Endocrine lecture HYPOTHALAMUS AND PITUITARY HORMONES 2023.pptx

Endocrine lecture HYPOTHALAMUS

1. Drugs affecting endocrine system . Hypothalamus & Pituitary Hormones. SULAYMAN ADEMOLA Department of Pharmacology MEDICAL SCHOOL,IUIU IUIU

2. BIBLIOGRAPHY Goodman and Gilman ’ s. The pharmacological basis of therapeutics . Basic and Clinical Pharmacology. Bertram G. Katzung . Pharmacology. Rang and Dale ’ s. 6 th edition . Pharmacology. 3 rd edition . Lippincott´s .

3. SUMMARY Introduction to endocrine system . Introduction to Hypothalamus Hormones Anterior pituitary hormones.

4. Major endocrine glands

5. Are recognized six main groups of drugs acting on endocrine system. Some of them are employed in clinical practice like replacement therapy because these types of drugs can act as natural hormone secretion. Others may act stimulating the natural hormonal production, secretion or potentiating their physiological action. But, also are employed in clinical practice a lot of drugs which can act on contrary, by inhibition of natural hormone action in biochemical or physiological level. Introduction

6. The Hypothalamus Small structure at the base of the brain. Regulates many body functions, including appetite and body temperature. Regulates the pituitary gland.

7. What is the endocrine system? The primary endocrine glands are Hypothalamus (the master gland), the pituitary, pineal, thyroid, parathyroid, islets of Langerhans, adrenals, ovaries in the female and testes in the male. The function of the endocrine system is the production and regulation of chemical substances called hormones.

8. Hormones… A hormone is a chemical transmitter. It is released in small amounts from glands, and is transported in the bloodstream to target organs or other cells. Hormones are chemical messengers, transferring information and instructions from one set of cells to another.

9. The Pituitary Gland A sort of master gland. It is a cherry-sized endocrine gland. The hormones it secretes affect the growth and secretion of other endocrine glands. The real boss is the hypothalamus.

10. Interaction between hypothalamus and pituitary (hypothalamic-pituitary axis) Hypothalamus Anterior pituitary Endocrine Glands ORGANS Releasing Factors Inhibitory Factors This interaction is a feedback control system.

11. Pituitary Hormones Neurohypophysis Adenohypophysis Hypothalamic neuron cells Bone Growth Hormone (GH) Adrenocorticotropic Hormone (ACTH) Adrenal cortex Ovary Thyroid gland Mammary glands Testicle Thyroid stimulating hormone (TSH ) Gonadotropic Hormones (LH & FSH) Prolactin Uterine muscle Antidiuretic Hormone (ADH) Mammary glands Renal tubules Oxytocin Skin Melanocyte stimulating hormone

12. ANTERIOR PITUITARY HORMONES

13. Anterior Pituitary Derived during embryological development from the roof of the mouth. Most of the hormones are released from the anterior pituitary. Hormones released from the anterior pituitary are dormant unless directed to be released by the hypothalamus via Releasing Factors. They are: Growth hormone (GH), Luteinizing hormone (LH), Follicle stimulating hormone (FSH), Prolactin (PRL), Adrenocorticotropic hormone (ACTH), Thyroid stimulating hormone (TSH).

14. Hypothalamic Hormones: Gondotropin RF Corticotropin RF (CRF) Thyrotropin RF Growth Hor RF Pituitary Hormones : Follicle SH & Lutenizing Hor. Thyrotropin SH Adrenocorticoptropic Hormone (ACTH) Prolactin Growth Hormone Target Gland or Structure: Ovaries & Testes (androgens, estrogen) Adrenal Gland (cortisol) Cells of body Thyroid Gland (thyroxine) Bones, breasts & cells of body

15. Anterior Pituitary hormones & their Receptors They are classified according to their structure and the types of receptors that they activate: GH & prolactin are single-chain protein hormones with significant homology. Both hormones activate receptors of the JAK/STAT superfamily ( Janus kinase family of intracellular tyrosine kinases and the Signal Transducer and Activator of Transcription family of nuclear transcription factors). TSH, FSH & LH are dimeric proteins that activate G protein-coupled receptors. They share a common chain. Their chains, though somewhat similar to each other, differ enough to confer receptor specificity. ACTH is a single peptide that is cleaved from a larger precursor that also contains the peptide endorphin. It acts through a G protein-coupled receptor.

16. GROWTH HORMONE (GH) It is a peptide hormone with 191-amino acids. Structurally similar to prolactin and chorionic somatomammotropin. GH stimulates somatic growth and regulates metabolism. Growth hormone–releasing hormone (GHRH) is its major stimulator. Somatostatin is the major inhibitor of its synthesis and release.

