, increases skin pigmentation). Loss of
Aldosterone -> hyperkalaemia, Na loss -> raised renin levels -> hypotension.
Hyperaldosteronism -> hyperplasia of cells in the zona glomerulosa (Conns
syndrome) or sometimes by aldosterone-secreting tumours.

Mineralocorticoid selectivity is enzyme based -> Cortisol and aldosterone

cross plasma membranes & bind to MR. Hormone receptor complex
translocate to nucleus to cause transcription of a variety of different proteins.
MR binds glucocorticoids and mineralocorticoids with equal affinity
Intracellular mineralocorticoid receptor
(MR). Plasma concentrations of cortisol
are much higher but NAD-dependent
11-hydroxysteroid dehydrogenase
type 2 (11HSD2) enzyme, which is colocalised with the MR, converts
intracellular cortisol to cortisone which
has low affinity for the MR, generates
high levels of NADH. Generated NADH
maintains cortisolMR complexes in an
inactive state and permits aldosterone
to selectively activate the receptor,
despite higher intracellular cortisol
levels. Inhibitors of 11HSD2
(glycyrrhetinic acid, active compound of licorice) allows
cortisol activation of MR, resulting in hypertension.
Innervation of medullary region -> innervated from the
thoracic T9 region of the sympathetic chain. Sympathetic
preganglionic fibres innervate (Ach neurotransmitter) and
stimulate chromaffin cells -> secrete catecholamines. Cortex
secretes steroids.
Medullary catecholamines -> secretes three catecholamines
derived from the amino acid tyrosine. Chromaffin cells
contain secretory granules containing catecholamine and a
variety of opioid peptides (enkephalins). Release via
exocytosis in response to acetylcholine release from
sympathetic pre-ganglionic fibres. About 80% of the granules
contain epinephrine and the remaining 20% norepinephrine,
<1% dopamine.
Medullary catecholamines -> Basal secretion is low,
stimulated in response to a number of stressful situations
e.g. exercise, haemorrhage, hypotension, cold, etc., also
emotional stimuli such as fear -> preparing the body for
acute stress (fight or flight response). Control of this secretion is dependent
on activity of the splanchnic nerves. Alpha and beta receptors -> GPCRs
coupled to specific second messenger systems (cAMP, PLC). Catecholamines
are degraded rapidly (half-life of 1-3 minutes), inactivated by uptake into
sympathetic nerve terminals, broken down by catechol-O-methyltransferase
and monoamine oxidases in liver, kidney and brain. Underproduction not a
clinical problem. Overproduction is serious. Tumour of chromaffin tissues
(chromaffinoma) = phaeochromocytoma -> life threatening hypertension.
Treated: surgical removal or administration of catecholamine receptor
blockers (e.g. phenoxybenzamine & attenolol).

Lecture 10
The hypothalamus and pituitary

Pea sized lump of tissue - closely associated

with the hypothalamus, near to the optic nerve.
Part of the posterior forebrain. Two main parts posterior and anterior pituitary. Lies anterior to
the pons and below the forebrain, connected to
the hypothalamus. Hypothalamus = under the
thalamus. Pituritary known as hypophysis,
means to grow under size and shape of a pea on a
stalk (the infundibulum). proximity of the hypothalamus
and pituitary -> connection by the neurohypophyseal
stalk
Adult gland -> Neurohypophysis median eminence; posterior pituitary &
infundibulum. Adenohypophysis pars distalis; tuberalis & intermedia
Posterior pituitary (neurohypophysis) consists of: the median eminence
neural tissue of the hypothalamus; the posterior pituitary itself and the
infundibular system - connects the two. Anterior pituitary (adenohypophysis)
consists of two portions: the anterior pituitary itself (also called the pars
distalis) and a much smaller, pars tuberalis which wraps around the
infundibulum. Neural tissue forms posterior pituitary (neurohypophysis). Nonneural forms anterior pituitary (adenohypophysis)
Sits within the sphenoid bone of the skull in a depression called the sella
turcica totally surrounded by bone. Held in place by a small connective
tissue diaphragm which surrounds the stalk of tissue that connects the
hypothalamus to the pituitary gland. Anterior pituitary = adenohypophysis
largely secretory cells, secrete hormones into the blood stream. Posterior
pituitary = neurohypophysis, made out of nerve tissue. Connected to the rest
of the brain by the infundibulum a stalk of nervous tissue, runs down from
below the third ventricle connecting to the neurohypophysis. Further
subdivide lobes. Optic chasm very close to pituitary, just posterior and
inferior. Pituitary isolated from the cranial cavity and locked into position by
thin dural sheets known as the diaphragma sellae.
Small sliver of tissue = boundary between the anterior and posterior
pituitary = pars intermedia, actively secretes Melanocyte Stimulating
Hormone: MSH during development, regresses after birth, and may even be
absent in the adult gland.
Development of the pituitary gland occurs in third trimester. Floor of the third
ventricle (nervous tissue) is very close to the roof of the mouth (buccal
ectoderm). Outgrowth of tissue from the the brain and an invagination of the
buckle tissue, called Rathkes pouch. Grow closer together. Rathkes pouch
pinches off from the rest of the pharyngeal ectoderm and folds around the
infundibulum. Down growth from the third ventricle forms the infundibulum
stalk that joins the hypothalamus to the posterior pituitary. Anterior lobe is
formed from the buckle ectoderm, part of this wraps around the stalk to form
the pars tuberalis of the anterior pituitary.

Anterior pituitary gland -> releases 6

peptide hormones. Very rich blood supply.
Superior hypophyseal artery comes into the
median eminence of the hypothalamus.
Capillary bed is closely associated with
neuro secretory neurones of the
hypothalamus -> release releasing
hormones into the capillary bed, carried by
the hypothalamic hypophyseal portal
system to another set of capillaries within
the anterior pituitary -> act on the
endocrine cells, causing them to release
hormones. no direct neural link
Released from the anterior pituitary are prolactin, thyroid stimulating
hormone, adrenocortical hormone, growth hormone, follicle stimulating
hormone and luteinising hormone. Controlled by the hypothalamus. Prolactin
release is stimulated by prolactin releasing hormone secreted by the
hypothalamic neurones, another hormone, prolactin inhibitory hormone
(dopamine), inhibits the release of prolactin.
Anterior pituitary
hormones =
peptides.
somatotropic
hormones: Growth
hormone (GH) and
Prolactin (PRL) are
similar peptides.
Powerful effects on
growth and
metabolism in most
peripheral tissues,
PRL has weak
somatotrophic effects, main action is to promote growth and maturation of
the mammary gland during pregnancy to prepare it for milk secretion.
Gonadotrophic hormones Follicle stimulating Hormone (FSH) and Luteinizing
Hormone (LH) play important roles in spermatogenesis by the testes and
production of sex hormones in both sexes

Corticotropin-related hormones are all derived from the same precursor

peptide = Pre-proopiomelanocortin: - consists of
265 amino acids . ACTH
regulates the function of the
adrenal cortex, MSH stimulates
epidermal melanocytes role in
skin pigmentation, binds to a
plasma membrane receptor on
melanocytes (MC-1), generates
the production of the enzyme
tyrosinase required for
production of melanin -> determining tanning ability in humans. Individuals
who tan poorly carry a polymorphism in the MC-1 gene.
Hypothalamic hormones can be stimulatory or inhibitory. Hypothalamic
neurones reside within a number of different nuclei, tend to be specific for a
specific releasing
hormone. Hypothalamus
controls the release of
hormones from the
anterior pituitary.
Specific hormones
synthesized in the cell
bodies of neurones in
discrete areas (nuclei) of
the median eminence. Transported to the nerve terminals -> released.
Releasing hormones modify the rates of secretion of TSH, FSH, LH, ACTH, MSH
and peptides related to ACTH. Inhibiting/inhibitory hormones modify the
release of prolactin, GH and TSH
Some of the hypothalamic hormones found in other parts of the body acting
in different ways. Somatostatin acts in the gut - inhibiting release of insulin
and glucagon. Also neurotransmitter in other parts of the brain.
Quite close negative feedback control of the release of these
hormones. Releasing hormone is negatively inhibited by the second
hormone that is secreted by the systemic endocrine organ. Hormone
released by the anterior pituitary acts on the endocrine organ, that
hormone feedbacks to inhibit the pituitary hormone and also the
releasing hormone from the hypothalamus. CRH released from the
hypothalamus -> ACTH -> cortisol from the adrenal cortex -> acts
back to inhibit the release of ACTH and CRH. Also applies to the
inhibitory factors. GH acts on the liver to release somatomedins,
inhibits GH-RH but stimulates GH-IH = stronger feedback loop.
Posterior pituitary gland -> Neurosecretory neurones in the
hypothalamus send axons into the posterior pituitary. Release
hormones within the PP, directly into the bloodstream. Releases 2
peptide hormones. Anti-diuretic hormone and oxytocin.
Released directly form the nerve cells -> two main nuclei in the
hypothalamus that project into the posterior pituaty. Cells of the
supraoptic nucleus secretes vasopressin, cells of the paraventricular
nucleus secrete oxytocin into capillary beds that supply the neurohypophysis

