Hypothalamic and Pituitary Hormones

Question 1

• required during childhood and adolescence
• Effects mediated mainly by IGF-1
• Mediates effects via cell surface receptors that activate JAK/STAT signaling cascades

Answer 1

Growth Hormone: Somatotropin

Question 2

Physiological effects of somatotropin

Answer 2

• Stimulation of longitudinal growth of bones
• Increased bone mineral density
• Increased muscle mass (in GH deficient persons)
• Increased GFR (Glomerular filtration rate)
• Stimulation of preadipocyte differentiation into adipocytes
• Anti-insulin actions (decreased glucose utilization & increased lipolysis)
• Development & increased function of the immune system

Question 3

Criteria for Diagnosis with growth hormone deficiency

Answer 3

(1) A growth rate < 4cm per year, and

(2) the absence of a serum GH response to two GH secretagogues

Question 4

Recombinant growth hormones

Answer 4

Somatropin: Recombinant GH
Somatrem: GH analog

• Active blood levels = persist for ~ 36 h
• Given subcutaneously 3-7 times a week

Question 5

Clinical Use of Recombinant Growth Hormone

Answer 5

Question 6

Adverse effects of recombinant growth hormone in children

Answer 6

• Scoliosis (during rapid growth)
• Diabetic syndrome (chronic use)
• Intracranial hypertension (rare)
• Otitis media (increased risk for Turner Syndrome patients)
• Pancreatitis, gynecomastia & nevus growth
• Hypothyroidism

Question 7

Adverse effects of recombinant growth hormone in adults

Answer 7

• Peripheral edema, myalgias & arthralgias (hands & wrists especially)
• Carpal tunnel syndrome
• Proliferative retinopathy (rare)

Question 8

Contraindications of Recombinant Growth Hormone

Answer 8

• Cytochrome P450 inducer

* Patients with a known malignancy

Question 9

IGF-1 deficiency in children is due mutations in gene that encodes for GH receptor and development of neutralizing antibodies to GH. Which drug should be used ?

Answer 9

IGF-1 Analog: Mecasermin: Complex of recombinant human IGF-1 and recombinant human IGF-binding protein-3

Question 10

AE of mecasermin

Answer 10

• Hypoglycemia (eat 20 minutes before or after administration)
• Intracranial hypertension (rare)
• Asymptomatic elevation of liver enzymes (rare)

Question 11

Growth Hormone Secreting Tumors

Answer 11

• Acromegaly (abnormal growth of cartilage, bone tissue, skin, muscle, heart, liver & GI tract)
• Gigantism (if occurs before long bone epiphyses close)

Question 12

Small GH-secreting adenomas can be treated with

Answer 12

• GH receptor antagonists- Pegvisomant
• Somatostatin analogs- Octreotide
• Dopamine receptor agonists- Bromocriptine and Cabergoline

• Larger pituitary adenomas require surgery or radiation

Question 13

• Reduces symptoms caused by hormone-secreting tumors: acromegaly, carcinoid syndrome, gastrinoma, glucagonoma, nesidioblastosis, watery diarrhea, hypokalemia, achlorhydria syndrome & diabetic diarrhea.
• Localizing neuroendocrine tumors
• Acute control of bleeding from esophageal varices

Answer 13

Somatostatin Analog: Octreotide

• 45x more potent in inhibiting GH release than somatostatin
• 2x more potent in reducing insulin secretion
• t 1⁄2 = ~ 80 min (30x somatostatin)
• Octreotide acetate long-acting suspension can be given at 4-week intervals

Question 14

AE OF Octreotide

Answer 14

*****Vit B 12 deficiency

• Nausea, vomiting, abdominal cramps, flatulence, steatorrhea (with bulky bowel movements)
• Constipation
• Biliary sludge & gallstones (20-30% patients after 6-month use)
• Sinus bradycardia (25%) & conduction disturbance (10%)

Question 15

Treatment of hyperprolactinemis and acromegaly

Answer 15

Dopamine Agonists: Bromocriptine and Cabergoline
- Dopamine agonists shrink pituitary prolactin- secreting tumors, lower circulating prolactin levels, and restore ovulation in ~70% of women with microadenomas & ~30% with macroadenomas

