Pituitary and Hypothalamic Hormones

1. Pituitary and Hypothalamic Hormones DR.FAROOQ ALAM M.B.B.S-M.Phil

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

5. Growth Hormone • Physiological actions • Mechanism – GH receptor stimulation activates an intracellular tyrosine kinase, JAK2(Janus kinase2 is a human protein that has been implicated in singling by members of the type 2 cytokines), resulting in phosphorylation of proteins and gene regulation.

6. Growth – almost all body tissues stimulated to grow •  synthesis of chondroitin and collagen •  skeletal growth •  soft tissue growth • Nitrogen metabolism – increased nitrogen retention, amino acid transport into tissues, and incorporation into protein. Urinary retention of nitrogen, potassium, phosphate

7. *Growth Hormone • Physiological actions • Carbohydrate and lipid metabolism – GH appears to promote use of lipids as energy source instead of carbohydrates • GH has a diabetogenic effect in diabetics 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

8. Growth hormone: pathology • HypersecretionÞ • Gigantism in children • Acromegaly in adults • progressive enlargement of head, face, hands, feet, thorax; heat intolerance, sweating, fatigue, lethargy • DeficiencyÞ • Postnatal growth retardation • Congenital • Acquired • Adult GH deficiency • Adult-onset pituitary/hypothalamic disease, surgery, radiation therapy, or trauma

9. 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.

10. Growth Hormone • Clinical applications • Treatment of AIDS – associated wasting • Treatment of adult onset growth hormone deficiency • Turner’s syndrome(a genetic defect in woemen in which there is only one X chromosome) • Anti-aging supplements – OTC(Over the counter) supplements which suggest they contain hGH. Contain amino acids that are supposed to release GH.

11. *Growth Hormone • Problems associated with therapy – possibility of intracranial hypertension and visual changes exist, so fundoscopic 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.

12. 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(Insulin like growth factor).

13. Gonadotropins • Luteinizing hormone (LH, interstitial cell stimulating hormone) • Chemistry – glycoprotein hormone with 2 peptide chains. • Physiological actions • Mechanism of action: Specific G protein-coupled receptors, activation of adenylate cyclase(Gs) Ovary – promotes ovulation and luteinization of ovarian follicles; stimulates synthesis and secretion of estrogen and progesterone from corpus luteum. • Testis – stimulate interstitial (leydig) cells to secrete androgens(Testosterone)

14. 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.

15. 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

16. 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

17. Testis – FSH stimulates production of androgen-binding globulin • maintains high testosterone levels in the seminiferous tubules required for spermatogenesis • stimulate testicular growth • Clinical application – promote & Induce ovulation for treatment of infertility

18. *Adverse effects: • Ovarian stimulation • Multiple births • Ovarian hyper-stimulation syndrome (OHSS) • Increase in vascular permeability Þ rapid fluid accumulation in the peritoneal cavity, thorax, pericardium • Monitor patient closely during and after treatment, when symptoms may peak • If ovaries become abnormally enlarged during gonadotropin treatment, hCG is not administered

19. Gonadotropins: Diagnostic uses • Leydig cell failure - stimulation test with CG • No testosterone response indicates primary failure • Normal testosterone response indicates secondary or tertiary disease

20. Prolactin - PRL • Chemistry – single chain polypeptide hormone • Physiological actions Binds to a specific receptor, similar to GHR Primary target: mammary gland development during pregnancy induces milk protein synthesis initiates and maintains lactation • Lactation – causes growth and development of breasts, and increased synthesis of milk proteins • Decreases release or effectiveness of gonadotropins

21. Hypersecretion – hyperprolactinemia may cause galactorrhea, amenorrhea and infertility. hypoprolactinemia extremely rare. Not used clinically Bromocriptine, pergolide (Permax), and cabergoline (Dostinex) are useful in suppressing PRL secreting tumors. Secretion: inhibited by dopamine