17. GROWTH HORMONE (GH) GH controls synthesis of insulin-like growth factor 1 (IGF-1, also called somatomedin-C), which largely controls growth. Although IGF-1 is produced by many tissues, the liver is the major source. A variant of IGF-1 occurs in muscle, where it plays a role in enhancing muscle strength. It is less under control of GH than is the liver variant.

18. GH- Pharmacological effects The metabolic effects of GH are biphasic. Initially exerts insulin-like effects, increasing glucose uptake in muscle and fat, stimulating amino acid uptake and protein synthesis in liver and muscle, and inhibiting lipolysis in adipose tissue. Several hours later, more profound anti–insulin-like metabolic effects occur: Inhibition of glucose uptake and use, causing blood glucose and lipolysis to increase, which increases plasma free fatty acids.

19. GH- Pharmacological effects cont. Promotes longitudinal growth indirectly through: Somatomedins (IGFs). ­GH stimulates growth plate cartilage & liver synthesis of: IGF-I & IGF-II Somatomedins are mediators of processes promoting bone growth: ­cellular proliferation, ­increased proline to hydroxyproline conversion (cartilage synthesis). GH deficiency Reduced somatomedin Short stature

20. Indirect effects skeletal growth  cell proliferation protein anabolism Direct effects  lipolysis   fat utilization  blood sugar (anti-insulin effect) GH- Summary of Pharmacological effects

21. GH as Juvenile Gigantism

22. GH as an Adult Acromegaly

23. Acromegaly

24. GH = Pituitary dwarfism

25. GH- Pharmacokinetics Endogenous GH has a half-life of 20-25 min and is predominantly cleared by the liver. Recombinant human GH (rhGH) is administered SC 3-6 times per week. Peak levels occur in 2-4 hrs and active blood levels persist for approximately 36 hrs. Somatropin injectable suspension is a long-acting preparation of rhGH enclosed within microspheres. These microspheres degrade slowly after SC injection such that the rhGH is released over about 1 month.

26. GH- Uses Growth failure in pediatric patients associated with: GH deficiency. Turner ’ s syndrome (chromosomal anomaly in girls). Chronic renal failure. Small for gestational age babies unable to catch up by 2. Prader-Willi syndrome(genetic disease associated with growth failure, obesity & carbohydrate intolerance). Growth hormone deficiency in adults. Wasting in patients with HIV infection (Increased lean body mass, weight, and physical endurance). (?) adult athletes – to increase muscle mass. (?) anti-aging. (?) Idiopathic short stature (Non-GH deficient short stature (NGHDSS) children).

27. GH- Adverse effects Creutzfeldt-Jakob disease (is a brain damage). Children generally tolerate the treatment well: rarely- hypothyroidism, scoliosis, intracranial hypertension. Following rapid growth : - Slipped capital femoral epiphyses: limp; lower extremity pain (rare). In adults : peripheral edema, myalgia, arthralgia, pancreatitis, gynecomastia . Leukemia incidence (slight increase may not be causal). Screening suggested for hypothyroidism & diabetes during GH treatment.

28. GH- Preparations Recombinant forms are used . somatropin (191-amino acid form ). somatrem (192 amino acid form (additional methionine).

29. GH- Antagonists Needed from the tendency of GH-producing cells to form secreting tumors. Pituitary adenomas occur most commonly in adults. Acromegaly adversely affects the skeletal, muscular, CVS, respiratory and metabolic systems. Small GH-secreting adenomas can be treated with GH antagonists. Larger pituitary adenomas are treated with transsphenoidal surgery or radiation. Somatostatin & somatostatin analogs. Bromocriptine - a dopamine receptor agonist reduce the production of GH. Pegvisoman t - prevents GH from activating its receptor.

30. SOMATOSTATIN Major inhibitor of GH synthesis and release. Also inhibits the release of TSH, insulin and glucagon; it decreases the release of most GI hormones and reduces gastric acid and pancreatic secretion. Octreotide and Lanreotide are long-acting analogues of somatostatin, used for the treatment of tumours secreting vasoactive intestinal peptide, carcinoid tumours, glucagonomas and various pituitary adenomas. They has a place in the therapy of acromegaly and of bleeding oesophageal varices.

31. SOMATOSTATIN Generally given SC. Peak action is at 2 hours, Suppressant effect lasts for up to 8 hours. ADR: Pain at the injection site and GI disturbances. Gallstones, postprandial hyperglycaemia and acute hepatitis has occurred in a few cases.