Closely related nonapeptides (nine amino acids). Synthesized by

magnocellular neurones in the supraoptic (SON) and paraventricular nuclei
(PVN). Transported in association with specific carrier proteins, neurophysins
along the axons of these neurones to the nerve terminals. Stored in secretory
granules either in the terminals or in varicosities (Herring bodies) that are
distributed along the axons. Hormones are released by Ca+-dependent
exocytosis into the capillaries and hence into the systemic circulation in
response to nerve impulses originating in the SON and PVN.
Vasopressin and oxytocin are structurally similar -> 9 amino acids with a
disulphide bond between the first and the sixth amino acid. Differ in their
amino acid compositions at position 3 and 8 -> common ancestor protein =
vasotocin. Arginine at position 8 in AVP critical for its anti-diuretic action.
Leucine substitution at position 8 in oxytocin does not remove all antidiuretic
activity, high doses oxytocin does stimulate water
reabsorption.Desmopressin synthetic derivative, N-terminal cystine is
deaminated, L-arginine at position 8 is replaced by the D form. ->
modifications extend the half life
ADH -> secreted along with their accompanying neurophysins, circulate as
free hormones. Both act via GPCRs. two subtypes of receptors V 1 in vascular
smooth muscle where is stimulates contraction, and V 2 in renal epithelial cells
of the distal nephron to stimulate water reabsorption. V 2 act via cAMP and V1
via phosphoinositide turnover -> increasing intracellular Ca 2+.
Dehydration/decrease in plasma volume -> increased plasma osmolality.
Sensed by osmoreceptors in the hypothalamus, stimulate the cell bodies of
the supraoptic nucleus to release ADH from the pituitary. Leads to increased
water reabsorption by the kidneys in the collecting ducts -> dilution of
plasma, lower volume of concentrated urine produced. Classical feedback
mechanism. Changes in blood volume can modulate the release, particularly
if accompanied by stress e.g. a haemorrhage -> goes down -> decrease in
baroreceptor activity, stimulates the nerves in the hypothalamus, release of
ADH. Stress increases ADH release and alcohol inhibits ADH release.
Oxytocin released by mechanical stimulation (suckling reflex). Stimulates milk
production (let down reflex). Plays a role in expelling the foetus and placenta
during labour. In males it may play a role in erection (partially), ejaculation
and sperm progression (sperm development). Prolactin causes an increase in
milk production, oxytocin causes the expression of milk. baby suckles, sends
signals to paraventricular nuclei -> release of oxytocin -> stimulates the
ejection of milk (let-down reflex) -> acts in cells of the mammary gland to
contract and cause milk ejection. Also collaterals go to the inhibitory
dopaminergic neurones of the hypothalamus = feedback control Oxytocin
increases during parturition -> set up contractions of the uterus. Response to
afferent input. Potent stimulus is mechanical stimulation of the nipple during
suckling by the baby. Afferent information travels via the spinothalamic tract
and brain stem. Some psychogenic stimuli such as the sound of a crying
baby
Hypothalamic-hypophyseal portal system -> System originates in capillary
beds in the median eminence the primary plexus. Blood flows in parallel
veins, the long portal veins down through the infundibulum to the anterior
lobe. Vessels break up into sinusoids (discontinuous endothelium) main blood
supply to the anterior pituitary. Transport specific releasing hormones

secreted by neurones in the median eminence to the anterior pituitary. blood

supply to the posterior lobe is not via the portal system, by the inferior
hypophyseal artery -> capillary bed with in the posterior lobe, drains via the
hypophyseal veins, carry the two peptide hormones from hypothalamic
magnocellular neurones located in the supraoptic and paraventricular nuclei

Lecture 11
Pathophysiology and pharmacology of
the hypothalamus & pituitary

Negative feedback loops to closely

control the release of hormones.
Periphery gland releases hormones, act
back to inhibit the release of the tropic
hormones from the pituitary and release
of releasing/inhibiting hormones from
the hypothalamus.
Endocrine diseases of the hypothalamic
pituitary system depends on part of that
system primarily affected to alter the
release of hormone from the peripheral
gland.
Primary, secondary (e.g. tumor in the
pituitary) and tertiary endocrine disease.
Thyrotropin RH is released from the hypothalamus into the portal system,
-> acts on anterior pituitary -> release thyroid
SH -> thyroid gland releases T3 and T4 ->
control of body metabolism. If something goes
wrong in the pituitary or hypothalamus there
will be effects on the whole body.
Negative feedback loops control secretion of
hypothalamic releasing hormones and of
secretion of pituitary hormones. Low or high
levels of a peripheral hormone due to defect at
the level of the peripheral gland or the pituitary
gland or the hypothalamus. Primary
deficiencies are often most severe, often
involved complete absence of the peripheral
hormone
Hypo or hyper thyroidism. Hypothyroidism =
reductions in the release of thyroid hormones
-> fat deposition around the face and eyelids,
susceptible to cold and arthritis, tiredness,
lethargic etc. results in a decrease in metabolism and a buildup of
metabolites called glycosaminoglycans inside of cells of various organs
and tissues and increase water and mucus, forming edema. Central
hypothyroidism caused by dysfunction of the pituitary gland or
hypothalamus. Hyperthyroidism -> bulging eyes (exophthalmos), restless,

sleeplessness etc. Both show enlargement of the thyroid gland (goiter),

conditions quite seriously effects individuals
Number of causes, most common cause is a tumor, usually in the
adenohypophysis = pituitary adenoma. Result of congenital problems,
inherited or develops with no clear genetic cause. Radiation -> exposure
damages the pituitary e.g. radiation therapy for a tumor within the
pituitary. Drug induced causes (e.g.
anticancer drugs). Less common
reasons include infection, graves
disease, genetic mutations and
patients with no clear reason
Central hypothyroidism -> typically
see low levels of thyroid hormones
+ low levels of TSH. Check other
hormone deficiencies (general
problem or not), gene test
(congenital reason). Mutations to a
number of genes will result in
hypothyroidism. Possible that the
hypothyroidism is a result of an
existing syndrome or medication for
another problem. Check for tumors
that might be causing problems.
Pituitary gland also secretes growth hormone, release is pulsatile, surging
10-100 fold. Deep sleep is a potent stimulus for GH (2-3 peaks). Has acute
effects on the liver (increase gluconeogenesis),
muscle (decrease glucose uptake) and adipose
tissue (increases lipolysis) -> oppose the actions
of insulin (diabetogenic effects). GH producing
tumors are usually insulin resistant, glucose
intolerant and diabetic.
GH has its effects during development ->
growth. Graph -> Rapid growth initially, reduces
to a lower, steady level until puberty -> growth
spurt. Pubertal peak rate of growth corresponds
to the peak in IGF1, but degrades with age. Growth is
mediated by part by IGF (controlled by GH), especially
important in controlling the pubertal growth spurt but not
so important in young children due to insulin. After this
time GH and IGF play a role in regulation of body mass
(anabolism). Early childhood rapid growth, low IGF
levels so other factors involved e.g. insulin.
Deficiency of GH in children results in pituitary dwarfism
-> lack of growth. Caused either by lack of GHRF release
(problem at hypothalamus) or failure of IGF generation or
action (problem at liver). GHRF = 40-44 aa peptide. GHRH
analogue, sermorelin is used as a diagnostic test for GH
secretion determine where the problem lies. GH
hormone used to re-establish linear growth. Former times, somatotropin
from cadaver pituitaries linked to Creutzfeldt-Jacob disease, a severe

neurodegenerative disease. Synthetic GH is now used to stimulate the

liver to release IGF-1.
Excessive production of GH in children results in gigantism. Pituitary
gigantism results in excessive longitudinal growth. In adults, excessive
secretion caused by a benign pituitary tumor = acromegaly ->
enlargement of facial structures and of the hands and feet. Can reduce the
release of GH from the anterior pituitary by using a synthetic somatostatin
analogue (octreotide [sandostatin] or bromocriptine), inhibits release of
GH.
Prolactin -> control of milk production in the suckling
reflex. Rise immediately following parturition, suckling
maintains lactation by raising prolactin levels 10 fold
within 30 minutes. Secretion from the anterior pituitary,
subject to tonic inhibitory control by the hypothalamus via
dopaminergic-tuberohypophyseal pathway. Inhibiting
factor is dopamine. Main stimulus is suckling. Neural
reflexes from the breast -> prolactin releasing factor.
Suppress its release to prevent lactation without causing
pain, suppress established lactation, and treat prolactin
secreting pituitary tumors (prolactinomas). Bromocriptine = dopamine
agonist. Dopamine antagonists -> used in antipsychotic regimens ->
potent stimulants for prolactin release by prevent its inhibition
Gonadotrophin-release Hormone (GnRH) controls
the release of the gonadotrophins FSH & LH.
Controlled by neural input and female negative
feedback by sex steroids.
Synthetic GnRH = gonadorelin, number of agonists
and antagonists available. Given continuously to
inhibit gonadotrophin release, given in pulses to
stimulate release. Agonists include: buserelin;
luoprelin & naferlin -> treat endometriosis, short
term used in the prevention of endogenous ovulation
in patients who undergo exogenous stimulation with FSH in the
preparation for in vitro fertilization therapy. Also inhibitors -> inhibit
receptors on the hypothalamus & anterior pituitary e.g. oestrogen.
Antagonists = cetrorelix and abarelix - used in oncology to reduce the
amount of testosterone & patients with advanced symptomatic prostate
cancer.
Danazol = testosterone derivative, inhibits the release of gonadotrophins.
Decreased sex hormone production beneficial e.g. endometriosis.
Clomiphene and cyclofenil stimulate the release gonadotrophin release
by antagonizing the negative feedback effects of androgens and
oestrogen.
ADH release is controlled primarily by plasma osmotic pressure, detected
by osmoreceptors in the paraventricular and supraoptic nuclei. ADH
deficiency -> Diabetes insipidus -> central = loss of pituitary secretion
of ADH, treated with desmopressin, higher selectivity for V2 receptors
and a much longer half-life. Nephrogenic = impaired response to ADH at
the renal collecting duct. Acquired condition, treated by fluid replacement
until the primary cause e.g. side effects of another drug are alleviated.

