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Hypothalamic Pituitary Hormones

Hypothalamic Pituitary Hormones. Dept. of Pharmacology, CIPS. The hypothalamic - pituitary axis:

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Hypothalamic Pituitary Hormones

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  1. Hypothalamic PituitaryHormones Dept. of Pharmacology, CIPS

  2. The hypothalamic - pituitary axis: • The pituitary is connected to the hypothalamus by a stalk (the infundibulum) which carries axons to the neurohypophysis (posterior pituitary) as well as blood vessels to the adenohypophysis (anterior pituitary). • Most feedback loops run through this axis • HPA mediates Growth, Metabolism, Stress response, Reproduction.

  3. The Hypophyseal Portal System

  4. Characteristics of Hypothalamic releasing and inhibiting hormones • Hypothalamic releasing and inhibiting hormones are carried directly ONLY to the anterior pituitary gland via hypothalamic hypophyseal portal veins. • Secretion is pulsatile • They have short half lives so their actions on the pituitary are of short duration. • Their actions are limited by negative feedback mechanisms. • They stimulate release of anterior pituitary hormones. • They stimulate synthesis of anterior pituitary hormones. • They stimulate hyperplasia and hypertrophy of target cells.

  5. Hypothalamic Neurohormones Seven neurohormones are made in the hypothalamus • Thyrotropin-releasing hormone (TRH) • Corticotropin-releasing hormone (CRH) • Gonadotropin-releasing hormone (GnRH) • Growth hormone-releasing hormone (GHRH) • Growth hormone-release inhibiting hormone (GHIH) or somatostatin • Prolactin-releasing factor (PRF) • Prolactin-inhibiting hormone (PIH)

  6. Negative Feedback Inhibition Hormone Homeostasis- Maintenance of hormone levels within a particular physiological range

  7. Anterior Pituitary

  8. Control of Anterior Pituitary • It has no neural connection with the hypothalamus • There is a capillary plexus in the hypothalamus • It gives rise to the Hypothalamo-hypophyseal portal system • Neurohormones from hypothalamus pass through this portal system to stimulate or inhibit the anterior pituitary Control of Posterior Pituitary • Neurons arising in : • Paraventricular nucleus • Supraoptic nucleus • Sends neurons down pituitary stalk (infundibulum) • They synapase with capillaries in the posterior pituitary • Secrete the neurohormonesOxytocin and vasopressin A • Directly into the blood stream

  9. Posterior Pituitary

  10. Anterior pituitary hormones: • SomatotropicHormones: 1- Growth Hormone (GH). 2- Prolactin (Prl). 3- Placental Lactogen (PL). • Glycoprotein Hormones: 1- Luteinizing Hormone (LH). 2- Follicle-Stimulating Hormone (FSH). 3- ChrionicGonadotropin (CG). 4- Thyroid-Stimulating Hormone (TSH). • Pro-Opiomelanocortin(POMC) derived Hormones: 1- Corticotropin: ACTH. 2- Melanocyte-Stimulating Hormones: a-MSH, b-MSH. 3- Lipotropins: b-LPH, -LPH

  11. Growth Hormone-Releasing Hormone (GHRH) • 44 amino acid peptide • Full biological activity in 1-29 • Structural homologies to GI peptide hormones • Function • Stimulates synthesis and release of growth hormone (GH) from the anterior pituitary • Research purposes only • IV, SubQor intra-nasally. • IV half life is 4 minutes Growth Hormone-Releasing peptides (GHRPS) • Group of synthetic peptide analogues that can stimulate GH secretion • Sermorelin {Geref} --Used as diagnostic agent. • Must have properly functioning pituitary.

  12. Somatostatin (GHIH) • Structure- 14- or 28-amino acid structure • Function • Inhibits growth hormone release in normal individuals, thus opposes GHRH • Inhibits the release of glucagon, insulin TSH, LH and gastrin (GI hormones) • Lowers the rate of gastic empting and reduces smooth muscle contractions and decreases blood flow of the intestine • Half life 1-3 minutes • Kidney is key in metabolism and elimination SOMATOSTATIN (SS) ANALOGUES Drug Type Dosing Octreotide Short-acting SC 3 times/day; dose range of 50-500 mg Octreotide LAR Long-acting IM every 28 days; dose range of 10-40 mg Lanreotide depot Long-acting IM every 7-14 days,30 mg. Lanreotideautogel Long-acting Deep SC every 28 days, supplied in prefilled syringes containing 60/90/120 mg

  13. Octreotide (SANDOSTATIN) • Somatostatin analogue. • 8 amino acid derivative of somatostatin that preferentially binds to SS receptors on GH-secreting tumors. • Inhibits release of GH from pituitary • Pharmacokinetics • Half life of 80 minutes • Administered SC or IM. • 45x more potent than endogenous peptide • Therapeutic use • Treatment of a variety of hormone-secreting tumors • Acromegaly • Adverse reactions • Biliary tract abnormalities • Gallstones, sludge without stones, biliary duct dilation • Bradycardia, nausea, vomiting, abdominal cramps, flatulence

