Beruflich Dokumente
Kultur Dokumente
257
Parvocellular hypophyseotropic
neurons
Magnocellular neurons
Hypothalamic projection
neurons
258
Hyperpituitarism
259
Prolactin (PRL)
During fetal development, prolactin cells
appear to differentiate from GH cells, some
cells maintain the ability to produce both GH
and prolactin
Lactotrophs which make up 40-50% of the
endocrine cells of the anterior pituitary
Prolactin binds to a specific receptor, similar
to GHR (cytokine receptor)
PRL secretion: tonic inhibition by tuberohypophyseal dopaminergic pathway
Primary target of PRL: mammary gland
Development during pregnancy
Induces milk protein synthesis
Initiates and maintains lactation
Milk ejection is a reflex process
mediated by oxytocin
260
Hyperprolactinemia
Hyperprolactinemia is the most common hormone secreting
pituitary tumor
Causes of hyperprolactinemia
1. Hypothalamic dopamine deficiency
Tumors, arterio-venous malformations, inflammatory processes
(sarcoidosis) result in either diminished synthesis or release of
dopamine
a-methyldopa and reserpine is capable of depleting the central
dopamine stores
261
4. Stimulation of lactotrophs
Hypothyroidism with increased TRH production
hyperprolactinemia
Estrogens act directly at the pituitary level, enhance prolactin
secretion, increase the mitotic activity of lactotrophs.
Injury to the chest wall (herpes zooster [HHV-3], post thoracotomy,
piercing)
262
Consequences of hyperprolactinemia
Inhibits pulsatile GnRH secretion hypogonadism
Female: luteal phase is shortened anovulation, galactorrhea,
amenorrhea, infertility, libido
Male: decreased testosterone synthesis, spermatogenesis and
libido or impotence; rarely galactorrhea & gynecomastia
Bitemporal hemianop(s)ia
263
264
Hypothalamus
GnRH
Dopamin
Hypophysis
Pergolide
Hyperprolactinemia
Gonadotroph
LH
Gonads
Cabergoline
265
Treatment of hyperprolactinemia
Dopamine agonists for GH or prolactin hyper secretion
Most useful when GH and prolactin secretion also is elevated
Paradoxical inhibitory effect on GH secretion: Somatroph
adenomas express receptor characteristics of lactotrophs
Given orally; adverse effects: nausea, vomiting, dizziness, postural
hypotension
Transsphenoidal microsurgery
Microadenomas - 85% long term remission
Macroadenomas outcome less satisfactory
266
An almost complete bitemporal hemianop(s)ia (pre-therapy), which had almost disappeared after 1
year of treatment with bromocriptine, returned on cessation of therapy and began to subside after
reinstitution of bromocriptine.
The black periphery indicates a normal visual field for comparison.
267
Hypopituitarism
Subnormal basal or stimulated secretion of one or more pituitary
hormones
> 50% of secretory cells detectable deficiency, > 80% lost for severe
basal loss
In pituitary failure a common sequence of hormone loss is GH >
FSH/LH > TSH > ACTH > PRL
Prolactin is often increased from compression of the pituitary stalk and
interruption of dopamine inhibition
Rathkes pouch
270
2. Sheehans syndrome
Ischemic necrosis of the anterior pituitary due to postpartum
hemorrhage and/or shock
Predisposing factors
Anterior pituitary doubles in size during pregnancy, low pressure
portal system unable to blood supply
Abrupt onset of hypotension (eg bleeding) hypoperfusion
infarction
271
Kallmanns syndrome
Isolated hypogonadotropic hypogonadism with anosmia (inability to smell) defect in KAL gene (Xlinked form)
Dominant, recessive and X-linked recessive/dominant forms are known
Mutation in a neural cell adhesion protein (anosmin encoded by KAL) which guides axon growth
and allows GnRH neurons to migrate from their site of origin in the cribriform plate to the anterior
hypothalamus
Because GnRH neurons are not in their appropriate anatomical location, axons to the anterior
pituitary do not develop; defective synthesis/release GnRH (FSH, LH, testosterone ); Anosmia,
273
microphallus
FSH/LH deficiency
Prepubertal hormone deficiency
Impaired development of secondary sex characteristics, primary
amenorrhea ()
Eunuchoid habitus due to delayed epiphyseal closure (arm span: 5
cm > height)
275
Growth-hormone excess
Childhood gigantism
Adults acromegaly (rare, 3-4 new cases per million)
Progressive enlargement of head, face, hands, feet, thorax; heat
intolerance, sweating, fatigue, lethargy
Levels of IGF-1 are greatly increased in acromegalics but IGF-2
levels are not.
