L13 – Treatment of Pituitary Disorder Flashcards
Outline the effects of gonadotrophin deficiency in women?
Amenorrhea (low menstrual cycle)
No ovulation = infertility
No FSH = no estrogen = regression of secondary sexual characteristics
Outline the effects of gonadotrophin deficiency in men?
Impotence
No spermatogenesis = infertility
Testicular atrophy cause Regression of secondary sexual characteristics
List 2 treatment options for FSH deficiency?
Follitropin (recombinant human FSH)
Human menopausal gonadotrophins (HMG): purified extract of human postmenopausal urine, contains FSH and LH
List 3 treatment options for LH deficiency?
Lutropin α (recombinant human LH)
Human chorionic gonadotrophin (HCG): purified extract from placenta in urine of pregnant women
Choriogonadotropin α (recombinant HCG)***
Describe the preparation of hormone therapy for gonadotrophin deficiency?
- Follitropin + Lutropin α/ Choriogonadotropin α
- Human menopausal gonadotrophins (HMG) + Lutropin α / HCG / choriogonadotropin α
MoA of gonadotrophin hormone replacement on women?
stimulate ovarian Graffian follicles development»_space; produce estrogen:
- thickening of endometrial wall
- development of Secondary sexual characteristics
Stimulate ovulation»_space; corpus luteum secretes progesterone to prepare implantation at endometrium
MoA of gonadotrophin hormone replacement on men?
stimulate spermatogenesis
testosterone production for secondary sexual characteristics
HMG has both FSH and LH activity so it can be used in isolation to treat gonadotrophin deficiency/ T or F?
False
LH activity is very low, still need LH therapy (lutropin α / HCG / choriogonadotropin α)
ADR of FSH and LH replacement therapy?
1) FSH and LH stimulate aromatase: convert testosterone to estrogen: gynaecomastia in men
2) ‘Ovarian hyperstimulation syndrome’
3) Fever
4) Multiple births
LH only:
Headache, depression, edema, precocious puberty
List some complications from Ovarian hyperstimulation syndrome.
1) Ovarian enlargement and burst > Hemoperitoneum
2) Ovary produces factors to increase BV permeability > edema:
a) Ascites
b) Hydrothorax
c) Hypovolemia leading to electrolyte imbalance and arterial thromboembolism
Compare the hormone therapy required in Hypopituitarism and Adrenocortical insufficiency.
Hypopituitarism:
- Hydrocortisone only
- Renin-angiotensin system maintain Aldosterone production = no need for Fludrocortisone
Adrencocortical insufficiency: e.g. Addison’s disease:
- hydrocortisone + fludrocortisone
Symptoms and signs of ACTH deficiency?
1) Hypoglycaema: less cortisol to elevate blood glucose
2) Impaired function of Adrenaline/ NE on heart, reduced vasocontriction:
a) Hypotension
b) Low blood flow to brain: fatigue, dizziness
c) Intolerance to stress, infection
3) Weight loss
List 2 treatment options for ACTH deficiency?
- Hydrocortisone
- Cortisone (converted to hydrocortisone)
Can corticosteroids like prednisolone and betamethasone be used for ACTH deficiency?
NO
Those are too strong, only for anti-inflammatory immunosuppression
> > many adverse effects
How does hydrocortisone exert it’s effect on target cells?
- Cross cell membrane and bind to intracellular steroid receptor
- Steroid receptor complex into nucleus, bind to chromatin
- trigger target gene transcription
List effects of hydrocortisone?
- Increase blood glucose:
a) decrease uptake in cells
b) Increase gluconeogenesis
c) increase proteolysis, lipolysis
d) Increase liver glycogen stores - Increase β-adrenoceptors (permissive effect) = potentiates adrenaline, NE effects = maintain cardiovascular function
List effects of Fludrocortisone?
Acts on DCT of kidneys:
Increase Na reabsorption
Increase K/H secretion
ADR of hydrocortisone?
Iatrogenic Cushing’s syndrome**
Hyperglycaemia (DM) and hypertension **
Increase risk of infection **
Osteoporosis ** and muscle weakness
- Growth suppression
- Peptic ulcer
- Cataracts
- Psychological distubances
Describe changes induced by Iatrogenic Cushing’s syndrome?
- Moon face
- buffalo hump
- Increase abdominal fat/ central obesity
- Thin arm and legs
- Thinning of skin
Stimulation and inhibition factors of Prolactin?
Stimulation = Prolactin- releasing factor/ hormone
Inhibition = tonic dopamine
Symptoms and signs of hyperprolactinaemia?
- Galactorrhoea
Inhibit GnRH, FSH and LH:
Amenorrhoea (no menstrual cycle)
Hypogonadism
Infertility
Treatment options for hyperprolactinaemia?
Dopamine receptor agonists – e.g. Bromocriptine, cabergoline
Cabergoline: longer t1/2 and higher selectivity for dopamine D2 receptor
MoA of Bromocriptine/ Cabergoline?