22. Hyperprolactinemia: Inhibits pulsatileGnRH secretion Þhypogonadism Female: luteal phase is shortened Þ anovulation, oligomonorrhea, amenorrhea Male: testosterone synthesis ß spermatogenesis ß Treatment of hyperprolactinemia Transphenoidal microsurgery:Microadenomas - 85% long term remission Macroadenomas - outcome less satisfactory

23. Dopamine agonists for GH or prolactin hypersecretion • Given orally • Adverse effects: • nausea, vomiting, dizziness, postural hypotension • Start at reduced doses to minimize adverse effects • Paradoxical inhibitory effect on GH secretion: • Somatroph adenomas express receptor characteristics of lactotrophs • Most useful for GH hypersecretion when prolactin secretion also is elevated • Cabergoline is more effective than bromocriptine • Normalizes IGF-I in 35% of patients

24. 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.

25. 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.

26. 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.

27. AdrenoCorticotropin hormone, ACTH) • Clinical use • Diagnosis of adrenal insufficiency • Treatment of infantile spasms (epilepsy)

28. 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(post menopausal symptoms), endometriosis, prostate cancer, and central precocious(Well before time) puberty. Experimental use as male contraceptive.

29. Hypothalamic Hormones • Gonadotropin releasing hormone (GnRH or LHRH) antagonists – ganirelix (Antagon) and cetrorelix (Cetrotide) • Used to inhibit premature endogenous LH(FSH) surges during treatment with exogenous menotropins for induction of ovulation. • Also abarelix (Plenaxis) – a GnRH receptor antagonist used to treat advanced prostate cancer. Danger of life-threatening allergic reactions in 4% of patients. • Also used for cryptorchidism(Testis fail to descend in scrotum), hypogonadism, and delayed puberty

30. GnRH: Adverse effects • Long acting agonists induce symptoms of hypogonadism, including detrimental effects on bone mineralization and lipids

31. GnRH: Diagnostic uses Secondary vs. tertiary hypogonadism: Stimulation tests- 100 µg infused i.v. over a period of 15 seconds Plasma LH and FSH measured at 0, 30, 60, and 90 minutes LH should increase 1.3 to 2.6 µg/L FSH response is less marked Long-standing hypothalamic disease and GnRH deficiency may cause lack of LH responsiveness in the absence of pituitary disease; requires prolonged or intermittent stimulation for a valid assessment

32. Somatostatin(somatotropin release-inhibiting factor, SRIF) • Secreted by hypothalamic anterior region and by d cells of the pancreatic islets • Secretion  by GH, IGF-I, thyroid hormones • Synthetic analogue: Octreotide • Properties: • More potent at inhibiting GH secretion than native SRIF • Less potent at inhibiting insulin secretion • Increased half-life: 1.7 hours (SRIF: 1 to 3 minutes) • Resistant to enzymatic degradation- D-Phe, D-Trp • Rebound hypersecretion lower than for SRIF • Sustained-release form recently approved for use

33. Somatostatin and octeriotide Actions: Inhibits GH secretion but not its synthesis Inhibits basal and TRH-stimulated TSH secretion Inhibits secretion of GI peptide hormones: insulin, glucagon, VIP, gastrin, and others Mechanism of action: Gi protein-coupled receptors Reduces cAMP production and Ca2+

34. Clinical uses Acromegaly For excess GH secretion by somatrope adenomas that remains or recurs after irradiation or surgery Does not induce hyperglycemia • Carcinoid tumors • Intestinal tumors, may secrete physiologically active substances (5-HT, prostaglandins, etc.) • Pancreatic cell tumors (VIPomas) • diarrhea, achlorhydria

35. Adverse effects Reduction of bile production, gallbladder contractility  biliary sludge and/or gallstones GI disturbances Pain, nausea, diarrhea

36. Hypothalamic Hormones • Somatostatin(somatotropin Release-Inhibiting Hormone,SRIF) – 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.