Excessive urine production and excessive thirst. Lypressin and Terlipressin

also used to treat diabetic insipidus.
ADH overproduction = Syndrome of inappropriate ADH secretion (SIADH)
-> water and salt retention. Posterior pituitary is not always the source of
ADH, ADH-secreting tumors has been associated with SIADH, as well as
various CNS disorders, pulmonary disorders, and drugs side effects.
Demeclocycline = tetracycline antibiotic, blocks ADH by binding to its
receptor. Tolvaptan = unrelated V2 antagonist under fast track trials by
the USFDA.
Oxytocin (Pitocin) and its agonists e.g. carbetocin, used
to induce or augment labour and to treat post-partum
haemmorhage. Antagonists = atosiban & barusiban,
reduces myometrial contractions - treatment of preterm
labour. Well known effects on uterine smooth muscle,
additional new role for oxytocin in neoplastic pathology. In
tumours, oxytocin acts as a growth regulator, activation of a
specific GPCR. Administration of long-lasting oxytocin
analogs, such as carbetocin, are suggested to achieve
prophylaxis or treatment of certain types of breast cancer.

Lecture 12
Anatomy of the Pelvis and Reproductive system

Bony Pelvis and pelvic girdle -> Function: Support of body weight transmits force. Movement - Trunk & Limbs, muscles are attached to
the pelvis. Front of the iliac is a strong flexor of the hip and the gluteal
muscles coming off the back are strong extensors, adductors and
abductors which move the leg laterally or medially. GI and Urinary
System - such as the sigmoid colon, rectum and anus and also the
urinary system, the ureters pass down on the posterior pelvic wall to
the bladder. Reproductive System - Support and protection for pelvic viscera,
especially gravid uterus, Attachment of muscles to aid the above - Pelvic floor
(important in micturition and defecation). Males - testes have passed through
the inguinal canal and they sit outside the pelvis in a sac in the perineum, the
scrotum. ducts pass back through in the pelvis and enter the urethra posterior
to the bladder
Pelvis essentially joins our vertebral column onto our legs. Bony cage in which
important organs lie, foetus can develop in relative protection. three bones
on each side the ileum, pubis and ischium -> fuse together and becomes a
single bone called the innominate or hip bone -> join onto the sacrum =
effectively 5 vertebra fused together. joint between the ilium and sacrum =
sacroiliac joint -> a synovial joint (normally associate with free movement),
shape of the joint is quite irregular and it tightly tied by lots of ligaments that
cross that joint so there isnt any significant movement. Older -> tends to
fibrose up & calcify. At the front sides of the pelvis are joined together by the
pubic symphysis = fibro-collagenous joint -> strong but ever so slightly
mobile joint. Becomes more mobile as the connections get weaker to allow a
degree and flexibility during childbirth/late pregnancy. Pelvis is effectively a
single ring = strong. Femur sits in the acetabulum. Pelvis sits at quite a steep

angle so the anterior superior iliac spine and the pubic symphysis lie in a
vertical plane.
Pelvic brim (also known as pelvic inlet)
separates the pelvis into two parts -> Greater
(or false) Pelvis superior to pelvic brim.
Protected by the wings of the ilium - well
protected at the back and laterally but not so
well anteriorly. Lesser (or true) Pelvis
inbetween pelvic inlet and pelvic outlet. Some
strong ligaments that run across between the
ischial spine and the sacrum and between the ischial tuberosity and the
sacrum = sacrotuberous and
sacrospinous ligaments and help
to define the lower boarder.
Males broadly speaking are
specialised for being strong and
stable, women are specialised
for having babies. In males the
wings of the ilium are taller and
more robust -> attachment of
big muscles, women - tend to be
more flat and open. Inlet is more circular and bigger in women because the
alae (the wings of the sacrum) are wider and flatter and the fronts of the
vertebral bodies dont project so much. Males = more robust so the vertebral
column in more stable at the price that the pelvic inlet is much smaller.
During pregnancy the uterus expands into the abdomen so there must be a
big enough space. Pelvic outlet is wider in women because the angle at the
bottom of the pubic symphysis is greater so the ischial bones are turned out
more and the ischial spines project in less, but less stable. Obturator foramen
= the window made by the pubis and ischium. Acetabulum = not as deep and
stable in women. Greater sciatic notch = a notch in the ilium that lies
between the posterior iliac spine and the ischial spine below. Women = a
channel, men = narrow so their perineum and pelvic floor is much more
stable. Its much more common for women to have problems with prolapse
and instability if that muscular wall becomes damaged
Pelvic floor anatomy -> Structure: Muscular sheet that covers pelvic outlet.
Three midline orifices (urethral, vaginal, anal). Function: Supports pelvic
viscera, Resists increases in intra-abdominal pressure. Can be damaged
during childbirth

levator ani is a broad, thin muscle,

situated on either side of the
pelvis. Formed from - the
puborectalis, the pubococcygeus
muscle and the iliococcygeus
muscle -> attached to the inner
surface of each side of the lesser
pelvis, unite to form the greater
part of the pelvic floor. Coccygeus
muscle completes the pelvic floor,
also called the pelvic diaphragm.
levator ani -> effectively wraps as
a sling around the anus, attaching
anteriorly to the pubic bone and
lower limb, either wrap directly
around the anus (puborectalis) or
they attach to a ligament which is
suspending the anus from the
sacrum -> act to hold the whole
floor up and prevent prolapse of
the anus. Obturator foremen ->
inside = obturator internus,
outside = obturator externus ->
involved with flexion and
extension of the hip, seal off the
muscle coccygeus, runs from the
ischial tuberosity to the sacrum,
also a pelvic floor muscle.
Pectineus comes off the sacrum
and passes laterally to the hip
and is therefore a lateral rotator of the hip and helps to seal off and stabilise
the pelvic floor. All of these muscles together form the perineum
Pelvic floor anatomy: Inferior view - The levator ani passing around the back
of the anus and attaching to the ligament. Lowest ends of the gluteal muscles
- extend the leg. Superior muscles join in the midline and pass around the
hiatus through which the urethra passes through and vagina in women.
Central tendon of the perineum = density of connective tissue, acts like an
anchor point. Superficial transverse perineals run over the top, wider deep
transverse perineals are effectively reinforcing the anterior part of the floor.
ischiocavernosus and bulbospongiosus muscles run from the bottom of the
pubis along the lateral boarder and running around to the perineal body ->
support muscles, important in penile function in men. When a babys head
comes through, crown of the head is leading, often there is splitting of the
muscle. Episiotomy = an incision made in the perineum to make extra space
for the head to come through. Important that this gets repaired - loss of the
supporting function, not uncommon for women to develop prolapse. Perineal
body, = central tendon of perineum, is a pyramidal fibromuscular mass
situated in the middle of the junction of urogenital triangle and anal triangle.

Pelvic floor anatomy: Male. Perineal

body = a continuous connective
sheath through the middle.
ischiocavernosus and
bulbospongiosus muscles attach into
the root of the penis. Scrotum =
extension of the skin of the
perineum, which a sack of perineum
will pass down - testis sit in there.
Pelvis Hemisections. Pelvic organs
-> project into abdominal cavity,
covered by peritoneum and forms
pouches. Males - bladder is at the front and the rectum is at the back.
Urethra comes out of the bladder, passes through the prostate = outpouching
of the urethra. Number of ducts develop out of the wall of the urethra and
form branching glands that secrete seminal fluid. Urethra passes down
through the erectile tissues of the penis. Peritoneal layer overlies the bladder
and the last part of the sigmoid and rectum. Pelvic organs are retroperitoneal
they are lying below the surface of the peritoneum. Females - uterus sit in
between the bladder anteriorly and the rectum posteriorly. Ovaries also
covered by peritoneum. Peritoneum forms the broad ligament. In females
utero-rectal pouch common site for accumulation of free-fluid or pus.
Peritonitis - tend to collect in this pouch as its the lowest point, can be
accessed via the transvaginal route by passing a needle up through the
vagina to pierce the pouch without putting a needle through the abdomen, a
sample of the fluid there can be taken. Rectum -there
are lots of infections/bacteria in the rectum that you
dont want to introduce into the peritoneum.
External Genitalia and Vagina. External genitalia or
vulva function = sensory and erectile tissue, direct
flow of urine, prevent entry of foreign material. Vagina
musculomembranous channel. Vestibule to cervix
function -> receives penis and ejaculate, part of the
birth canal, canal for menstrual fluid. Labia majora =
folds of skin on the outside, developmentally
equivalent to the scrotum, round ligament passes
down into the majora. Labia minora = folds of skin
that enclose a region called the vestibule. In a virgin the vagina is protected
by the hymen = thin layer of membrane with a small slit in it through which
menstrual fluid can pass, normally destroyed during intercourse. Peroneal
body = a thickening. Mons pubis = layer of fatty tissue, overlies the pubic
symphysis. Clitoris = developmental equivalent of the penis, has a small
amount of erectile tissue, is heavily innervated - has a very strong sensory
input. Vagina, volt and cervix projects to the top of the vagina. Bladder lies
anteriorly, urethra is short and straight, fused with the anterior vaginal wall.
Vagina = relatively large opening and is normally collapsed anteriorly and
posteriorly. Ejaculate collects in the volt before making its way up to the
cervix to the uterus and fallopian tubes where it will hopefully meet an egg.
Uterine lining turns over each month and involves loss of blood and other
material which must pass through the vagina

Female reproductive organs

-> Uterus (Think 3!!) -> 3
Parts = Fundus (curved
upper part), Body, Cervix ->
Are all continuous in terms
of muscles but they are
defined anatomically 3
Layers = Peri (epithelial
layer around the uterus),
Myo (muscular area which
contracts to provide force to
expel the baby) &
Endometrium (lining turns
over during menstruation,
becomes more
vascularised, thickened so
its prepared for the egg to
implant). 3 Openings = Uterine Tube, Os. 3 Paired Ligaments = Round,
Ovarian, Suspensory. Vaginal shaft passes up to the volt. cervix projects down
a significant distance into the vagina, creating a space around the edge which
is part of the volt known as the fornixes - anterior posterior and lateral, one
continuous ring. Wrapped around is the peritoneum forming a sheet. follapian
or uterine tubes pass around and open up, has frimbae which help to catch
the eggs -> wafted along the tube by ciliary action and typically fertilisation
occurs in the ampulla, then implant into the body of the uterus. ovaries are
attached to the wall of the uterus by the ligament of the ovaries =
condensation of connective tissue, also attached by a continuation of that
called the suspensory ligament attaches to the side of the pelvis - ovaries are
suspended into position. Ligament continues back around to the posterior
wall of the uterus, comes off as the round ligament = embryological
equivalent to the spermatic cord as it passes through the inguinal canal to the
labium majora
Use a tool called a speculum, introduce it into the vagina
and open it, can see the cervix projecting through and the
entrance passing into the uterus and also the continuous
ring of the fornix. Cervix inspected e.g. for cervical cancer
Uterus normally has an anteverted - anteflexed
disposition. Three orientation axes: Vagina, Cervix &
Uterus. Vagina projects slightly backwards and the uterus
projects forwards, sitting over the top of the bladder,
usually curved slightly forwards. Abnormalities in this which can matter to
different degrees, not normally a problem, effect how things are packed
within the abdomen. Retroverted = cervix is sitting too straight with the
vagina. When a baby starts to develop the whole space fills up anyway so this
is not normally a problem, it can be a problem if youre a surgeon and things
arent in the normal place.