• Oral or as vaginal inserts
• Bromocriptine t1/2 = ~7 h
• Cabergoline t1/2 = ~65 h

Question 16

AE OF Dopamine Agonists: Bromocriptine and Cabergoline

Answer 16

• Nausea (bromocriptine>cabergoline), headache, light-headedness, orthostatic hypotension, fatigue
• Psychiatric manifestations occasionally occur
• High doses = cold-induced peripheral digital vasospasm • Chronic high-dosage therapy = pulmonary infiltrates

Question 17

Gonadotropins in women

Answer 17

FSH: ovarian follicle development
• FSH & LH: ovarian steroidogenesis
• Luteal stage of menstrual cycle: estrogen & progesterone production is primarily under control of LH. (During pregnancy hCG takes over.)

Question 18

Gonadotropins in men

Answer 18

• FSH: Spermatogenesis, conversion of testosterone to estrogen.
- Maintains high local androgen concentrations in vicinity of developing cells
• LH: Stimulus for production of testosterone

Question 19

Act through GPCRs and is used for

• ovulation induction
• male infertility
• female infertility

Answer 19

Gonadotropins

Male Infertility
• Treatment of hypogonadal men requires both FSH and LH.
- Treatment can consist of hCG alone or alternative protocols using urofollitropin, rFSH and rLH
• Stimulate spermatogenesis
Female Infertility: induce ovulation in women (IVF)

Question 20

Gonadotropins

Answer 20

Question 21

AE OF GONADOTROPINS IN WOMEN

Answer 21

• Ovarian hyperstimulation syndrome
• Multiple pregnancies (15-20%)
• Headache
• Depression
• Edema
• Precocious puberty

Question 22

AE OF GONADOTROPINS IN MEN

Answer 22

Gynecomastia

Question 23

gonadotropin-releasing hormone
synthetic human GnRH
Given IV or SC
Half life of 4 mince

Answer 23

Gonadorelin

Question 24

gonadotropin-releasing hormone analogs
more potent & longer-lasting than gonadorelin
Given SC, IM, nasal spray (Nafarelin) or as SC implant

Answer 24

Gonadotropin analogs- Goserelin, leuprolide, nafarelin

Question 25

Continuous administration of Gonadotropin-Releasing Hormone & Analogs gives biphasic response:

Answer 25

* First 7 days = agonist response ‘flare’ | * Chronic effects (> 1 week) = inhibitory action (due to receptor down-regulation & changes in signaling pathways)

Question 26

Gonadotropin-Releasing Hormone & Analogs stimulates

Answer 26

* Female infertility * Male infertility: In men with hypothalamic hypogonadotropic hypogonadism (pulsatile gonadorelin) * Diagnosis of LH responsiveness: Whether delayed puberty is due to constitutional delay or hypogonadotropic hypogonadism

Question 27

• Controlled ovarian hyperstimulation : Critical to suppress endogenous LH surge that could prematurely trigger ovulation

Answer 27

leuprolide, nafarelin

Question 28

Endometriosis: Pain often decreased by abolishing exposure to cyclical changes in estrogen & progesterone concentrations during menstrual cycle. - Treatment limited to 6 months

Answer 28

(leuprolide, goserelin, nafarelin)

