Hypothalamic and Pituitary Hormones: LH, FSH, ACTH, Oxytocin and ADH

Question 1

Gonadotropic Hormones include LH, FSH and hCG. Pituitary gonadotropin production is stimulated by what?

Answer 1

GnRH which is further regulated by feedback effects of the gonadal hormones.

• -intermittent release of GnRH is crucial for the proper synthesis and release of gonadotropins
• -Continuous release leads to desensitization and down regulation of GnRH receptors on pituitary gonadotrophs and this down regulation forms the basis for the clinical use of long acting GnRH analogs to suppress gonadotropin secretion

Question 2

A number of GnRH analogs have been synthesized what are these?

Answer 2

Synthetic native GnRH (gonadorelin -- administered in a pulsatile fashion to stimulate patterned gonadotropin release, used to treat male and female infertility)
GnRH analogs (leuprolide, nafarelin, goserelin) -- these exhibit enhanced potency and a prolonged duration of action compared to GnRH

Question 3

The pharmacological castration induced by long acting GnRH analogs is useful in disorders that respond to reductions in gonadal steroids like?

Answer 3

Controlled ovarian hyperstimulation
Endometriosis
Uterine leiomyomata
Prostate cancer
Gonadotropin dependent precocious puberty
Advanced breast cancer and ovarian cancer
PCOD

Question 4

The long acting agonists are well tolerated but what are some side effects?

Answer 4

Occur when gonadal steroidogenesis is inhibited
–hot flashes, sweats, headaches, decreased bone density
Do not give to pregos or breast feeding mothers

Question 5

The drawback of these long acting agonists is that gonadotropin suppression does not occur immediately, instead what happens?

Answer 5

Transient (Several days): increase in sex hormone levels

followed by a lasting suppression of hormone synthesis and secretion (therefore use GnRH antagonists)

Question 6

The GnRH competitive receptor antagonists are Ganirelix and Cetrorelix which inhibit the secretion of FSH and LH in a dose dependent manner. What are their uses?

Answer 6

Prevent LH surge during controlled ovarian hyperstimulation
Suppress surge in LH in the early to mid follicular phase of the menstrual cycle, resulting in improved implantation and pregnancy
Palliation of metastatic prostate cancer
–has the advantage of avoiding the initial surge in testosterone caused by treatment with GnRH agonists

Question 7

The function of FSH and LH in women is to direct ovarian follicle development and ovarian steroidogenesis. Estrogen and Progesterone production is under the control of LH, but during pregnancy hCG takes over. In men what is the role of these hormones?

Answer 7

FSH is the primary regulator of spermatogenesis, whereas LH is the main stimulus for testosterone synthesis

Question 8

Gonadotropins are purified from human urine or prepared using recombinant DNA. What are these gonadotropins?

Answer 8

Human Chorionic Gonadotropin (hCG): mimics action of LH, and is obtained from the urine of pregos
Menotropins: comes from the urine of postmenopausal women and contain roughly equal amounts of FSH and LH
Urofollitropin: highly purified FSH preparation, while two recombinant forms of FSH are available: Follitropin alfa and Follitropin Beta

Question 9

When are gonadotropins used?

Answer 9

States of infertility to stimulate spermatogenesis in men and to induce ovulation in women that is secondary to hypogonadotropic hypogonadism, PCOD, or obesity.
–due to the cost and monitoring requirements this tx is last resort

Question 10

What are the side effects of gonadotropin tx?

Answer 10

Ovarian hyperstimulation syndrome and multiple pregnancies

In men, gynecomastia

Question 11

Moving on to Corticotropin-Releasing Hormone (CRH) this binds to cell surface G protein coupled receptors on corticotrophs of the anterior pituitary and stimulate what?

Answer 11

Corticotrophs to synthesize and release adrenocorticotropin (ACTH)
–ACTH stimulates the synthesis and secretion of adrenocortical steroid hormone, including glucocorticoids, androgens and mineralocorticoids.

Question 12

ACTH (corticotropin) and Recombinant ACTH (cosyntropin) can be used to diagnose what?

Answer 12

Suspected cases of adrenal insufficiency (whether the insufficiency is primary or secondary) 
Infantile spasm (West sydrome) and MS treatment

Question 13

Lastly the posterior lobe of the pituitary gland secrete two hormones, ADH and oxytocin. What are the roles of oxytocin?

Answer 13

Muscular contraction

–milk release during lactation and uterine contraction

Question 14

What is the mechanism of action of oxytocin?

Answer 14

Acts via specific G protein coupled receptors

–Gq and G11 and they activate PLC-IP3 Ca2+ pathway and this stimulates the release of prostaglandins and leukotrienes

Question 15

Oxytocin is administered IV for what?

Answer 15

Initiation and augmentation of labor
It can also be administered IM for control of postpartum bleeding
Toxicity: excessive stimulation of uterine contractions, inadvertent activation of vasopressin receptors and hypotension

Question 16

The other posterior lobe hormone of the pituitary gland is Vasopressin or ADH and is released in response to rising tonicity or falling blood pressure. Possesses anti-diuretic and vasopressor properties. What is the MOA for vasopressin?

Answer 16

Activates tow subtypes of G protein coupled receptors

• -V1 found on vascular smooth muscle cells and mediates vasoconstriction via the coupling protein Gq
• -V2 are found on the renal tubule cells and reduce diuresis through increased water permeability and water resorption in the collecting tubules vis Gs

Question 17

Disruption of ADH homeostasis results in what conditions?

Answer 17

Excessive secretion of ADH causes syndrome of inappropriate ADH (SIADH)
Deficient secretion of ADH or decreased responsiveness of to ADH causes diabetes insipidus

Question 18

Vasopressin and Desmopressin (long acting vasopressin analogs) are treatments for what?

Answer 18

Treatment of choice: Pituitary Diabetes Insipidus
Vasopressin: effective in some cases of esophageal varices and colonic diverticular bleeding
Desmopressin: tx of coagulopathy in hemophilia A and von Willebrand’s Disease

Question 19

Finally what is the vasopressin antagonist?

Answer 19

Conivaptan

• -high affinity for both V1 and V2 receptors
• -approved for SIADH-induced hyponatremia