Uterine support and prolapse ->

broad ligament = double layer of
peritoneum draped over uterus
and uterine tubes. Relatively
week structure but does provide
a bit of support. Contains ->
round ligament (uterus to labia
majorium), ovarian ligament
(ovary to uterus), suspensory
ligament (ovary to lateral pelvic
wall, contains ovarian vessels).
Weakening of pelvic for muscles
or damage during childbirth can lead to prolapse. Round ligament on the
posterior wall, tying the lower parts of the uterus to the abdominal wall to
provide support. Testes and ovaries arise from high up in the pelvis and
migrate down into the pelvis during development, bringing their vascular
supply with them. The ovarian arteries and veins and testicular arteries and
veins arise typically from the renal arteries. If the ligaments holding the
uterus becomes damaged uterine prolapse can occur, uterus sits down
because its not being fully supported. 1 st degree prolapse, uterus sits into the
vagina, distortion of the vagina. Can then sit even further down close to the
entrance = 2nd degree prolapse. 3rd degree prolapse the structure is
completely unsupported and the cervix is constantly in the environment.
Inconvenient, effect sexual function and potentially future childbearing.
Crucial that good repairs are made to the perineum + exercises to restrengthen up the pelvic floor muscles to prevent prolapse.
Uterine fibroids -> non-cancerous benign uterine growths (20-25% of female
pop.). Variable in size pea size to melon size. Variable locations. Symptoms
= menorrhagia, pain (also during penetrative sex) and bladder and bowel
problems. Treatments = myomectomy, uterine artery embolism and
hysterectomy.
Abnormal developments of the muscle, can form within the wall and project
into the cavity which can implicate child bearing or can sit on the outside
where they are less critical in terms of effecting uterine function, they can be
pedunculated (fibroid tumour grows on a stalk). Some people - doesnt really
have any impact but they can be quite large - cause a lot of problems,
increased pain and bleeding during menstruation, pain during intercourse and
large tumours sitting next to the bladder can potentially effect urinary
function. Uterine artery embolism = passing a catheter through the uterine
artery to a region near the fibroid and cutting off its blood supply by using a
coil and forming a blood clot -> tissue ischemic and die, fibroid dies back,
becoming a fibrous structure. Can cut them out if wanted children later to try
and preserve the uterus. Typically in older women the simplest solution is a
complete hysterectomy to remove the uterus entirely. Two approaches
through the abdomen (pfannenstiel incision) just above the pelvic brim and a
vaginal hysterectomy (endoscopic approach). Bigger/more fibroids may
require the abdominal route which is simpler.
Male reproductive organs -> testes enclosed in scrotal sac. Attached to body
wall by spermatic cord. SC includes: ductus deferens, blood vessels, nerves,
enclosed in muscular sheath. Testes develop high up in the abdomen and

migrate down on the posterior abdominal wall and pass through the
inguinal canals down into the scrotum. Enclosed in this sac of skin =
extension of the perineal skin, bring with them a sack of peritoneum
which normally seals off around them = tunica vaginalis, secretes a
slippery fluid to allow the testes to move freely within the sac without
irritation and inflammation. Occasionally this wont close and a hydrocele will
form as the sac becomes full of extra fluid and becomes enlarged. Simple test
by shining a light into the
sac - light up clearly = not
cancer. Within the tunica
vaginalis are the testes,
wrapped in a coat of dense
white connective tissue =
tunica albuginea ->
penetrate into the testicular
structure -> series of septa,
divide up into
compartments. Inside each
compartment sits a
seminiferous tubule which
produce the sperm = a
single long tube -> drain into rete testes at the back, 200 odd ducts combine
together in this meshwork -> drain in about a dozen or so ducts into the
epididymis, divided into the head, body and tail. sperm coming out of the
seminiferous tubules cant swim or do anything as of yet, takes about 2
weeks for them to grow and start swimming etc. wafted along by peristaltic
waves through the ductus/vas deferens = a muscular walled tube -> mix with
extra fluids, provide them with energy. Meet vaginal secretions, will activate
them, and initiate the acrosome reaction which will allow them to fuse with
the egg. Blood vessels come down from the renal arteries as the testicular
artery, will pass through to the testes. Veins going back breakup to form a
plexus of venules which wrap around the testicular artery portal system. Act
as a heat exchanger -> testes are dangerously out in the environment as
sperm develops in a cooler temperature than body temp. Testes = couple of
degrees colder than the body. By running a heat exchanger the arterial
temperature is cooled to the appropriate temperature before going to the
testes and the venous blood is rewarmed on the way back so heat energy is
not wasted. Attached to this cord are muscle which control the position of the
testes, cremaster muscles pull the testes up closer to the perineum if its very
cold (temp regulated reflex), also when being stroked on the inside of the
thigh, triggers the cremasteric reflex to protect the testes from danger.
Ductus deferens then picks up an input from the seminal vesicles, together
form the ejaculatory duct - passes a short distance through the posterior wall
of the prostate into the urethra and from there to the penis. Peristaltic
movements of the ductus deferens which are primarily responsible for moving
the sperm along and producing the ejaculate.
Consequences of gonad descent in males inguinal hernia. Superficial
inguinal ring = Direct. Deep inguinal ring = Indirect. Can enter scrotal sac.
Inguinal canal is formed by the tendons of the anterior abdominal wall
muscles. Superior oblique muscle slopes down, the edge wraps around and

forms a channel, the internal oblique closes the inside

walls, forming a tunnel, passes along the edge of the
peritoneum. gives a route for which the testes can
pass into the scrotum, bad as its a weak point/
passage way by which things (such as peritoneum, fat
and bits of bowel) can get from the peritoneum and
abdomen to the scrotum = hernia. Common for people
who have raised abdominal pressures such as sports
people. Deep inguinal ring is inside the canal and the superficial ring is on the
outside, just above the pubic tubercle. Things can either follow the same
route along the canal = indirect inguinal hernia or they can push against the
musculature forming the posterior wall of the superficial inguinal ring = direct
inguinal hernia. Much more common in men - open inguinal canal, women
dont as fibrosed up. another possible route -> inguinal ligament runs from
the anterior superior iliac spine down to the pubic tubicle, behind it there is
space through which things can get through to the leg (e.g. blood, nerves
etc.), called the femoral canal and this is also a possible weakness so both
males and females will suffer from problems here. Scrotum becomes greatly
enlarged. Fat or peritoneum is not a problem, however, if a loop of bowel
passes through then this is a serious problem as its blood supply can be cut
off so you can get infarcted bowel. Hernia is potentially a very server issue
Deposition of male reproductive organs -> vas deferens passes back up
through the canal, wraps around the inferior epigastric artery crosses over
the external iliac artery and vein, passes down into the pelvis over the pelvic
brim, crosses over in front of the ureter and passes down. enlargement called
the ampulla of the vas deferens, seminal vesicles develop as an outpouching
of the ureter, long winding branches of the duct produces extra fluid which
will feed into the vas deferens. two ducts combine, forms the ejaculatory
duct, passes into the posterior wall of the prostate, urethra passes through
there from the bladder, passes through the penis via the corpus spongiosum.
Composition of semen, formed from 3 organs. Testes/ductus deferens sperm
(2-5%), seminal vesicles semen (65-75%, contains quite a lot of fructose
and other nutrients, activates the sperm and gives them energy) and prostate
prostatic fluid (25-30%, involved in pH control etc.). tucked away in the
perineum are two bulbourethral glands = mucus secreting glands, lubricates
both the urethra and the penis prior to ejaculation, mucus is also secreted
from the equivalent glands in females.
Prostate and urethra -> Prostate gland sits under the bladder and has the
urethra passing through it. Anatomy: Accessory gland of reproductive
system, Seminal Colliculus, Ejac. Ducts, Urethral sinuses, Prostatic ducts.
Urethra four parts -> Pre-prostatic (short part, passes through the wall of
the bladder itself, is where the internal urethral sphincter is), Prostatic,
Membranous, Spongy or Penile. Ducts of the prostate drain independently
(develop as a series of outpouchings and retain their own ducts). Seminal
colliculus = enlargement in the posterior wall of the urethra and the
ejaculatory duct passes through this. Prostatic utricle is a small blind ended
sac which is embryological the same as the vagina. External urethral
sphincter control urine output, relaxed during intercourse. Bulbourethral
glands pass into the blub of the urethra as it passes into the corpus
spongiosum.