Etiology
98%: benign GH-producing pituitary tumor
2%: Ectopic GHRH secretion
Small cell lung cancer, bronchial or intestinal carcinoid tumors,
pancreatic islet cell tumor, pheochromocytoma
276
Complications
Local due to mass effect (marcoadenoma)
Abnormal glucose tolerance (DM 1/3) GH is insulin antagonist
se triglyceride
Cardiovascular complications
Left or bi ventricular hypertrophy heart failure, arrhythmia
Hypertension: due to Na retention, sympathetic activity
Diagnosis
Abnormal net GH secretion over time & non-suppressible GH
secretion
24 hour GH profile (night-time GH levels)
Elevated IGF-1 and IGFBP-3 (most important binding protein of
IGF-1)
277
278
2. Congenital/developmental abnormalities
Structural brain development disorders (septo-optic dysplasia, agenesis
of corpus callosum); midline facial defects (cleft lip/palate)
Laron syndrome
Dwarfism
Prominent forehead, depressed
nasal bridge, underdeveloped
mandibule
Truncal obesity
Hypoglycemic episodes
Resistance to DM and cancer
Intellectual retardation
281
Short stature
(dwarfism) is defined
as height less than 2
standard deviations
below the mean,
which is near the
third percentile.
282
5. Chromosomal abnormalities
Turner syndrome (45,X) and Down syndrome (trisomy 21)
284
285
286
287
8. Endocrine causes
GH deficiency and GH insensitivity (IGF-1 deficiency) see earlier
Thyroid hormone deficiency (hypothyroidism)
Thyroid hormone is necessary for normal growth (thyroid hormone
levels should be measured in all children with slow growth)
Androgen excess
Due to exogenous androgen, precocious puberty, and congenital
adrenal hyperplasia
The growth velocity increases in the short term, but epiphyseal fusion
occurs early, resulting in a short adult height
288
Adult GH deficiency
Adult-onset pituitary/hypothalamic disease, craniopharyngioma, surgery,
irradiation therapy, or trauma
Features of GH deficiency in adults
Increased fat mass (apple type obesity) and reduced lean body mass
Decreased insulin sensitivity, impaired glucose tolerance
Accelerated atherosclerosis (LDL, HDL cholesterol)
Impaired cardiac function
Decreased bone density
Mood changes
Hypopituitarism is associated with premature mortality (mainly in females)
290
Iodine
Deficiency
Moderate iodine deficiency euthyreoid goiter
Severe iodine deficiency
Endemic myxedema in adults; endemic cretinism in infants
Toxicity
Increased iodine uptake inhibition of thyroid hormone synthesis
(Wolff-Chaikoff effect)
Hyperthyroidism (Jod-Basedow phenomenon = iodine-induced
hyperthyroidism)
Very high doses of iodide
A brassy taste, increased salivation, and acneiform skin lesions
291
Wolff-Chaikoff effect
Increasing doses of I- increase hormone synthesis initially
Higher doses cause cessation of hormone formation.
This effect is countered by the iodide leak from normal thyroid
tissue and the hormone synthesis resumes.
