L13 – Treatment of Pituitary Disorder

Question 1

Outline the effects of gonadotrophin deficiency in women?

Answer 1

 Amenorrhea (low menstrual cycle)

 No ovulation = infertility

 No FSH = no estrogen = regression of secondary sexual characteristics

Question 2

Outline the effects of gonadotrophin deficiency in men?

Answer 2

 Impotence

 No spermatogenesis = infertility

 Testicular atrophy cause Regression of secondary sexual characteristics

Question 3

List 2 treatment options for FSH deficiency?

Answer 3

Follitropin (recombinant human FSH)

Human menopausal gonadotrophins (HMG): purified extract of human postmenopausal urine, contains FSH and LH

Question 4

List 3 treatment options for LH deficiency?

Answer 4

Lutropin α (recombinant human LH)

Human chorionic gonadotrophin (HCG): purified extract from placenta in urine of pregnant women

Choriogonadotropin α (recombinant HCG)***

Question 5

Describe the preparation of hormone therapy for gonadotrophin deficiency?

Answer 5

• Follitropin + Lutropin α/ Choriogonadotropin α

- Human menopausal gonadotrophins (HMG) + Lutropin α / HCG / choriogonadotropin α

Question 6

MoA of gonadotrophin hormone replacement on women?

Answer 6

stimulate ovarian Graffian follicles development&raquo_space; produce estrogen:

• thickening of endometrial wall
• development of Secondary sexual characteristics

Stimulate ovulation&raquo_space; corpus luteum secretes progesterone to prepare implantation at endometrium

Question 7

MoA of gonadotrophin hormone replacement on men?

Answer 7

stimulate spermatogenesis

testosterone production for secondary sexual characteristics

Question 8

HMG has both FSH and LH activity so it can be used in isolation to treat gonadotrophin deficiency/ T or F?

Answer 8

False

LH activity is very low, still need LH therapy (lutropin α / HCG / choriogonadotropin α)

Question 9

ADR of FSH and LH replacement therapy?

Answer 9

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

Question 10

List some complications from Ovarian hyperstimulation syndrome.

Answer 10

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

Question 11

Compare the hormone therapy required in Hypopituitarism and Adrenocortical insufficiency.

Answer 11

Hypopituitarism:

• Hydrocortisone only
• Renin-angiotensin system maintain Aldosterone production = no need for Fludrocortisone

Adrencocortical insufficiency: e.g. Addison’s disease:
- hydrocortisone + fludrocortisone

Question 12

Symptoms and signs of ACTH deficiency?

Answer 12

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

Question 13

List 2 treatment options for ACTH deficiency?

Answer 13

• Hydrocortisone

- Cortisone (converted to hydrocortisone)

Question 14

Can corticosteroids like prednisolone and betamethasone be used for ACTH deficiency?

Answer 14

NO

Those are too strong, only for anti-inflammatory immunosuppression

> > many adverse effects

Question 15

How does hydrocortisone exert it’s effect on target cells?

Answer 15

• Cross cell membrane and bind to intracellular steroid receptor
• Steroid receptor complex into nucleus, bind to chromatin
• trigger target gene transcription

Question 16

List effects of hydrocortisone?

Answer 16

• 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

Question 17

List effects of Fludrocortisone?

Answer 17

Acts on DCT of kidneys:
Increase Na reabsorption

Increase K/H secretion

Question 18

ADR of hydrocortisone?

Answer 18

Iatrogenic Cushing’s syndrome**

Hyperglycaemia (DM) and hypertension **

Increase risk of infection **

Osteoporosis ** and muscle weakness

• Growth suppression
• Peptic ulcer
• Cataracts
• Psychological distubances

Question 19

Describe changes induced by Iatrogenic Cushing’s syndrome?

Answer 19

• Moon face
• buffalo hump
• Increase abdominal fat/ central obesity
• Thin arm and legs
• Thinning of skin

Question 20

Stimulation and inhibition factors of Prolactin?

Answer 20

Stimulation = Prolactin- releasing factor/ hormone

Inhibition = tonic dopamine

Question 21

Symptoms and signs of hyperprolactinaemia?

Answer 21

• Galactorrhoea

Inhibit GnRH, FSH and LH:
 Amenorrhoea (no menstrual cycle)
 Hypogonadism
 Infertility

Question 22

Treatment options for hyperprolactinaemia?

Answer 22

Dopamine receptor agonists – e.g. Bromocriptine, cabergoline

Cabergoline: longer t1/2 and higher selectivity for dopamine D2 receptor

Question 23

MoA of Bromocriptine/ Cabergoline?