Penis and erectile bodies ->

Structure: 3 erectile bodies. Corpus
cavernosa (x2; dorsally), Corpus
spongiosum (ventrally). Attached to Urogenital Triangle. Has spongy or penile
urethra running through. Corpus Spongiosum. Function: Forms part of
Reproductive and Urinary system. Transmits both Semen and Urine. Made up
of three cylinders of erectile tissue, relatively big artery passing through the
middle, network of venous structures in between them which normally drain
quite freely so the blood can get in and out quite easily, during sexual
excitation the outflow becomes obstructed and therefore the pressure rises
close to systemic blood pressure, filling them with fluid = more ridged,
changing the shape of the penis. Corpora cavernosa at the back, corpus
spongiosum at the front, forming a triangular structure. Wrapped in a sheath
of dense connective tissue, holds all of this together, sheath is filled because
of the rising pressure to make the penis ridged. Over the top - loosely
attached skin, quite dispensable with loose connective tissue, surface is quite
mobile. tip the corpus spongiosum extends to form the glands of the penis,
lies over the top of the two corpora cavernosa, base the corpus spongiosum
has an enlargement called the root which is attached to the corpora
cavernosa, lies along the bottom of the pelvis along the lower part of the
pubis and ischial bones, two muscles also attach to the root of the penis to
anchor it in place

Lecture 13
Female Reproduction and pregnancy

Cyclic changes in activity-menstruation. Restricted periods of fertilityovulation. Limited gamete production-atresia

Each month the female reproductive system undergoes through a series of
quite dramatic changes, both structural and functional changes, termed the
menstrual cycle. Changes in the hormones secreted from 3 main endocrine
glands -> the hypothalamus, ovaries and anterior pituitary. Normally takes
around 28 days and begins with a period of menstruation = shedding of the
lining of the uterus. The ova/eggs mature at different rates within the ovaries,
tend to be released usually singularly every 28 days and usually occurs at
around 14 days. Release of the egg is termed ovulation and is required for
fertilization to occur. A female is normally only fertile for a few days per cycle
-> 12- 48 hours. Ova (eggs) develop form a germ cell pool and this number is
fixed at birth, between 2-4 million, but the number of ova decline with age
due to degeneration (atresia), so only 400 eggs are released during a female
life time.
Ovaries are the female gonads. Follicles are embedded within the connective
tissue. As the ovum develops, the rest of the follicle develops around it. It
starts of as a primordial follicle containing the oocyte and layer of epithelial
cells surrounding the outside known as follicle cells, which develop into
granulosa cell once the epithelial layer is more than one layer. They
eventually become theca cells, seen around a more mature follicle
Ovarian cycle made up of two phases -> first phase = the follicular phase
(starts with menstruation until ovulation), second 14 days = the luteal phase.
Diagram -> (1) primordial follicle, most follicles are in this phase. Small
fraction start to develop independently of each other. (2) Primary follicle
(preantral follicle) -> epithelial layer has growth and theca cells around the
outside. (3) Early antral follicle -> fluid filled cavity = antrum. (4) Dominant
follicle (late antral follicle) -> antrum grown bigger, almost surrounds the
oocyte. Before ovulation this develops to around 2-2.5 cm in diameter.
Ovulation, marks the beginning of the luteal phase. The follicle ruptures and
releases the oocyte into the uterine tube, leaves a structure within the ovary
known as the corpus luteum.

Hormone key to ovulation = luteinising

hormone, or LH. As LH suddenly
increases, this releases proteolytic
enzymes, which rupture the follicle wall. If
the oocyte doesn't become fertilised, the
corpus luteum will remain intact for
around 10 days, reaches max activity
before it is broken down. The corpus
luteum stimulates the secretion of
oestrogen and progesterone. Corpus
luteum -> corpus albicans, decrease in
the secretion of oestrogen and
progesterone, stimulates menstruation. If the oocyte is fertilised and
implantation takes place the corpus luteum will persist within the ovary,
important during gustation and pregnancy in the secretion of progesterone
and oestrogen at certain levels.
The uterine cycle -> 3 phases -> the menstrual phase (day 0-5), proliferative
phase (day 5-14) and the secretory phase (day 14-28). Menstrual phase =
shedding of the uterine lining triggered by a decrease in oestrogen and
progesterone secretion. Proliferative = uterus starts to renew itself and is
promoted by an increase in oestrogen due to the development of the
dominant follicle. Involves the generation of new blood vessels and supply of
nutrients = favorable place for implantation. Secretory phase ->
endometrium is transformed into a favorable place.
Before the placenta develops the embryo takes a lot of
the mothers nutrients from the endometrium.
Four key hormones -> oestrogen, progesterone, LH and
FSH. Oestrogen peaks just before ovulation and
progesterone is relatively low until mid-secretory phase.
LH and FSH peak/ surge at ovulation. Early/mid
follicular phase -> FSH increases slightly as it
stimulates the growth of follicle, small increase in
oestrogen. FSH binds to receptors on the granulosa
cells, causing growth and proliferation of the follicle.
Binding of FSH stimulates granulosa cells to secrete
inhibin, which decreases FSH via negative feedback.
Dominant follicle develops, outer layer of theca cells
develop -> more LH receptors = more sensitive to the
secretion of LH. Dominant follicle (theca cells) secretes
androgens, particularly oestrogen -> negatively
feedbacks to the hypothalamus and the anterior pituitary to maintain levels
of FSH and LH/ prevent the surge.

Early to mid-follicular phase. GnRh =

gonadotrophin releasing hormone.
Negative feedback mechanisms to the
hypothalamus and anterior pituitary to
prevent ovulation from occurring too
soon. Oestrogen also has a role in
preparing the female body
Late follicular phase/ Period just prior to
ovulation. Oestrogen switches form
having negative feedback to having a
positive feedback to increase LH and
FSH secretion (mainly LH) -> LH surge in
order for ovulation to take place.
Oestrogen stimulates the granulosa cells
to express more LH receptors. See LH peak a few hours
before ovulation. LH stimulates proteolytic enzymes,
which weaken and rupture the follicle, releasing the
oocyte into the uterine tube, leaving the corpus luteum.
Luteal phase. Plasma oestrogen starts to decrease as the
corpus luteum doesn't secrete as much oestrogen as the
dominant follicle did. This removes the stimulus for LH,
and therefore ends the LH surge. Progesterone promotes
changes which help adapt the body for pregnancy. If there
is no implantation then the corpus luteum starts to degenerate -> oestrogen
and progesterone secretion starts to decrease, which leads to menstruation.
Progesterone has a negative feedback mechanism to the anterior pituitary
and the hypothalamus, which limits the growth and maturity of a new follicle
and therefore prevents a second ovulation occurring very close together
when the uterus wouldn't be prepared
Changes to the uterus during menstrual cycle. Take 3-6 days for menstruation
to occur. Proliferation stage endometrium
thickens = Follicle Oe, glands, blood
vessels. Ovulation endometrium 2-3mm
thick. During secretory phase = cellular
proliferation (Oe), secretion of hormones
and cytokines, lipids and glycogen, blood
supply, Corpus Luteum secretes P and Oe,
Endometrium 4-6mm thick. PURPOSE highly
secretory endometrium containing large
amounts stored nutrients to provide optimal
conditions for implantation of fertilised ovum.
rich supply of lipids and glycogen = nutrients that could be useful if the
embryo is fertilized
Menstruation (Oe and P) -> Vasodilation (vasospasms of blood vessels
PGF2) -> Necrotic outer layers of endometrium separate from uterus ->
Separated tissue and blood initiate uterine contractions expel contents
Prostaglandin 2 alpha is a particular growth factor that causes vasospasms of
the blood vessels -> vasodilation

Sperm deposited into the vagina, moves via self-propulsion through the
cervical canal into the uterus. It then needs to move up the uterine walls and
into the uterine tubes in order for it to fertilize an egg. There
are millions of sperm release during ejaculation, but only
about 100 reach the egg. The sperm must meet the egg
within 12-24 hours after ovulation in order for fertilization to
occur. The sperm is relatively robust and can live within the
uterine tube for about 3-4 days. Only takes 1 sperm to bind
to a receptor on the surface of the oocyte, sperm into its
cytoplasm -> disintegrates and releases its chromosomes.
Those chromosomes combine with the oocyte chromosomes
in order for fertilization to occur = zygote = fertilized ovum.
Morula = solid ball of approx. 16 blastomeres (daughter
cells). blastocyst has a fluid filled cavity. Cells termed an
embryo from 2 weeks 7-8 weeks post fertilization. After 8
weeks termed a foetus. A lot of processes can go wrong along the way, one of
the big issues is implantation of the embryo into the uterine wall
Implantation occurs around 6-7 days post fertilization. The blastocyst
attaches to the uterine wall -> requires nutrients and oxygen from the
endometrial tissue. Eventually the trophoblastic cells develop the placenta
which allows the maternal and fetal
blood to become very close, not actually
mix. Implantation is actually quite
invasive, and after the endometrium has
allowed most of its nutrients to be
consumed it then becomes less
receptive to second implantation - highly
unlikely (non-identical twins when this
does happen)
The average pregnancy around 279
days, most women dont go over 300
days as labor is induced 2 weeks post
their predicted due date. Before 24 weeks the lungs aren't adequately
developed for the foetus to survive, however there are new treatments now.
During the early stages of pregnancy the foetus can get its nutrients form the
endometrium, but as it starts to grow bigger the demand of the foetus is
much greater than the endometrium can provide. It relies on developing a
placenta, which is essential for the exchange of gases and nutrients between
the maternal and foetal blood stream. The placenta develops between the
endometrium and the myometrium. The maternal blood vessels run very
close to the placenta and the foetal blood vessels run into the placenta so
nutrients and oxygen can cross between the maternal and foetal circulation
without actually mixing, hence different blood types between the foetus and
mother can occur.
Hormonal changes during pregnancy aid the successful growth of the baby
and the processes of birth. Human chorionic gonadotropin/ HCG -> during the
first 3 months of pregnancy the corpus luteum stays intact. HCG secretion
begins at implantation, and is produced by the trophoblast cells that implant
into the endometrial tissue. HCG is a glycoprotein with a similar structure to
LH and is tested for in a pregnancy tests, as its released only after successful