Patients with autoimmune thyroiditis may fail to adapt and
become hypothyroid (suppressive effect of iodide persist)
Jod-Basedow effect
Aberration of the Wolff-Chaikoff effect
Excessive iodine loads induce hyperthyroidism
Observed in several disease processes
Basedow-Graves disease
Multinodular goiter
292
Well
Sick
Recovery
Well
reverseT3
freeT4
Reference range
T3
totalT4
Mortality
Thyrotoxicosis
With thyroid hyperfunction (Hyperthyroidism sustained
hormone overproduction)
Excess production of TSH: hypophyseal tumor
Abnormal thyroid stimulation
Basedow-Graves disease (see autoimmune diseases),
throphoblast tumor (chorionic gonadotophin-induced)
294
295
Hypothyroidism
A hypometabolic state caused by deficiency of T3 & T4
1. Primary hypothyroidism thyroid gland failure (95%)
Thyroid gland dysfunction
Congenital developmental disturbances
Radioactive iodine therapy or subtotal thyreoidectomy in BasedowGraves disease
296
Surgical ablation
Iodine deficiency
Drugs (lithium, thio-uracyl)
Idiopathic primary hypothyroidism
Hypothalamic and hypophyseal disturbances
298
Hashimotos thyroiditis
299
300
Myxedema
After treatment
301
History of goiters
Aristotle: individuals with goiter are spirited and rash
Galen: tumor of larynx and pharynx
Aetius of Amida: bronchocele that is a rupture of larynx
Paul of Aegina: two varieties: the steatomatous and the aneurysmatic
Emperor Leon VI the Wise: the man, who has a great walnut around the
neck, and has bulging eyes, is considered as healthy
302
Sporadic goiter
Goitrogens
Hereditary defect in thyroid
hormone synthesis
Multinodular goiter
Nodular enlargement, derived
from diffuse goiter (both
monoclonal & polyclonal
nodules (adenomatous goiter)
Clinical
Most patients are euthyroid
Mass effects: compression of
trachea, vessels & nerves, &
dysphagia
Hyperthyroidism (toxic
multinodular goiter)
Due to a hyperfunctioning nodule
but not accompanied by
opthalmopathy or dermopathy
303
304
Vasopressin
Pro-inflammatory
cytokines
Adrenal gland
gluconeogenesis and uptake of glucose by fat & muscle
protein synthesis, protein degradation
vascular tone, some mineralocorticoid activity, antiinflammatory & immunosuppressive effects
305
Adrenal gland
Connective tissue
capsule
Adrenal cortex
Adrenal medulla
Kidney
Adrenal medulla
Androgens
Adrenal cortex
Zona
reticularis
Glucocorticoids
Zona
fasciculata
Zona
glomerulosa
Synthesis of aldosterone
C-18-OH present only here
ACTH dependent
ACTH acts on
melanocortin-2 receptors
[MC2-R]
306
Angiotensinogen
Renin
Cathepsin
t-PA
Angiotensin I (1-10)
Bradykinin
Inactive fragments
Prorenin
ACE
(lung)
Chymase
Angiotensin II (1-8)
ACE-2
NEP
ACE-2
PRR
Contractility
Hypertrophy
Fibrosis
Apoptosis
Mas
Vasodilatation
Anti remodeling
Anti fibrotic
Anti thrombotic
Angiotensin (1-9)
ACE
Angiotensin (1-7)
APA
Angiotensin (2-8)
AT1
Vasoconstriction
Antidiuresis/antinatriuresis
Cell growth and proliferation
Aldosterone and vasopressin
release
Oxidative stress
AT2
Vasodilatation
Diuresis/natriuresis
Anti-proliferation
Bradykinin and NO production
APN/APB
Angiotensin (3-8)
AT1
AT2
AT4
NFB activation
Proinflammatory factors:
TNF-a, MCP-1, IL-6, ICAM-1
PAI-1
307
Adrenogenital syndromes
(congenital adrenal hyperplasia)
Hypoadrenalism
Acute Addisonian or adrenal
crisis (e.g. WaterhouseFriderichsen syndrome)
Chronic
Primary (due to adrenal cortical
insufficiency, e.g. Addisons
disease)
Secondary (due to ACTH
deficiency)
Tertiary (rarely due to
hypothalamic CRH deficiency)
308
Cushings syndrome
Overproduction of glucocorticoids
ACTH-dependent forms
Primary bilateral macronodular adrenal hyperplasia
Increased intra-adrenal ACTH release stimulates MC2-Rs to produce
cortisol by paracrine manner
Non-ACTH-dependent forms
Autonomous hypersecretion of cortisol by an adrenal adenoma,
carcinoma
Exogenous/iatrogenic: high dose cortisone therapy
309
Endocrine changes:
LH,FSH
TSH
GH
Glaucoma
Carbohydrate/lipid metabolism
Glucogenolysis & gluconeogenesis
Free fatty acid (FFA)
Impaired glucose tolerance, insulin
resistance, diabetes mellitus
Fat distribution: Obese, visceral
obesity, centripetal fat distribution:
supraclavicular fat (buffalo hump),
facies lunata (moon face)
Osteopenia/osteoporosis
Skin/muscle/connective tissue:
Loss of muscle, proximal myopathy,
Plethora, striae rubrae distensae, increased capillary fragility
Short stature
Peptic ulcer
311
Unilateral hyperplasia
Aldosterone-producing cortical carcinoma
312
1. Presence of hypertension
Reninism
Decreased kidney perfusion (renovascular, parenchymal
hypertension)
314
315
Adrenogenital syndromes
Adrenogenital syndromes: ambiguous genitalia & virilism in
girls, and precocious puberty in boys
Causes
1. Androgen-secreting adrenal cortical neoplasms
2. Congenital adrenal hyperplasia (CAH): corticosteroid
biosynthetic defect
C-21-hydroxylase deficiency (90% of CAH cases; autosomal
recessive)
cortisol feedback inhibition of ACTH ACTH levels
bilateral adrenocortical hyperplasia
Aldosterone synthesis is blocked salt wasting adrenogenitalism
(se Na+ , K+, hypovolemia)
production of androgens
316
317
* DOC
Estradiol
318
319
320
Adrenal medulla
Composed of specialized neuroendocrine (chromaffin) cells, and is the
major source of catecholamines: epinephrine, norepinephrine & dopamine
Chromaffin cells secrete catecholamines in response to signals from
preganglionic sympathetic nerve fibers and variety of bioactive amines
and peptides, such as: histamine, serotonin, & neuropeptide hormones
322
sympathetic
Catecolamine secretion
parasympathetic
No catecolamine secretion
324
Diagnosis
Serum & collected urine (24 hour) for catecholamines,
metanephrine, normetanephrine & vanillylmandelic acid (VMA)
determination
Free metanephrine has the highest diagnostic sensitivity and
specificity
325
326
Secondary amenorrhea
Absence of menstruation for a time equivalent to 3 or more cycles
or 6 months in women who have previously menstruated
May result from impediment in hypothalamic-pituitary axis or from
dramatic weight loss or other physiologic conditions
329
Anovulations
Physiologic: pubertal and postmenopausal anovulation
Chronic anovulations
331
332
333
Ovarian
Polycystic ovarian syndrome (PCOS)
Hyperthecosis (severe variant of PCOS)
Ovarian tumor (Sertoli-Leydig cell tumor)