37. Vasopressinarginine vasopressin (AVP) antidiuretic hormone (ADH) • Clinical preparations: • synthetic arginine vasopressin (human form) • desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP), synthetic analog with longer duration of action and selective activity for renal effects

38. Vasopressin secretion Stimulated by: Increasing extracellular fluid osmolality Falling blood pressure Decreased extracellular fluid volume without change in osmolality (as in hemorrhage) The renin-angiotensin II system

39. *Vasopressin secretion Other stimulatory factors: acetylcholine cholecystokinin prostaglandins histamine neuropeptide Y dopamine substance P glutamine VIP Inhibitory factors: stress: atrialnatriuretic factor (ANF) pain GABA hypoxia opioid peptides nausea

40. *AVP secretion: Pharmacological agents • Stimulators: • nicotine • epinephrine • vincristine (antimitotic) • cyclophosphamide (antineoplastic agent) • morphine (at high doses) tricyclic antidepressants • imipramine • lithium • Stimulates secretion but inhibits renal response • Inhibitors: • ethanol • glucocorticoids • phenytoin morphine (at low doses) • butorphanol, oxilorphan (K agonists) • antipsychotics • tricyclic phenothiazines • chlorpromazine • butyrophenones haloperidol

41. Vasopressin: Clinical uses Treatment of central Diabetes Insipidus reduced water permeability and polyuria Causes of DI: AVP deficiency Central = neurogenic = pituitary D.I. May be congenital or acquired Impaired renal response to AVP nephrogenic D.I.

42. Vasopressin: Clinical uses Replacement therapy for central DI: Use desmopressin V2 effects much greater than V1 effects 10 µg once or twice a day using aqueous solution as metered nasal spray or 1 to 2 µg once or twice a day s.c.

43. Vasopressin: Clinical uses G.I. Applications Based on V1-mediated contraction of GI smooth muscle: for post-operative ileus and to dispel intestinal gas before abdominal imaging Based on V1-mediated contraction of vascular smooth muscle: for emergency treatment of bleeding esophageal varices (varicose veins) and for acute hemorrhagic gastritis DDAVP is not appropriate for these uses.

44. Vasopressin: Clinical uses Diagnostic: To differentiate central and nephrogenic D.I. Challenge with 1 µg desmopressin s.c., i.m., or i.v. following water deprivation One hour after treatment, urine osmolality should increase > 50 % if cause is AVP deficiency

45. Vasopressin: Adverse effects Primarily a result of unwanted V1 effects: constriction of blood vessels coronary vessels stimulation of GI muscle Cross-reaction with the oxytocin receptor stimulation of uterine muscle Adverse effects rare: V2-mediated effects at lower doses than V1-mediated effects

46. Syndrome of Inappropriate ADH Secretion (SIADH) Impaired water excretion in the presence of hyponatremia and hypoosmolality Hypotonicity may produce lethargy, anorexia, nausea and vomiting, muscle cramps; may eventually lead to coma, convulsions, and death From inappropriately high secretion of AVP/ADH Ectopic malignant neoplasms CNS trauma and infections Endocrine disease Drug interaction

47. Syndrome of Inappropriate ADH Secretion (SIADH) Treatment: water restriction i.v. hypertonic saline loop diuretics such as furosemide demeclocycline, 1 to 2 g/day orally reduces renal sensitivity to AVP nephrotoxic: monitor renal function

48. Oxytocin Differs from AVP in only two amino acids Synthetic oxytocin is used clinically By hypothalamic oxytocinergic neurons In response to neural stimulation Parturition (distention of the cervix and vagina) Suckling Stimulated by plasma hypertonicity, hemorrhage

49. Action and mechanism of action Specific G protein-coupled receptors  frequency and force of uterine smooth muscle contraction during parturition  contraction of mammary myoepithelial cells and milk ejection Half-life: 5 to 12 minutes • OT receptor binding • ß • phospholipase C • ß • IP3, Ca2+ • ß • contraction of uterine smooth muscle and mammary myoepithelial cells

50. Oxytocin: Clinical uses Induction of term labor: drug of choice Infused as dilute solution at 10 mU/mL Begin at a rate of 1 mU/minute Increase gradually to 4 mU/minute Maintain for 1 hour before increasing rate Monitor uterine activity, fetal heart rate Adverse effects Uterine rupture Trauma or death to the infant Risks minimized by conservative protocol