1) Stimulate dopamine D2 receptors on anterior pituitary gland = inhibit prolactin production and lactation
2) Significant decrease size of prolactin-secreting adenomas
ADR of bromocriptine/ Cabergoline?
- Trigger D2 receptor in CTZ, nucleus of solitary tract = Nausea, vomiting**
- Decrease parasympathetic activity in gut = Constipation**
- Direct vasodilation: baroreceptor less sensitive to BP change = Postural hypotension = dizziness**
Effects of Growth hormone hypersecretion during childhood and adults?
Childhood = pituitary gigantism
Adult = acromegaly
Trigger and inhibitor of Growth hormone secretion?
Growth hormone releasing factor = stim
Somatostatin = inhibit
Can somatostatin be used to treat GH hypersecretion?
No
Very short t1/2
Treatment options for Acromegaly and GIgantism? (4)
Somatostatin analogues:
Octreotide, Lanreotide
Growth hormone receptor antagonist: pegvisomant
Dopamine D2 receptor agonists (e.g. bromocriptine, cabergoline)
MoA of Lanreotide and Octreotide?
Inhibit release of growth hormone from anterior pituitary
Decrease pituitary tumor size in a minority of patients
ADR of Lanreotide and Octreotide?
3 G’s:
GI disturbances: •Nausea & vomiting •Abdominal cramps •Flatulence •Steatorrhoea
Gallstones: Inhibition of gall bladder motility
Impaired Glucose tolerance: somatostatin inhibits pancreatic insulin secretion
Explain how Lanreotide and Octreotide cause GI disturbance?
Octreotide inhibits secretion of gastrointestinal peptides (e.g. gastrin, vasoactive intestinal peptide, secretin, motilin, pancreatic polypeptide)
> > > inhibits digestion, motility of gut
MoA of Pegvisomant?
Growth hormone receptor antagonist
Selectively blocks growth hormone receptor
> > interferes with Growth hormone signal transduction + Hepatic production of somatomedins
ADR of Pegvisomant?
Elevated liver enzymes (AST, ALT): damage liver, but no symptoms of liver failure / hepatotoxicity / hepatitis
Nausea
Diarrhoea
MoA of Bromocriptine and Cabergoline to treat gigantism and acromegaly?
Normally = D2 receptor agonist stimulates growth hormone secretion
In Acromegaly = D2R agonist cause paradoxical decrease in growth hormone secretion
Treatment against Cushing’s syndrome?
•Metyrapone •Trilostane
MoA of Metyrapone and Trilostane?
Inhibit biosynthetic pathways of corticosteroids conversion (cortisol,aldosterone) (exam):
Metyrapone inhibits 11β-hydroxylase
Trilostane inhibits 3β-dehydrogenase
ADR of Metyrapone and Trilostane?
- Decrease cortisol = Hypotension
- Nausea, vomiting
- Headache and dizziness
- Rash/ allergy
Physiological effects of ADH?
1) Stimulate V1 receptor on vascular smooth muscles = vasoconstriction = increase BP
2) Stimulate V2 receptor on collecting ducts = increase expression and trafficking of AQP2 = increase water reabsorption
Pathological effects of ADH deficiency?
Diabetes insipidus
Increase plasma osmolarity
Decrease blood volume
Decrease blood pressure
Treatment options for ADH deficiency?
Vasopressin (synthetic)
Desmopressin: long-acting synthetic Vp analogue
Desmopressin is V1 selective. T or F?
False
Desmopressin is More selective to V2 receptors in kidney (rather than blood vessels) = less vasopressor effect
MoA of Vasopressin and Desmopressin?
Stimulate V2 receptor on renal distal tubules, collecting ducts
> > translocate AQP2 from cytoplasm to luminal membrane
> > increase permeability to water
ADR of Vp and desmopressin?
- Fluid retention and edema
- Hyponatremia
- Headache, nausea, allergy
Vp: stimulate V1R:
- Vasoconstriction
- Angina
- Abdominal and uterine cramps
What is pituitary dwarfism caused by?
Lack of GH
Treatment option for pituitary dwarfism?
Somatropin (recombinant GH)
MoA of somatropin?
- Stimulate peripheral tissue growth + Amino acid uptake
- Initial ‘insulin-like’ effect to increase glucose uptake, later peripheral insulin antagonistic effect with impaired glucose uptake and increased lipolysis
- Stimulate Somatomedins (IGF-1) production from liver:
i) uptake of sulphate into cartilage for growth
ii) mediate bone growth
Describe the early and later phase activity of somatotropin?
Initial ‘insulin-like’ effect:
- Increase tissue uptake of glucose
- Decrease lipolysis
After a few hours = peripheral insulin-antagonistic effect:
- Impaired glucose uptake
- Increase lipolysis
ADR of Somatotropin?
- Increase T4 to T3 conversion = quickly degraded = hypothyroidism
- Activate Na channel in collecting ducts :
a) peripheral edema
b) Papilledema near optic nerve = vision chnage
c) Raised ICP and headache - Impaired glucose tolerance (anti-insulin effect)