implantation. HCG production is autonomous, no higher brain center control,

stimulated by trophoblast cells. Linked to morning sickness in the first 3
months of pregnancy.
Human Placental Lactogen =Polypeptide hormone, actions
similar to growth hormone. Secreted in increasing
concentrations during pregnancy as the foetus has more
demand. Stimulates lipolysis in the mother -> increases
free circulating fatty acids. Inhibits glucose uptake in the
mother. Promotes the growth and differentiation of the
breasts in preparation for lactation post-delivery.
Adaptations in the maternal brain -> behavioral changes
e.g. mother less anxious, adapts to having a baby.
Oestradiol produced by corpus luteum and placenta.
Oestriol produced by foetus and placenta :- foetal-placental
unit. Early: growth/strengthening of myometrium;
contractile proteins accommodation of growing foetus. Mid: in blood flow
through placenta exchange of nutrients/waste products. Late: Part of multihormonal , preparation of breasts for lactation, in sensitivity of uterus to
smooth muscle contractants PGF2a, oxytocin, contractility of myometrium,
towards term
Progesterone steadily increases through the 40 weeks of gestation. Initially
inhibits smooth muscle contractility (oestrogen antagonist) to keep the uterus
quiescent to prevent contractions. Inhibits the production of contractile
proteins (PGF2 alpha and oxytocin). Also has a role in the immune response.
Inhibits T-lymphocyte cell-mediated responses blocks cellular immune
response, e.g. to foreign foetus?
Prolactin released after birth to stimulate lactation. Prostaglandins E2 and P4.
They block actual breast milk synthesis, then decrease at term ready for
lactation. Together they block prolactin receptors during pregnancy to prevent
lactation. late pregnancy there is a spike release that allows lactation to take
place

Lecture 14
Male Reproductive system

The primary function of the male reproductive system is to produce sperm

and deliver that sperm into the female ready for fertilization to take place.
The testes are placed into some external genitalia, known as the scrotum

which hangs below the penis which is the copulatory organ. It also has a
reproductive tract which delivers the sperm from being produced within the
testes around the pelvic cavity and out directly through the urethra at the end
of the penis. Some important accessory glands (Seminal vesicles, Prostate
gland, and Bulbourethral gland) which secrete fluids that are important for
the sperm to travel in inside the female.
Male copulatory organ -> Penetrates vagina and deposits sperm. At rest,
penis flaccid. Sexual arousal, penis undergoes erection -> Blood flow to penis
increases, Engorges erectile tissue & Penis swells and elongates. Ejaculation
-> Sperm ejects through urethra
Scrotum -> Suspended beneath penis. Houses testes. Sperm cannot develop
at body temperature. Allows a cooler environment for sperm development.
Sperm of higher quality and greater motility if its allowed to develop at a
lower temperature.
The testes are encapsulated in a layer of fibrous connective tissue. Each
testes is divided into 250 - 300 different compartments, each of these have
highly coiled thin tubes = seminiferous tubules = sperm production -> lots of
sperm can be produced at one time.
Key -> Leydig cells. Sertoli cells. Smooth muscle. Blood-testis barrier.
Leydig cells secrete many hormones, in particular
testosterone and other androgens to help control sperm
development. The walls of the seminiferous tubules
have an outer smooth muscle layer and an inner layer
of epithelial cells, it is between epithelial cells where
the sperm develop. More immature sperm cells are
closer to the basement membrane, more mature sperm
cells are closer to the lumen. The lumen is filled with
fluid as the sperm remain there for some time to
undergo further maturity. The smooth muscle is
important as peristaltic contractions help propel the
sperm and the fluid along the highly coiled tubes. Tight junctions exist
between epithelial cells in the tubules = the blood-testes barrier. isolates the
luminal fluid with the more mature sperm in from that of the spermatogonia
(original cells that develop into sperm). Reason -> as the sperm develop the
chromosomes half from 46 to 23, immune system would attack these sperm.
Different infections or trauma to the testis can cause the breakdown of these
tight junctions leading to infertility.
Sertoli cells -> Support sperm development, help transport the sperm in the
right direction. Secrete luminal fluid in which sperm develop, helps transport.
Secrete androgen-binding protein - acts as a buffer to maintain levels of
androgens. Target cells to testosterone and FSH -> Secrete chemicals that
stimulate spermatogenesis, hormones important in the control of
development. Secrete inhibin = hormone of negative feedback loop for FSH.
Secrete Mullerian inhibiting substance (MIS) (embryonic only)

Reproductive tract. epididymis = a much larger tube with thicker

walls. Onto the vas deferens where is goes into the pelvic cavity. In
the pelvic cavity the two vas deferens circulates around the bladder
and converges together near the seminal vesicles to the ejaculatory
duct, passes through the prostate gland and urethra and out of the
penis.

The accessory glands include the seminal vesicles, prostate

gland and bulbourethral glands. Seminal vesicles -> Secrete alkaline
fluid with fructose, enzymes, and prostaglandins. inside the vagina =
acidic environment, needs to be protected, otherwise becomes immotile.
fructose to give the sperm energy in order to swim.
Other things to aid in the motility of sperm such as
enzymes and prostaglandins. Prostate gland -> another
source of energy from citrate and further enzymes. Also
in some males the prostate starts to secrete prostate
specific antigen (PSA), which can be monitored
particularly in older males - indicates prostate cancer.
Bulbourethral glands secretes viscous fluid with mucus
which is ejaculated first before the sperm, helps with
lubrication in the female.
Hormonal Regulation. inhibin as dont want to develop
too much sperm, however sperm development is a continuous
process.
Testosterone is one of the androgens. Blood levels of hormones in
males if fairly constant unlike in females -> short term control.
Before puberty there are lower blood
levels of testosterone, post puberty =
higher levels, hence the sex drive and
why
males tend to be muscular and taller.
Sperm. Head -> 23 Chromosomes,
Acrosome = Enzymes necessary for
fertilization, allows the sperm to penetrate the egg. Midpiece -> Mitochondria
to produce ATP to allow motility to swim in one direction. Tail = Whip like
movements propel sperm. Not all sperm in one ejaculate are healthy.

Spermatogenesis in Testes. Development occurs

between sertoli cells/ epithelial cells in the
seminiferous tubules. Develops from the basement
membrane down to the lumen, getting more mature
as sperm go along. Starts from undifferentiated germ
cells = spermatogonia. The tight junction temporally
opens to allow the movement of maturing sperm
through it. Cells at different levels of maturity can be
found at any one time. Spermatogonia, which
undergo mitosis, one daughter cell goes back into the
germ cell pool, so the germ cell pool never decreases through age (unlike
females) fertile for whole life. Primary spermatocyte with 46 chromosomes
passes through the tight junctions and undergoes meiosis -> two secondary
spermatocytes which have split their chromosomes so 23 each. These
undergo another meiosis to form 4 spermatids which differentiate into
spermatozoa, which remain immotile for around 20 days in the luminal fluid
before they move down the epiphysis via peristaltic waves. Sperm cells under
constant development so there is always some mature sperm available.

Contraception

Fertility control -> Contraception = hormonal controls, natural methods &

other methods
Hormonal controls include the pill, intrauterine
devices, injections etc. Natural methods relies on
understanding the hormonal control of the menstrual
cycle. Other methods include barrier methods etc.
Lots of contraceptive methods relies on the female,
only one that is linked to the male. So these methods
rely on the female understanding contraceptive
methods and revolve around the female reproductive
cycle.
The Oral Contraceptive Pill -> Hormonal
contraception. Available since 1960s. In UK approx.
25% of sexually active females use it aged 16-49. Combined pill (Oestrogens
and progestins) or Mini pill (progestin only)
Primary effect is to prevent ovulation and therefore the production of the egg,
also has secondary effects to discourage fertilization e.g. implantation.
Synthetic versions tend to be isoforms e.g. oestodiol and progestin.
Synthetic oestrogens = Ethinylestradiol and mestranol. Similar potency, seem
to be well tolerated by the body. Nearly all combined pills have either of
these oestrogens. Progesterone's more complex as it tends to be progestin
that cause the side effects. Synthetic progestins = Northisterone,
levonorgestrel first generation, had lots of side effects because they were
androgenic (increased levels of oestrogen), so tend to stimulate the
development of male characteristics. Desogestrel, gestodene- newer agents/
Different potencies. Androgenic, antiandrogenic (oestrogen receptor
antagonists, decrease levels of oestrogen), oestrogenic or antioestrogenic
properties -> Northisterone- androgenic activity, Gestodene & desogestrel
antiandrogenic - SHBG = Sex hormone binding globulin, which is usually