  14. Induces lipolysis in adipose tissue and growth in skeletal muscle • Binding to its receptor (direct) • Adipose tissue stimulated to break down triglyceride and stops the uptake of circulating lipids • Insulin-like growth factor-1 (indirect) • Stimulates the liver to release IGF-1 target tissues>produces growth at open epiphyses • Lanreotide (SOMATULINE-LA) slow release, long-acting octapeptide causes • prolonged GH suppression. Most effective for patients with non-pituitary tumours

  15. Growth Hormone (GH): • Structure: It is a single polypeptide chain composed of 191 amino acid residues. It has two disulfide bonds. • Secretion: Somatotropes of the Anterior Pituitary. • Level: High in children Maximal during adolescence Lowest during adulthood. • Measurments: During 24 hours After stimulation • Regulation: Stimulation: By Growth Hormone Releasing Hormone (GHRH). Inhibition: By Somatostatin. • Direct Effects: 1- Stimulation of Lipolyses (Hydrolyses of Triglycerides). 2- Stimulation of Hepatic glucose output. 3- Production of Insulin-like growth factors (IGF’s, Somatomedins) • Indirect Effects: Mediated by IGF-1: 1- Increase cell numbers. 2- Positive Nitrogen balance. 3- Increase Protein synthesis.

  16. Disease Conditions Related to GH: • Deficiency: * Dwarfism. • Excessive Secretion: * Giantism: Due to tumor in somatotrpes in young children or adolescents. * Acromegaly: Rare disease (3/Million). Causes: 1- Benign tumor of Pituitary gland (90%). 2- Tumors of pancreas, lung or adrenal Symptoms: Enlargements of extremities. • Uses of Growth Hormone: * Replacement therapy for children with GH deficiency. * Administered by intramuscular or subcutaneous. • Sources: * Recombinant DNA technology.

  17. Treatment of GH insufficiency (all SC or IM) : • GH SUPPLEMENTATION • Somatropins GH preparations whose sequence matches native hGH. • Somatrem: GH derivative with an additional methionine at the amino terminus. • For Children • To mimic the normal pattern of secretion, they typically are administered to GH-deficient children in a dose of 40 mg/kg per day subcutaneously in the evening; • Higher daily doses (e.g., 50 mg/kg) are employed for patients with Turner's syndrome, who have partial GH resistance. • In children with overt GH deficiency, measurements of serum IGF-1 levels are used to monitor initial response and compliance; long-term response is monitored by close evaluation of height • For adults, • the FDA recommends a starting dose of 3 to 4 mg/kg, given once daily by subcutaneous injection, with a maximum dose of 25 mg/kg in patients £35 years old and 12.5 mg/kg in older patients.

  18. Side Effects of GH Therapy: • In children: • GH therapy is associated with remarkably few side effects. • Rarely, intracranial hypertension,visual changes, headache, nausea, and/or vomiting. • Leukemia has been reported in some children receiving GH therapy; and conditions associated with GH deficiency (e.g., Down's syndrome, cranial irradiation for CNS tumors) probably explain the apparent increased incidence of leukemia. • An increased incidence of type 2 diabetes mellitus has been reported. • In adults • Side effects associated with the initiation of GH therapy include Peripheral edema, carpal tunnel syndrome, arthralgia, and myalgia. • These symptoms, which occur most frequently in patients who are older or more obese, generally respond to a decrease in dose.

  19. IGF-1 THERAPY For Pts with GH Receptor mutation Mecasermin: complex of recombinant human IGF-1 (rhIGF-1) and recombinant human insulin-like growth factor-binding protein-3 (rhIGFBP-3). Clinical response is monitored Serum IGF-1 levels. Treatment of Acromegaly: Trans-sphenoidal surgery to remove tumor. Radiation therapy usually follow the surgery. Drug Therapy: 1- Dopaminergic Agonists: Bromocriptine 2- Synthetic Somatostatin analogs: Octeroide (Sandostatin).

  20. Growth Hormone Receptor Antagonist: • Binds to GH receptors, blocks GH-stimulated, hepatic production of IGF-1 • Pegvisomant {Somavert} • Injection,SC. • Treatment of • Acromegaly • Increased growth hormone in adults • Adverse reactions • Pain/redness/itching at the injection site, diarrhea, or nausea may occur. • Liver toxicity, yellowing of the skin, abdominal pain, dark urine, vomiting • Allergic reactions • CI • Liver disease

  21. Prolactin: • 198 amino acid peptide with three disulfide bonds • Lactation • Recombinant agents not available • Hypothalamic dopamine inhibits the secretion and release of prolactin . • Major function of prolactin is milk production – oxytocin stimulates ejection • Release is tonically inhibited by PIH (dopamine) • Suckling response inhibits PIH release Other Physiological Roles of Prolactin: • important for reproduction • female – produced in uterine • endometrium during menstrual cycle • male – absence decreases fertility • involved in immune system • involved in T lymphocyte differentiation