32. GONADOTROPIC HORMONES and Analogues FSH– stimulates gametogenesis. LH– regulates gonadal steroid hormone production. Human chorionic gonadotrophin (hCG): extracted from urine of pregnant women. Contains the biologic activity of LH. It is secreted by t he chorion and placenta. S timulates ovarian corpus luteum to produce progesterone and to maintain placenta. Human menopausal gonadotrophin (hMG): extracted from urine of postmenopausal women. Contains a mixture of LH and FSH.

33. GONADOTROPIC HORMONES Both control the production of the sex hormones. Their synthesis and release are stimulated by GnRH and suppressed by estrogen and testosterone by negative feedback mechanism. Pulsatile GnRH is required to stimulate the gonadotroph cells to produce and release LH & FSH. Sustained, nonpulsatile administration of GnRH or GnRH analogs inhibit the release of FSH & LH by the pituitary in both women and men, resulting in hypogonadism .

34. GONADOTROPIC HORMONES In women, they stimulate ovarian follicular development and ovulation. In men, FSH acts in Sertoli cells and is essential for spermatogenesis; LH acts on Leydig cells of the testes to stimulate testosterone biosynthesis.

35. GONADOTROPIC HORMONES Therapeutic Uses: Female infertility controlled ovarian hyperstimulation in assisted reproductive technology ( ART) such as in vitro fertilization. anovulation Male infertility: oligospermia – hCG + hMG Adverse Effects: Multiple pregnancies (15-20%) Ovarian hyperstimulation (OHSS) (0.5-4%) Headache, Depression, Precocious puberty Edema, Gynecomastia in men

36. GONADOTROPIC HORMONES Preparations hCG (Pregnyl, Profasi, APL ® ) Menotropin (hMG) Urofollitropin (uFSH) rFSH – shorter t 1/2 , more expensive Follitropin  (Gonal-f ® ) Follitropin  ( Puregon ® ) rLH (Lutropin, Luveris ® ) r- recombinant u- urinary

37. Prolactin (PRL) Produced in lactotrophs (constitute about 30% of the cells of the anterior pituitary). The pituitary doubles in size during pregnancy, largely because of hyperplasia and hypertrophy of lactotrophs. In humans, its major function is stimulating milk production when appropriate circulating levels of estrogens, progestins, corticosteroids, and insulin are present. Its release also occurs during sexual activity and stress. It may be a sensitive indicator of pituitary dysfunction; it is the hormone most frequently produced in excess by pituitary tumors and it may be one of the hormones to become deficient from infiltrative disease or tumor compression of the pituitary.

38. Prolactin (PRL) Estrogens increase both prolactin secretion and proliferation of lactotrophs through release, from a subset of lactotrophs, of the neuropeptide galanin. Prolactin production is inhibited by the catecholamine dopamine acting through the D 2 subtype of dopamine receptors. Agonists of Dopamine ( bromocriptine, pergolide, cabergoline, quinagolide ) suppress prolactin release. Bromocriptine and pergolide are antiparkinson drugs. Dopamine antagonists (used mainly as antipsychotic drugs) are potent stimulants of prolactin release ( chlorpromazine, thioridazine, fluphenazine, haloperidol, etc. ).

39. Adrenocorticotropic hormone (ACTH) Also known as corticotropin. Corticotropin-releasing hormone (CRH) is the primary stimulator of its release. ACTH induces the adrenal cortex to release cortisol and several weak androgens, such as dehydroepiandrosterone (DHEA). Circulating cortisol and other corticosteroids (including exogenous corticosteroids) inhibit the release of CRH and ACTH. The CRH-ACTH-cortisol axis is a central component of the response to stress. Without ACTH, the adrenal cortex atrophies and cortisol release virtually ceases.

40. ACTH- Preparations ACTH is available as a synthetic derivative in the forms of cosyntropin (trade name cortrosyn), and synacthen. Both are very rarely used in place of glucocorticoids to treat secondary adrenal insufficiency, but are used primarily to conduct the ACTH stimulation test.

41. Moon face in a patient suffering Cushing ’ s syndrome Signs & symptoms associated with prolonged exposure to inappropriately high levels of hormone cortisol . Can be caused by taking glucocorticoid drugs, or diseases that result in excess cortisol, ACTH or CRH levels.

42. Thyroid hormones Thyrotrophin-releasing hormone (TRH), released from the hypothalamus in response to various stimuli, is the major stimulus for the release of TSH (thyrotrophin) from the anterior pituitary. Thyroid gland releases two different types of hormones: Tetraiodothyronine or Thyroxine (T 4 ) and Triiodothyronine (T 3 ). They have functions in growth, metabolism and the regulation of thyroid function. Calcitonin (involved in the control of plasma Ca 2+ ).

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