Pituitary and Hypothalamic Hormones

1. Pituitary and Hypothalamic Hormones Akrum Hamdy

2. Introduction Most pituitary and hypothalamic hormone are trophic hormones. This and other factors limit their use as drugs. Exceptions – growth hormone and gonadotropins

3. Growth HormoneGH or Somatotropin • Chemistry – a single chain polypeptide. • Significant differences in amino acid sequence between humans and other species prevent use of non-human hormone

4. Growth Hormone Physiological Actions

5. Growth Hormone • Physiological actions • Mechanism – GH receptor stimulation activates an intracellular tyrosine kinase, JAK2, resulting in phosphorylation of proteins and gene regulation. • Growth – almost all body tissues stimulated to grow • Nitrogen metabolism – increased nitrogen retention, amino acid transport into tissues, and incorporation into protein • Carbohydrate and lipid metabolism – GH appears to promote use of lipids as energy source instead of carbohydrates • GH has a diabetogenic effect in diabetics

6. Growth Hormone • Physiological actions • Conserves muscle at the expense of fat during stress • Insulin-like growth factor (IGF, somatomedins) – peptides produced by liver and other tissues in response to GH; appear to mediate many GH effects. rhIGF-1 (mecasermin, Increlix) now available for treatment of growth failure in GH-resistant patients

7. Growth Hormone • Clinical applications – one of the few pituitary hormones with long-term therapeutic utility. Recombinant human growth hormone (rh-GH) is used clinically. There are two forms, somatotropin and somatrem. • Hypopituitary dwarfism – in children with insufficient GH secretion, GH will generally produce an increased growth rate over several years. Recently, FDA approved use in children with idiopathic, non-GH-deficient short stature.

8. Growth Hormone • Clinical applications • Treatment of AIDS – associated wasting • Treatment of adult onset growth hormone deficiency • Turner’s syndrome • Anti-aging supplements – OTC supplements which suggest they contain hGH. Contain amino acids that are supposed to release GH.

9. Growth Hormone • Problems associated with therapy – possibility of intracranial hypertension and visual changes exist, so fundascopic exams needed. • Also possibility of type 2 diabetes and respiratory difficulties in patients with obesity or sleep apnea due to Prader-Willi syndrome. • Possible contamination of human-derived GH with Creutzfeldt-Jakob virus.

10. Growth Hormone • Acromegaly – hypersecretion of GH may result in acromegaly. • Octreotide (Sandostatin) or other somatostatin analogs are most commonly used to decrease GH secretion. • Dopamine agonists such as bromocryptine will inhibit GH secretion from some GH secreting tumors. • Pegvisomant (Somavert), a GH receptor antagonist, is now available to treat acromegaly in patients who have not responded to other treatment. Pegvisomant prevents GH stimulation of IGF.

11. Gonadotropins • Luteinizing hormone (LH, interstitial cell stimulating hormone) • Chemistry – glycoprotein hormone with 2 peptide chains. • Physiological actions • Mechanism – LH receptor stimulation activates Gs • Ovary – promotes ovulation and luteinization of ovarian follicles; stimulates synthesis and secretion of estrogen and progesterone from corpus luteum.

12. Gonadotropins • Luteinizing hormone • Physiological actions • Testis – stimulate interstitial (leydig) cells to secrete androgens

13. Figure 56-4. The hypothalamic-pituitary-gonadol axis A single hypothalamic releasing factor, gonadotropin-releasing hormone (GnRH), controls the synthesis and release of both gonadotropins (LH and FSH) in males and females. Gonadal steroid hormones (androgens, estrogens, and progesterone) cause feedback inhibition at the level of the pituitary and the hypothalamus. The pre-ovulatory surge of estrogen also can exert a stimulatory effect at the level of the pituitary and the hypothalamus. Inhibin, a polypeptide hormone produced by the gonads, specifically inhibits FSH production by the pituitary.