produced when someone is pregnant, tells the brain that the body is pregnant
to stop ovulation.
Combined oral contraceptives -> 3.5 million women currently taking the pill in
the UK. 28 brands on the market. Monophasic (most popular and cheapest) ->
Preps contain oestrogen plus progesterone (depending on potency of
progestin) -> Low strength preparations (containing ethinylestradiol 20g).
Standard strength preparations (containing ethinylestradiol 30 or 35 g or in
3040 g phased preparations). Pills given in a pack of 21, which are taken
consecutively and then have 7 days off when the menstrual period will
happen. Each pill identical. Lower strengths tend to be given to regulate
female cycles and help with acini, not as an oral contraceptive. Biphasic and
triphasic (more complex, more expensive, but less side effects) -> Designed
to mimic cycle more closely, Both oestrogen and progestin dose varied once
or twice (dose varies throughout the 21 days), Often need higher oestrogen
dose to inhibit ovulation, Progestin overall intake reduced less side effects.
Side effects -> Breakthrough bleeding, Weight gain, Effect sexuality,
Depression
28 different brands on the market that all vary from each other slightly.
Mechanism of combined pill -> Based on the fact that ovulation is suppressed
in pregnancy. Progesterone is responsible. Feedback at hypothalamus and
pituitary -> suppressed secretion of FSH and LH (Low FSH suppressed by
oestrogen, Low LH, Progestin effects LH surge), cervical mucus thickens,
viscous and scanty, Impairs motility of uterus and oviduct, Endometrial
changes not conducive to implantation, Decreased production of glycogendecreased energy for blastocyst to survive in uterus. Efficacy 92-99.7% in
carefully controlled trials
It is the oestrogens secreted from granulosa cells that has a negative
feedback effect on the anterior pituitary and the hypothalamus to decrease
secretion of FSH and LH to prevent ovulation from occurring
Progestin only contraceptives. Oral progesterone (mini pill) -> Small dose of
progestin given continuously (no 7 day break). Over 100,000 women in UK
(Not as popular as the combined pill). Side effects: irregular bleeding,
amenorrhoea (no bleeding), ectopic pregnancy, unpredictable bleeding,
mastalgia (tenderness in the breasts), weight gain but less than combined,
small risk of breast cancer but less than combined. Has a slightly higher
failure rate than the combined as you have to take it at very regular times. It
inhibits ovulation, thickens mucus, reduces motility and impairs implantation
(similar to the combined pill). Pills vary in potency of progestin.
Recommended for: Breast-feeding mothers (as some of the components of
the combined pill can pass into the baby and can also effect lactation),
Women who cannot take oestrogens, Diabetics-though younger ones may
take the combined pill, Older women, Heavy smokers, Anyone who wants to
take a break from the combined pill, if someone has a risk of a thrombosis
Failure rate -> combined oral perfectly use 0.3%. Protection may be lost if
there is a delay of more than 12 hours between the regular time you take
your pill-typical use 8%. Progestin only-perfect use 0.5%. Protection may be
lost if delayed more than 3 hours of regular time-typical use 8%.
There are often problems with interactions with other drugs e.g. broad range
antibiotics & ampicillins in particular effects the way the pill works

Benefits and Risks of oral contraceptives. Benefits -> Can reduce period
pains, sometimes prescribed for this. Periods shorter and lighter (uterus not
thickened in normal way) - because of this, you are less likely to become
anaemic. Acne, the Pill should improve it. Delay menstruation. Can decrease
chances of getting certain cancers (though it increases the risk of others).
Risks -> DVT, clotting. Heart attacks, strokes. More common if smoke,
overweight, diabetic, high blood pressure, high cholesterol. Generally these
potential side effects dont happen unless you have one of these risk factors
Other hormone based contraception that can be done prior to sexual
intercourse. Injectable progestin (Depo Provera) -> Intramuscular injection of
medroxy-progesterone acetate (DMPA, an isoform of progesterone): prevents
surge LH. Lasts 12-14 weeks, but cannot be removed, any side effects will last
for 12-14 weeks. Widely used in the USA, getting more popular in the UK.
Subcutaneous implants (Norplant) -> Progestin e.g. levonorgestral released
from implanted silicone capsules/tubes. Have contraception for up to 3 years,
avoids first pass metabolism so smaller doses used. Can be removed if having
side effects. Hormone impregnated IUD (Mirena) -> IUD = intrauterine device,
made from T shaped inert plastic that is put inside the uterus (not copper
coil). Progestin impregnated, affects ovulation. Affects the way sperm can
swim up the uterus. Prevents sperm reaching fallopian tube. Been
significantly improved over last few years, used to be a copper coil insert,
good at preventing fertilisation, but after 3-5 years when removed it had
formed a structure within the uterus and ripped out some endometrial tissue
when removed, resulting in scarring of the uterus, affecting future fertility
Post-coital preps -> Morning after pills. Effective if first dose taken within 2472 hours post sexual intercourse. More effective the sooner its taken. Taking
first dose ASAP increases efficacy. Lessens the later you leave it. Progesterone
based preparation. Levonorgestrel 1500g. Levonelle-one step
(levonorgestrel) pharmacists. Over the counter. Cost 26, GP free but not
convenient. Delays ovulation, Interfere with transport of the egg/ sperm and
implantation, interferes with endometrial development. Failure rate 10%. Side
effects = Nausea and vomiting
Mifepristone -> Anti-progesterone (abortion pill). For pregnancies up to 63
days (9 weeks). Binds to progesterone receptors. Gestation up to 63 days. 3648 hours after taking mifepristone insert prostaglandins in vagina and
causes uterine contractions leading to miscarriage. Quite controversial as it is
abortion done at home
Potential new developments -> Continuous dose GnRH, Immunisation against
pregnancy hormone (hCG) & Male pill - (P)
Continuous dose of GnRH. Normally secreted from the hypothalamus and acts
on the anterior pituitary which secretes FSH and LH. Continuous
administration of GnRH desensitizes the process, prevents ovulation from
taking place. Side effects in female - causes irregular bleeding. A vaccine
against pregnancy -> normally hCG peaks for up to three months in
pregnancy. Immunisation against pregnancy hormone (hCG), so if pregnancy
does occur the body will trigger an immune response to get rid of the egg,
controversial as it involves getting pregnant. Male pill -> temporarily blocks
the effects testosterone and therefore the development of healthy sperm, but
needed for sexual drive. Synthetic testosterone now developed which is
mixed with progesterone, stops the testes from producing normal

testosterone and therefore producing healthy sperm but the synthetic version
would help with the sexual dive
Rhythm methods -> based around understanding the female cycle. Failure
rate 20% (1/5 chances of getting pregnant). Calendar monitor cycle ->
Ovulation 14 days, Subtract 18 days beginning fertile period, Subtract 11
days end of fertile period. Temp monitor BBT. Temp increase by 0.4 -0.8F
between 1 and 3 days after ovulation. Assessment of cervical mucus
(becomes more viscus at the time of ovulation) Billingss method/ Kits
predicting ovulation (test urine). Quite expensive, not often used for
contraception, but when a female wants to get pregnant. Not useful in women
who have irregular cycles, cant predict ovulation. Some religions say this is
the only way to prevent pregnancy. Would not have sexual intercourse around
day 14 (ovulation), about between day 10 to day 17 of the cycle. Can monitor
temperature, basal body temperature tends to decrease before ovulation and
increase after
Failure rates for different methods of contraception. Implant -> 1 pregnancy
in 100, same with IUD. Vasectomy (cut the epididymis so sperm can no longer
travel down) and tubal ligation or implants (prevents the egg moving into the
uterus) no longer fertile, tend to be given when decided no longer want to
have children. Barrier methods have higher incidence of pregnancy e.g.
spermicide alone 29%. The hormonal ones tend to be quite effective.
Hormonal contraceptives and IUD are also quite safe.

Lecture 15
Fertility

What potentially could cause infertility? Infertility = the inability to fertilize an

egg. Can be a mixture of male factors, female factors, a
combination of both or something unexplained. There's a Large
proportion of unexplained factors seems to be nothing wrong
with their reproductive systems.13% other - tends to cover
combined with problems in the male and female.
Fertility -> After 12 months, approx. 80% of couples of are successful in
conceiving. Couples have a 25% chance of achieving conception each month.
15% of couples have difficulty conceiving. After 1 year without conception,
investigations to determine if infertility is present. exception if the female in
the couple is over 35 further investigations 6 months after having problems
conceiving. Many couples are infertile NOT sterile = cant have children at all.
early 20s there is a 25% chance of conceiving, 29-30
this starts to decrease, with a significant decrease
throughout the 30s, with about a 7% chance of
conceiving by the age of 40, chance almost nonexistent by 48. This is quite an issue, especially in the
developed world were women are being pushed to have
successful careers and thinking of having children at a
later age.
As a female gets older maximum fertility decreases and
miscarriage rate increase - greater chance that a
fertilized embryo would then end in miscarriage->
natural termination of the early pregnancy, this significantly increases in the
late 30s - early 40s

Female Factors causing infertility. Ovulatory failure. Polycystic

ovarian syndrome, gonadal dysgenesis (defective embryonic
development of the gonads). Impaired gamete/zygote transport
e.g. pelvic inflammatory disease, immotile cilia. Implantation
defects-progesterone low. Other endocrine problems. Genetic
defects. Stress, alcohol. Developmental abnormalities of internal
genitalia e.g. atresia of the cervix. Hostile cervical mucus. 10% other ->
alcohol, stress diet etc
Ovulation disorders -> the endocrine process has an effect on ovulation,
therefore, problems in secreting hormones etc. can cause problems, some
conditions can lead to this e.g. polycystic ovarian syndrome = a condition
where the female tends to secrete more androgens than nearly, in particular
testosterone -> causes cysts to appear on the ovaries, making ovulation
difficult. These patients are quite often overweight, have facial hair growth
etc. This can be managed with treatments that help ovulation occur. Patients
who have had cancer and underwent chemotherapy can also effect ovulation.
Some patients undergo premature ovarian failure = early menopause,
normally occurs in the 40s, can occur in the early 30s or late 20s etc. this is
linked in a genetic way to their mother and grandmother.
Tubule factors -> STDs, pelvic inflammatory disease and chlamydia can effect
what happens in the uterine tubes. Cilia that brush the egg down the fallopian
tube, such diseases can affect their function, cant push the egg down.
Previous pelvic surgery and having a previous ectopic pregnancy in the
uterine tube can damage or burst the uterine tube. Endometriosis is a fairly
common condition (affects 1 in 10 women), results in heavy painful periods
-> retrograde menstruation where the cells that are normally shed into the
vagina actually move up inside the pelvic cavity and into the uterine tubes,
they can attach onto the ovaries, attach in abdominal walls and even the
lungs. Every hormone cycle -> increase in oestrogen (stimulus), the shedded
endometrium starts to grow. They contract and become painful. often causes
pain over the entire 28 days, discomfort, and pain during sex. Can be treated
by giving the pill, but not going to help with fertility or can remove some of
the endometrial tissue, but will never cure the condition. Uterine/ cervical
issues -> abnormal uterine structure e.g. uterus can be separated in two,
effecting implantation. Scarring can also effect fertility (e.g. inter uterine
device used to be a copper coil, its removal caused scarring), hostile
environment in the cervix e.g. wrong pH, too thick, exacerbated from
infections, which can be treated, or if an individual has had a cervical smear
-> abnormal cells and gone onto a cone biopsy where they take an area of
the cervix to test for cancerous tissue - sometimes cause scarring to the
cervix. General other factors include stress (this is well known and recorded),
increase alcohol intake, diet (obese) or not eating enough (ovulation may not
take place), endocrine problems and genetic defects can also effect the
female reproductive system.
Fallopian tube has a septum running down the middle, which prevents the
egg moving down the tube. Can be treated other than giving assisted
conception techniques. Polyps can also grow inside the uterine tubes,
potentially can be removed depending on how severe they are. Blocked and
enlarge tube. Actually stuck (adhesion) to pelvic scar tissue. Minor surgery
could elevate this problem.