Answer 23

1) Stimulate dopamine D2 receptors on anterior pituitary gland = inhibit prolactin production and lactation
2) Significant decrease size of prolactin-secreting adenomas

Question 24

ADR of bromocriptine/ Cabergoline?

Answer 24

• 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**

Question 25

Effects of Growth hormone hypersecretion during childhood and adults?

Answer 25

Childhood = pituitary gigantism Adult = acromegaly

Question 26

Trigger and inhibitor of Growth hormone secretion?

Answer 26

Growth hormone releasing factor = stim Somatostatin = inhibit

Question 27

Can somatostatin be used to treat GH hypersecretion?

Answer 27

No Very short t1/2

Question 28

Treatment options for Acromegaly and GIgantism? (4)

Answer 28

Somatostatin analogues: Octreotide, Lanreotide Growth hormone receptor antagonist: pegvisomant Dopamine D2 receptor agonists (e.g. bromocriptine, cabergoline)

Question 29

MoA of Lanreotide and Octreotide?

Answer 29

Inhibit release of growth hormone from anterior pituitary Decrease pituitary tumor size in a minority of patients

Question 30

ADR of Lanreotide and Octreotide?

Answer 30

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

Question 31

Explain how Lanreotide and Octreotide cause GI disturbance?

Answer 31

Octreotide inhibits secretion of gastrointestinal peptides (e.g. gastrin, vasoactive intestinal peptide, secretin, motilin, pancreatic polypeptide) >>> inhibits digestion, motility of gut

Question 32

MoA of Pegvisomant?

Answer 32

Growth hormone receptor antagonist Selectively blocks growth hormone receptor >> interferes with Growth hormone signal transduction + Hepatic production of somatomedins

Question 33

ADR of Pegvisomant?

Answer 33

 Elevated liver enzymes (AST, ALT): damage liver, but no symptoms of liver failure / hepatotoxicity / hepatitis  Nausea  Diarrhoea

Question 34

MoA of Bromocriptine and Cabergoline to treat gigantism and acromegaly?

Answer 34

Normally = D2 receptor agonist stimulates growth hormone secretion In Acromegaly = D2R agonist cause paradoxical decrease in growth hormone secretion

Question 35

Treatment against Cushing's syndrome?

Answer 35

•Metyrapone •Trilostane

Question 36

MoA of Metyrapone and Trilostane?

Answer 36

Inhibit biosynthetic pathways of corticosteroids conversion (cortisol,aldosterone) (exam):  Metyrapone inhibits 11β-hydroxylase  Trilostane inhibits 3β-dehydrogenase

Question 37

ADR of Metyrapone and Trilostane?

Answer 37

- Decrease cortisol = Hypotension - Nausea, vomiting - Headache and dizziness - Rash/ allergy

Question 38

Physiological effects of ADH?

Answer 38

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

Question 39

Pathological effects of ADH deficiency?

Answer 39

Diabetes insipidus Increase plasma osmolarity Decrease blood volume Decrease blood pressure

Question 40

Treatment options for ADH deficiency?

Answer 40

 Vasopressin (synthetic) |  Desmopressin: long-acting synthetic Vp analogue

Question 41

Desmopressin is V1 selective. T or F?

Answer 41

False Desmopressin is More selective to V2 receptors in kidney (rather than blood vessels) = less vasopressor effect

Question 42

MoA of Vasopressin and Desmopressin?

Answer 42

Stimulate V2 receptor on renal distal tubules, collecting ducts >> translocate AQP2 from cytoplasm to luminal membrane >> increase permeability to water

Question 43

ADR of Vp and desmopressin?

Answer 43

- Fluid retention and edema - Hyponatremia - Headache, nausea, allergy Vp: stimulate V1R: - Vasoconstriction - Angina - Abdominal and uterine cramps

Question 44

What is pituitary dwarfism caused by?

Answer 44

Lack of GH

Question 45

Treatment option for pituitary dwarfism?

Answer 45

Somatropin (recombinant GH)

Question 46

MoA of somatropin?

Answer 46

- 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

Question 47

Describe the early and later phase activity of somatotropin?

Answer 47

Initial ‘insulin-like’ effect: - Increase tissue uptake of glucose - Decrease lipolysis After a few hours = peripheral insulin-antagonistic effect: - Impaired glucose uptake - Increase lipolysis

Question 48

ADR of Somatotropin?

Answer 48

- 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)