14. Gonadotropins • Luteinizing hormone • Clinical application • Infertility – menotropins (a mixture of urinary LH and FSH) and chorionic gonadotropin have been used to induce ovulation. Recombinant human LH lutropin alpha (Luveris) is now available. • Hyperstimulation of ovary may occur • May also increase fertility in men • Kits available to predict time of ovulation by measuring urinary LH

15. Gonadotropins • Follicle stimulating hormone (FSH) • Chemistry – glycoprotein with 2 peptide chains. Agents available are recombinant human FSH, follitropin (Gonal-F and Follistim), and urinary human FSH, urofollitropin • Physiological actions of FSH • Mechanism – activates Gs • Ovary – promote follicular development • Testis – stimulate testicular growth and maintain seminiferous tubules • Clinical application – promote ovulation

16. Gonadotropins • Chorionic gonadotropin (HCG) – not a pituitary hormone but is similar to the pituitary gonadotropins • Chemistry – glycoprotein with 2 polypeptide chains. Synthesized by syncytiotrophoblasts of placenta. Recombinant human HCG, choriogonadotropin alfa (Ovidrel) is used clinically. • Physiological actions – stimulate and sustain function of corpus luteum

17. Gonadotropins • Chorionic gonadotropin (HCG) • Clinical application – induction of ovulation, promote descent of testes in cryptorchism • Presence of HCG in urine used to confirm diagnosis of pregnancy

18. Prolactin - PRL • Chemistry – single chain polypeptide hormone • Physiological actions • Lactation – causes growth and development of breasts, and increased synthesis of milk proteins • Decreases release or effectiveness of gonadotropins • Hypersecretion – hyperprolactinemia may cause galactorrhea, amenorrhea and infertility. Bromocriptine, pergolide (Permax), and cabergoline (Dostinex) are useful in suppressing PRL secreting tumors.

19. Thyrotropin (TSH) • Chemistry – glycoprotein with 2 polypeptide chains. Thyrotropin alpha, human recombinant TSH, is used clinically. • Physiological actions – Receptor stimulation activates Gs which increases function of thyroid gland • Increases uptake of iodine by thyroid, synthesis and release of hormone, and growth of gland.

20. Thyrotropin (TSH) • Clinical application • Increases uptake of radioactive iodine. Used as a diagnostic tool for serum thyroglobulin testing or whole body scanning in the follow-up of patients with thyroid cancer.

21. Corticotropin(Adrenal cortex trophic hormone, ACTH) • Chemistry – natural hormone is a single chain polypeptide of 39 amino acids. A synthetic form containing amino acids 1-24 is available. • Physiological actions – stimulates adrenal cortex to synthesize and secrete cortisol, corticosterone, and aldosterone (slightly). Prevents atrophy of adrenal cortex. • Mechanism – receptor interaction results in activation of adenylate cyclase and synthesis of cAMP. cAMP activates enzymes involved in steroid synthesis.

22. CorticotropinAdrenal cortex trophic hormone, ACTH) • Clinical use • Diagnosis of adrenal insufficiency • Treatment of infantile spasms (epilepsy)

23. Hypothalamic Hormones • Peptides synthesized in hypothalamus and transported to the anterior pituitary via portal circulation • Gonadotropin releasing hormone and analogs – drugs available include Gonadorelin (natural hormone) and • Long-acting analogs histrelin (Suprelin), leuprolide (Leupron), gosrelin (Zoladex), triptoreline (Trelstar), and nafareline (Synarel). • Gonadorelin is used for induction of ovulation. • Long acting analogs are used for treatment of PMS, endometriosis, prostate cancer, and central precocious puberty. Experimental use as male contraceptive.

24. Hypothalamic Hormones • GnRH antagonists – ganirelix (Antagon) and cetrorelix (Cetrotide) • Used to inhibit premature LH surges prior to harvesting eggs for in vitro fertilization • Also abarelix (Plenaxis) – a GnRH receptor antagonist used to treat advanced prostate cancer. Danger of life-threatening allergic reactions in 4% of patients.

25. Hypothalamic Hormones • Somatostatin – an analog, octreotide acetate (Sandostatin) used to treat acromegaly, carcinoid, and VIP secreting tumors. Long acting form now available (once per month). • Growth hormone releasing hormone – Semorelin (Geref), a synthetic form of GHRH, has been approved for treatment of GH deficiency. Will only work in patients with functioning pituitary.