Testosterone or androstendione
Testosterone is
directly secreted
by the ovaries to
the blood
Skin
Aromatase
17HSD
Fat
A Androstendione
E1 Estrone
T Testosterone
17HSD
Estradiol
Estrogen dependent
Malignancies of breast
& endometrium
5-a reductase
Dihydrotestosterone
Androgen dependent
Hirsutism & virilization
335
Increased GnRH
pulsatile activity
Estradiol
LH FSH
Low circulating
progesterone level
Androgens
Hyperinsulinemia
Inzulin resistance
Obesity
Dyslipidemia
336
338
339
340
Cryptorchism: ; Most common congenital condition of testes; one or both testes fail to
descend into scrotum; testis that is not 4 cm or more below the pubic trabecule in an
infant
Does not interfere with puberty or maintenance of secondary sex characteristics
Increased risk of testicular cancer;
Untreated infertility
Treat with hormonal therapy or surgery preferably by age 2
342
Neonatal life
Puberty
1. Sexual precocity
Sexual development prior to age 9
Complete: virilization with spermatogenesis
Incomplete: virilization no spermatogenesis
Virilizing syndromes
Hypothalamo-pituitary activity is normal, testosterone level is
Leydig cell tumors
Human chorionic gonadotropin-secreting tumors
Congenital adrenal hyperplasia
2. Delayed/incomplete puberty
See hypothalamic and pituitary diseases with undervirilization and
infertility
343
344
345
Mycoplasma infection
Radiation
Drugs: alkylating agents
Environmental toxins: ethylene glycol,
cadmium, lead
Autoimmunity
Antibodies to the basement membrane
of seminiferous tubules or to sperms
Anti-sperm antibodies prevent
penetration of cervical mucus
Systemic disease-related testicular defects
Acute febrile illness
Celiac disease
Spinal cord injury
Acquired androgen resistance
Increased CAG sequence in androgen
receptor
Sperm transport defects
Obstruction of epididymis or vas
deferens: cystic fibrosis, vasectomy
346
Pathologic gynecomastia
Relative estrogen excess (decrease in
testosterone)
Congenital defects
Congenital anorchia
Klinefelters syndrome
Reinfensteins syndrome (partial deficiency of the
androgen receptors)
Defects in testosterone synthesis: 3-HSD and 17HSD deficiency
Drugs that
Act like estrogens (diethyl stilbestrol, cosmetics, phytoestrogens)
Enhance endogenous estrogen production (gonadotropins)
Inhibit testosterone synthesis (see before)
Act by unknown mechanism (e.g. marihuana, heroin)
Idiopathic gynecomastia
348
349
Dehydration
Osmotic
concentration
of blood increases
Negative
feedback
Lowers
blood
volume
and
pressure
Negative
feedback
Osmoreceptors
ADH
synthesized by
neurosecretory
cells in
hypothalamus
ADH
Increased
water
retention
Reduced
urine
volume
ADH released
from posterior
pituitary into
blood
Increased
vasoconstriction
leading to higher
blood pressure
350
Non-osmotic stimulation
Baroreceptors: cardiopulmonary, sino-aortic
Intracardial, intra-aortic
pressure
Angiotensin II (AT-II)
Central a2 adrenergic, opiate,
dopamine receptor
351
2% increase
ECF osmolality
10% decrease in
circulating volume
CNS
osmoreceptor
Baroreceptor
ADH release
Angiotensin II
Antidiuresis
Thirst
ET-1
Oropharyngeal
reflex
Water
conservation
PGE2 incr
2.
3.