Question 29

``` Uterine Leiomyomata (fibroids): - Can reduce fibroid size and combined with supplemental iron can improve anemia ```

Answer 29

(leuprolide, goserelin, nafarelin)

Question 30

Prostate Cancer: - Combined therapy with continuous GnRH agonist and an androgen receptor antagonist is effective as castration in reducing serum testosterone

Answer 30

(leuprolide, goserelin)

Question 31

Gonadotropin-Releasing Hormone & Analogs other suppression effects

Answer 31

* Central Precocious Puberty (leuprolide, nafarelin) * Advanced Breast & Ovarian Cancer * Treatment of Amenorrhea in women with Polycystic Ovary Disease * Thinning of Endometrial lining: Preparation for endometrial ablation procedure in women with dysfunctional uterine bleeding

Question 32

Adverse effects of Gonadotropin-Releasing Hormone & Analogs

Answer 32

* Headache, light-headedness, nausea, flushing * Swelling at SC injection site * Generalized hypersensitivity dermatitis (long-term administration) * Rare acute hypersensitivity reactions * Sudden pituitary apoplexy & blindness

Question 33

Adverse effects of Gonadotropin-Releasing Hormone & Analogs for continuous treatment

Answer 33

Women • Menopausal symptoms (hot flushes, sweats, headaches) • Depression, diminished libido, generalized pain, vaginal dryness & breast atrophy can occur • Ovarian cysts (generally resolve) • Reduced bone density & osteoporosis (long treatment) Contraindications - Pregnant and breast-feeding women Men • Hot flushes, sweats, edema, gynecomastia, decreased libido, decreased hematocrit, reduced bone density, asthenia, & injection site reactions

Question 34

These drugs suppress Gonadotropin Production: Prevent LH surge during controlled ovarian hyperstimulation

Answer 34

Cetrorelix, ganirelix = Competitive antagonists of GnRH receptors

Question 35

These drugs - Act via MC2R (GPCR → cAMP) to stimulate adrenal cortex to secrete glucocorticoids, mineralocorticoids & androgen precursor • Diagnostic tool for differentiating between primary adrenal insufficiency (Addison’s disease) and secondary adrenal insufficiency (inadequate ACTH secretion) • Infantile spasm (West Syndrome) treatment

Answer 35

Corticotropin, cosyntropin = ACTH analogs

Question 36

* Acts on GPCRs → stimulates release of prostaglandins & leukotrienes that augment uterine contraction * Small doses increase force & frequency of contractions * Higher doses evoke sustained contractions. Weak antidiuretic & pressor activity (vasopressin R activation) * Contraction of myoepithelial cells surrounding mammary alveoli → milk ejection

Answer 36

Oxytocin * IV: initiation & augmentation of labor * IM: control of postpartum bleeding * t1/2=5min

Question 37

Clinical applications of oxytocin

Answer 37

• Labor Induction: When early vaginal delivery is required (Rh problems, maternal diabetes, preeclampsia, ruptured membranes) • Augment Normal Labor: When labor is protracted or displays arrest disorder • Control of uterine hemorrhage

Question 38

AE of oxytocin

Answer 38

* Excessive stimulation of uterine contractions * Inadvertent activation of vasopressin receptors: Excessive fluid retention, water intoxication → hyponatremia, heart failure, seizure, death * Bolus injections can lead to hypotension: Administer IV as dilute solution at a controlled rate

Question 39

Oxytocin contraindications

Answer 39

* Fetal distress * Prematurity * Abnormal fetal presentation * Cephalopelvic disproportion * Uterine rupture predisposition

Question 40

Oxytocin antagonist used for treatment of preterm labor

Answer 40

Atosiban

Question 41

Long-acting synthetic analog of vasopressin Minimal V1 activity Antidiuretic-to-vasopressor ratio 4000 x vasopressin

Answer 41

Desmopressin (Vasopressin (ADH) Agonists)

Question 42

V1R

Answer 42

vascular smooth muscle→vasoconstriction

Question 43

V2R

Answer 43

renal tubule cells→increased water permeability & water reabsorption

Question 44

Drugs of choice for Diabetes Insipidus

Answer 44

Vasopressin (ADH) Agonists

Question 45

Used for Esophageal variceal bleeding & colonic diverticular bleeding

Answer 45

Vasopressin

Question 46

Used for Coagulopathy treatment in Hemophilia A and von Willebrand’s disease

Answer 46

Desmopressin

Question 47

This drug is • Approved for use in patients with hyponatremia (due to elevated vasopressin) • High affinity for V1 & V2 R’s

Answer 47

Conivaptan

Question 48

Adverse effects of vassopressin agonists

Answer 48

* Headache, nausea, abdominal cramps, allergic reactions | * Overdosage = hyponatremia & seizures