Male Factors. Sperm quality -> Count: approx. 40 million.

Concentration: 20 million/ml. Motility: approx. 50%. Speed &
Morphology of the head, mid-piece and tail
Abnormal morphology of sperm. In nearly all male sperm
samples there is some abnormal morphology of some sperm
cells. Could have larger or smaller head, two heads
(therefore doesnt have the appropriate number of chromosomes), two tails
(swim in circles instead on swimming forwards), different head shapes
(effects how the sperm binds the egg), mid-piece disruption so not enough
ATP produced from the mitochondria for motility.
Conditions of reduced sperm quality -> Low sperm count known as
oligozoospermia. Poor sperm motility asthenozoospermia. Sperm
morphology is wrong- teratozoospermia. Everything is wrong
oligoasthenoteratozoospermia. No sperm - azoospermia
Male factors -> Varicocele (35-40%). Idiopathic (25%). Infection (~10%).
Genetic (~10%). Endocrine (<5%). Immunologic (<5%). Obstruction (<5%).
Cryptorchidism (<5%)
Varicocele = an abnormal enlargement of the pampiniform venous plexus
which normally drains the testicles, therefore, blood in the testes is not being
removed fast enough, results in blood pooling in the testicles. This effects the
amount of oxygen going to the testicles and also increases the temperature
of testicles. Can do surgery to relieve this to become fertile. Idiopathic =
unexplained reason e.g. cooler environment, lifestyle factors such as
smoking, alcohol, drugs, medication etc. Some of these things we can do
things about, some not so easy to treat. Infection STD but also other
infections such as mumps etc. genetic disorders -> Klinefelter syndrome = a
condition where males have XXY chromosomes, results in small testis and
reduced fertility. Cystic fibrosis and other diseases can also effect sperm
quality. Endocrine testosterone is needed to create good quality sperm
hypogonadism = decreased testosterone levels. Immunological the body
creates anti-sperm antibodies -> blood testes barrier breached. Obstruction
-> anatomical defects that can affect spermatogenesis and how the sperm
can be deposited in the female e.g. in some males the urethra can be on top
or below the tip of the penis, not on the tip. Cryptorchidism = testes are not
in the scrotum, but further up in the abdominal cavity. Occurs during
development in utero when the testes move from the abdominal cavity into
the scrotal sack. Usually picked up by ultrasound scanning or after the baby is
born, therefore surgery can move testis back after birth. Retrograde
ejaculation = goes into the bladder, therefore not depositing it in the right
way. Common in conditions such as multiple sclerosis, spinal cord trauma and
advanced diabetes etc.
Ovulation Induction -> The use of medication to stimulate the ovaries into
producing oocytes. Clomiphene citrate: orally active increased FSH and LH.
Injectable gonadotrophins. GnRH pump. Bromocriptine
Clomiphene Citrate -> Selective Estrogen Receptor Modulators (SERMs). A
non-steroidal compound with close structural similarity to oestradiol.
Clomiphene is a partial agonist in the ovaries and ER antagonist in the
hypothalamus. Enables it to bind to ERs in various tissues including the
hypothalamus. Has a reduced effect compared to oestrogens themselves.
Mechanism of action -> inhibits the negative feedback of oestrogen back to

the hypothalamus, in turn promotes gonadotrophin release, promotes release

of FSH and LH, stimulates ovulation
acts as a partial agonists in the ovaries - increases oestrogen secretion from
the ovaries and therefore increases the growth of a follicle, but it is also an
oestrogen antagonist that acts on the hypothalamus, stops negative feedback
from oestrogen in the early to mid-part of the cycle, so the hypothalamus and
anterior pituitary secretes more LH and FSH, therefore continues to grow the
follicle and hopefully release it. Usually taken on day 3-7 or 5-9 in the female
cycle. Then the treatment is stopped, hopefully ovulation takes place
Intrauterine insemination = take the sperm and directly inject it into the
uterus of the female at the time their ovaries have been hyperstimulated with
clomiphene citrate to allow fertilisation to take place.
How effective is clomiphene? Ovulation is induced in about 70% of cases,
pregnancy occurs in only 10-15% of cases - looking over a 3 cycle period,
after 3 cycles of taking clomiphene this reduces even further. Why low rate of
pregnancy? Anti-oestrogenic effects on cervix -> makes hostile to sperm
penetration (IUI treatment bypasses the cervix so may be better), affects
embryo implantation (negative effect on the endometrial lining). Can cause
premature luteinisation. Decrease in quality of ova produced. Side effects for
the female including abdominal discomforted as the ovaries are
hyperstimulated which also increases the risk of multiple pregnancy if more
than one follicle develops, also nausea and vomiting, hot flushes, hair loss,
cysts etc.
Injectable Gonadotrophins. Follitropin -> FSH, Started early in cycle 8-14
days, induces production of follicles. Menotrophin -> HCG, Induces ovulation
approx 36 hours later, Risk of overstimulation, 90% anovulatory women
ovulate, Pregnancy rate 15%. Risk of multiple births with both treatments.
Bromocriptine-dopamine agonist -> increases dopamine which acts on the
pituitary gland to decrease prolactin, which is normally secreted during breast
feeding and therefore prevents ovulation. Used in cases of
hyperprolactinaemia. Uncommon. Could be due to pit tumour. Treatment
restores ovulation. It can be quite a successful treatment because its aimed
at a specific cause of infertility. Success rate of around 50-70% in women.
Side effects include nausea, constipation, headaches and drowsiness.
Methods of Assisted Conception -> Intrauterine insemination (IUI), Artificial
insemination (AI), IVF-ET: in vitro fertilisation and embryo transfer
Intrauterine insemination = either the female ovulates naturally or we
hyperstimulate the ovulation. at the appropriate time the sperm is injected
using a long tube directly into uterus, therefore bypassing the cervix. This
means the sperm doesnt have to swim as far or fast to reach egg, can be
useful if there's a problem with the male factors such as the morphology of
the sperm. Most couples are advised to have 3 or 4 treatments of IUI before
using another form of assisted conception. Its not hugely successful, success
peaks at around the age of 25-30 (15% success rate), significantly decreases
by the age of 40. After this use in vitro fertilization, where the egg is fertilized
by the sperm in a test tube in the lab, which is replaced back into the uterus
post fertilization for implantation to occur.
IVF-ET -> Fertilisation occurs outside the body. Embryo transferred
afterwards. Most useful where the women has absent or blocked fallopian
tubes. Ovarian down regulation followed by stimulation. Ovulation trigger

(hCG): 36-40 hours pre-operatively. Egg collection (vaginally). Short

incubation period. Fertilisation using partner sperm (pronuclei present). ET to
uterine cavity after 48-72 hours via the cervix. Maximum of 2 embryos
transferred -> the more embryos they implant, the greater the chance of
miscarriage.
IVF-ET was first developed in the UK, the first successful test tube baby was
Louise Brown, who is now 38 years old, so its quite an established technique,
however, it is quite an invasive technique with lots of issues. its a demanding
process and is very invasive
Forms of Artificial insemination -> GIFT: gamete intra fallopian transfer. ZIFT:
zygote intra fallopian transfer
GIFT = take the egg (after hyperstimulation of the ovary) and sperm, mix the
two in vitro without allowing fertilisation to take place by implanting straight
away into the female bought the sperm and the egg closer together so
hopefully the egg is fertilised. Religious beliefs that fertilisation shouldn't take
place in vitro. isnt used as often these days = ZIFT instead of getting to the
4-8 cell stage before implantation, its at a slightly more developed stage at
the zygote stage before implantation, however, not shown to be that
successful
Forms of Artificial insemination -> ICSI: intracytoplasmic sperm injection.
Used when low sperm count or abnormal sperm.
ICSI in vitro, if there's something wrong with the quality of the sperm, would
select a single morphologically correct sperm and directly inject that into the
females egg, allow fertilization to occur and then IVF would hopefully be
successful. Major issues with male sperm, or cant produce any, or female
cant produce an egg, sperm or egg can be donated, undergo IVF
Gamete Donation. Sperm Donation. Aged 18-55. Normal/High Sperm count.
Health Screening including HIV and Hep B. Paid up to 15 plus expenses per
donation
Egg Donation. Aged 18-35 (past 35 the quality of the egg starts to decrease).
Normally women requesting sterilisation. Completed family. Ovarian
Stimulation followed by laparoscopic collection (very invasive). No payment.
There is a register of sperm donors/ egg donors so the child can trace back to
their original genetic father/ mother.
IVF -> IVF births in the UK account for 1.8% of all births. Since the first IVF
baby was born in 1978, more than 3 million children have been born through
IVF worldwide. Costs of IVF treatment is about 5,000 per cycle. In the UK,
about 25% of IVF treatments are provided by the NHS. Funding is discretional,
depends on where you live, what the local NHS regulations are, if have
children already, etc.
The success rate of IVF depends on the age of the woman undergoing
treatment as well as the cause of the infertility (if it's known). Younger women
are more likely to have healthier eggs, which increases the chances of
success. In 2008, the percentage IVF treatments that resulted in a birth (the
success rate) was:
o 33.1% for women under 35
o 27.2% for women aged 35-37
o 19.3% for women aged 38-39
o 12.5% for women aged 40-42
o 4.9% for women aged 43-44

2.5% for women aged over 44