Decrease in
circulating volume:
bleeding, GI and
renal fluid loss
After surgery: due to
pain, hypotension,
hypoxia and
anesthesia
Edema formation:
cardiac, liver,
pregnancy
Water
acquisition
352
353
Diabetes insipidus
Common features of diabetes insipidus
Decreased reabsorption of free water in kidney isovolemic
hyperosmotic hypernatremia (plasma osmolality > 295
mOmsol/kg)
Excretion of large volumes of dilute (< 200 mOmsol/kg) urine
(polyuria, nocturia)
Stimulation of thirst (polydipsia)
354
3. Gestational DI
Vasopressinase produced by placenta inactivates circulating
vasopressin
Treatment: desmopressin (DDAVP resistant to vasopressinase)
356
Physiological conditions
>90%
357
Pulmonary disease
Pneumocystis jirovecii HIV + CNS infections and malignancies
CNS disorders
Tumors, infections, trauma releasing excess ADH
358
Therapy
Restriction of fluid intake, inhibition of ADH
359
Oxytocin (OT)
Action and mechanism of action: specific G protein-coupled receptors
Clinical uses
OT test for uteroplacental insufficiency: indicates whether placental reserve is
sufficient for continuation of a high-risk pregnancy (Fetal heart rate used as a
measure of distress)
Induction of term labor
Control of postpartum bleeding
For increasing milk ejection: administered as a nasal spray 2 to 3 minutes
before breast-feeding
Other effects of OT
OT attenuates endocrine and autonomic responses to stress, mediator for the
stress-protective effects of social support, attenuate amygdala reactivity to
social stimuli and reduce brainstem activity to autonomic arousal and
enhanced readiness to show social approach behavior and empathy
361
Parathyroid gland
363
Ca
Phosphate
PTH phosphaturic effect
365
Calcitonin
Non-essential hormone.
Patients with total
thyroidectomy maintain normal
Ca++ concentrations
Produced by parafollicular C
cells of thyroid gland in
response to increased iCa++
Inhibit osteoclastic resorption of
bone and Ca resorption from
intestine
Inhibit renal Ca++ and PO43reabsorption
Vitamin D
Sources
Food Vitamin D2
UV light mediated cholesterol
metabolism D3
Metabolism
Function
Stimulation of osteoblasts
Increases GI absorption of dietary
Ca++ and phosphate
366
367
368
369
Symptoms of hypocalcaemia
Neuromuscular irritability: Paraesthesiae of the distal extremities and
circumoral area; muscle cramps, laryngospasm, tetany and seizures
Erb sign: Increased electric excitability of the muscles to the galvanic
current, and frequently to the faradic, in tetany
Chvostek sign: Facial twitch elicited by tapping on the facial nerve just
below the zygomatic bone with the patients mouth slightly open
Trousseau sign: Brachial artery occlusion with a sphygmomanometer cuff
inflated above the systolic blood pressure for 3 min: Wrist and
metacarpophalangeal joint flexion, hyperextended fingers, and flexion of
the thumb on to the palm
Peroneal sign: dorsiflexion and abduction of the foot on tapping the
peroneal nerve on the lateral surface of the fibula just before the knee
2. Tertiary hyperparathyroidism
Increased PTH response persists (to renal and intestinal
hypocalcaemia)
Adenoma formation in patients with secondary
hyperparathyroidism due to parathyroid hyperplasia
374
II. Pseudo-hyperparathyroidism
Neoplasia without skeletal involvement (circulating tumor-derived
agents with bone-resorbing capacity
Immunologically distinct form PTH; e.g. EGF, PDGF causes
prostaglandin dependent bone resorption)
PTH level is not high
375
Overdose of vitamin A
Immobilization: bed rest over 4 weeks
V. Endocrine disorders
Hyperthyroidism and pheochromocytoma ( bone resorption)
Adrenal insufficiency (nonionic compartment of Ca )
Acromegaly
376
Symptoms of hypercalcaemia
Neurological manifestations
Mild drowsiness, progressing to weakness, depression, lethargy,
stupor, and coma
Gastrointestinal symptoms
Constipation, nausea, vomiting, anorexia, and peptic ulcer
disease
Recurrent pancreatitis (Ca deposition and ductal obstruction)
Renal symptoms
Nephrogenic diabetes insipidus - polyuria leading to ECF volume
depletion and a reduction in the glomerular filtration rate (GFR),
which may lead to a further increase in Ca concentration.
Nephrolithiasis, nephrocalcinosis
Ca kidney stones, metastatic calcification of glomerulus
378
Cardiac symptoms
Potentiating digitalis toxicity
Arrhythmia
Tachycardia
Decreased Q-T interval
Metastatic calcification
Calcification of soft tissues resulting from hypercalcemia or
hyperphosphatemia
379
QTc 0.48/0.92=0.52
381
382