  22. Hyperprolactinemia • Galactorrhea • Amenorrhea • Male impotence • Associated with autoimmune diseases: multiple sclerosis, lupus • Dopamine Agonists: • Decrease prolactin secretion through a dopamine-mimic action • Bromocriptine –D2 receptor agonist,D1 anta. • Pergolide • Cabergoline • Quinagolide –Non ergot dopamine agonist. • Oral administration • Treatment of • Prolactin secreting adenomas • Acromegaly • Parkinson’s disease • Adverse reactions • Headache, light headedness, fatigue, Psychotic reactions

  23. Glycoprotein hormones: • LH, FSH, TSH and hCG • a and b subunits • Each subunit encoded by different gene • a subunit is identical for all hormones • b subunit are unique and provide biological specificity Gonadotropin-Releasing Hormone • PulsatileGnRH secretion stimulates the gonadotroph cells in the anterior pituitary to produce and release LH & FSH • Sustained non-pulsatile administration inhibits the release of FSH and LH by the pituitary in both males and females

  24. Gonadorelin {Factrel}: • Synthetic GnRH - Small peptide • Diagnostic purpose only • Portable pump system - Male and female infertility • Administered SC and IV GnRH Analogs: • Synthesized by selective substitution of amino acids • Leuprolide {Eligrad} • Highly effective at decreasing estrogen levels • Given IM/SC. • Nafarelin {Synrel} • Nasal spray • Goserelin{Zoladex} • Implantable cylinders Histrelin,Triptorelin.

  25. Treatment of • Endometriosis and Uterine fibroids • Breast cancer • Prostate cancer • Central precocious puberty • Male and female infertility • Adverse reactions • Hot flashes, acne, depression, vaginal bleeding • Tachycardia, lightheadedness, ED • GnRH Antagonist • Binds to pituitary GnRH receptors without activation • Blocks secretion and release of LH and at high doses FSH • Immediate suppression of LH • Ganirelix{Antagon} • Cetrorelix{Cetrotide}

  26. Treatment of • In vitro fertilization • Endometriosis and uterine fibroids • Advantage • Decrease risk of LH surge • Injectables SC. • Adverse reactions • Nausea • HRs. • Vaginal bleeding Follicle Stimulating Hormone: • Glycoprotein hormone consisting of two chains • Produced by gonadotroph cells in the anterior pituitary • Stimulates gametogenesis and follicular development in women and spermatogenesis in males • Stimulates androgen conversion into estrogen

  27. Menotropin {Humegon}: • Commercially available since 1960s • human Menopausal Gonadotropins (hMG) • Purified from urine of post-menopausal females • Combination of FSH and LH • MENOPAUSE happens when no follicles remain in the ovaries • ESTROGEN and PROGESTERONE are no longer made, thus leading to high levels of circulating FSH and LH Urofollitropin {Bravelle} • Purified FSH • Derived from post-menopausal females Follitropin Beta {Follistim} • 1996, recombinant technology • Batch to batch consistency, and highly pure • Cost 3x as much as hMG • Injectables, SC. • Treatment: Anovulatory females; Pituitary and hypothalamic hypogonadism with infertility

  28. Adverse reactions • Abdominal pain, vaginal bleeding, ovarian cysts • Injection site pain, rash • Risk of multiple births Luteinizing Hormone • Glycoprotein consisting of two chains • Regulation of gonadal steroid production • No LH clinically available • human Chorionic Gonadotropin (hCG) • IM injection • Half life of 8 hours Human Chorionic Gonadotropin (hCG): • Diagnostic use • Treatment of infertility • Induce ovulation • Adverse reactions • Headache • Depression

  29. ACTHACTH is made up of 39 amino acids • Regulates adrenal cortex and synthesis of adrenocorticosteroids • a-MSH resides in first 13 AA of ACTH • a-MSH stimulates melanocytes and can darken skin • Overproduction of ACTH may accompany increased pigmentation due to a-MSH. Regulation of ACTH: • Stimulation of release • CRH and ADH • Stress • Hypoglycemia • CRH and ADH both synthesized in hypothalamus • ADH is released by posertior pituitary and reaches anterior pituitary via inferior hypophyseal artery.

  30. Corticotropin-Releasing Hormone: • Secreted in response to stress • Stimulates corticotropin cells to produce adrenocorticotropic hormone (ACTH) • Diagnostic use only Thyroid Stimulating Hormone: TSH • Thyrotrophs: Thyroid Stimulating Hormone (TSH) • Hypothalamic Control Thyrotropin Releasing Hormone (TRH) • Target Tissue Follicular cells of the Thyroid gland • Hormone effects: controls the production of T3 and T4

  31. Hormone + Receptor Thyrotropin-Releasing Hormone: • Stimulates secretion of thyroid stimulating hormone (TSH) from the anterior pituitary • Protirelin {Relefact TRH} • Diagnostic purposes only

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