1. 1 PITUITARY & THYROID HORMONES

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3. 3 Neuroendocrine system is mainly controlled by pituitary and hypothalamus, which coordinates many of the body functions by transmitting the messages to the individual cells and tissues. Neuroendocrine system is mainly controlled by pituitary and hypothalamus, which coordinates many of the body functions by transmitting the messages to the individual cells and tissues.

4. 4 1 Thyrotropin-realising hormone – is to control the release of TSH from the is to control the release of TSH from the adenohypophysis. adenohypophysis. 2 Gonadotropin-releasing hormone – to control gonadotropin secretion to control gonadotropin secretion 3 Corticotropin releasing hormone – to control ACTH secretion to control ACTH secretion 4 Growth hormone releasing hormone -major role is to control GH release

5. 5 ANTERIOR Pituitary Gland Six hormones Six hormones TSH- Thyroid stimulating hormone TSH- Thyroid stimulating hormone ACTH-Adreno corticotrophin hormone ACTH-Adreno corticotrophin hormone LH - Luteinizing hormone LH - Luteinizing hormone FSH- follicle stimulating hormone FSH- follicle stimulating hormone PROLACTIN PROLACTIN GH- growth hormone GH- growth hormone

6. 6 POSTERIOR PITUITARY HORMONES – Oxytocin, vasopressin. POSTERIOR PITUITARY HORMONES – Oxytocin, vasopressin. Hormones secreted by the hypothalamus and pituitary are all peptides Hormones secreted by the hypothalamus and pituitary are all peptides Hormones of the anterior and posterior pituitary are administered either IM, SC or intranasally but not orally Hormones of the anterior and posterior pituitary are administered either IM, SC or intranasally but not orally

7. 7 Growth hormone(somatotropin, somatrem) Released by the ant. Pituitary following stimulation by GHRH of the hypothalamus Released by the ant. Pituitary following stimulation by GHRH of the hypothalamus GH is released in a pulsatile manner, with the highest levels occurring during sleep GH is released in a pulsatile manner, with the highest levels occurring during sleep It is inhibited by the hormone somatostatin It is inhibited by the hormone somatostatin It mediates it action directly at its target tissues, as well as others through somatomedins (IGF-I, IGF-II) It mediates it action directly at its target tissues, as well as others through somatomedins (IGF-I, IGF-II)

8. pharmacokinetics Plasma half life: 20-25 minutes Plasma half life: 20-25 minutes Clearance: hepatic Clearance: hepatic Administration: Mostly I.M Administration: Mostly I.M 8

9. THERAPEUTIC USES Somatotropin is used to treat growth deficiency in children (pituitary dwarfism), osteoporosis Somatotropin is used to treat growth deficiency in children (pituitary dwarfism), osteoporosis Somatotropin and somatrem should not be used in individuals with closed epiphysis or an enlarging intracranial mass. Somatotropin and somatrem should not be used in individuals with closed epiphysis or an enlarging intracranial mass. 9

10. 10 Somatostatin -Growth hormone- inhibiting hormone It suppresses GH and TSH release It suppresses GH and TSH release half-life-- 1-3 minutes half-life-- 1-3 minutes Has limited clinical use Has limited clinical use Ocreotide the synthetic analog of somatostatin has a longer half-life than the natural compound. Ocreotide the synthetic analog of somatostatin has a longer half-life than the natural compound.

11. Therapeutic uses of Ocreotide Treatment of acromegaly Treatment of acromegaly Treatment of secretory diarrhea associated with tumors producing vasoactive intestinal peptide Treatment of secretory diarrhea associated with tumors producing vasoactive intestinal peptide Treatment of acute esophageal variceal bleeding Treatment of acute esophageal variceal bleeding Carcinoid syndrome Carcinoid syndrome Side effects: flatulence, nausea, steatorrhea and gall stone formation Side effects: flatulence, nausea, steatorrhea and gall stone formation 11

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13. pegvisomant Treatment of acromegaly that is refractory to other modes of surgical, radiologic or pharmacologic intervention Treatment of acromegaly that is refractory to other modes of surgical, radiologic or pharmacologic intervention 13

14. Adrenocorticotropic hormone(corticotropin) CRH is responsible for the synthesis and release of ACTH causing the synthesis of adrenocorticosteroids and adrenal androgens CRH is responsible for the synthesis and release of ACTH causing the synthesis of adrenocorticosteroids and adrenal androgens CRH is used to diagnostically differentiate between cushing’s disease and ectopic ACTH – producing cells CRH is used to diagnostically differentiate between cushing’s disease and ectopic ACTH – producing cells ACTH is released from the pituitary in pulses with the highest being around 6am, and lowest in the evening ACTH is released from the pituitary in pulses with the highest being around 6am, and lowest in the evening Synthetic form of ACTH--cosyntropin Synthetic form of ACTH--cosyntropin

15. 15 Adrenocorticotropin, ACTH SYNTHETIC - COSYNTROPIN Clinical Use: To differentiate between primary(↑ACTH) and secondary adrenal insufficiency( ↓ACTH) To differentiate between primary(↑ACTH) and secondary adrenal insufficiency( ↓ACTH) following cosyntropin: following cosyntropin: In primary adrenal insufficiency: no change in cortisol levels (i.e., still reduced) In primary adrenal insufficiency: no change in cortisol levels (i.e., still reduced) In secondary adrenal insufficiency: ↑cortisol levels In secondary adrenal insufficiency: ↑cortisol levels Therefore cosyntropin is used for diagnosis of adrenal insufficiency as well as treatment of infantile spasm Therefore cosyntropin is used for diagnosis of adrenal insufficiency as well as treatment of infantile spasm

16. Gonadotropin releasing hormones (GnRH) Also called Gonadorelins Also called Gonadorelins Pulsatile secretion is important for the release of gonadotropins (FSH, LH) from the pituitary. Pulsatile secretion is important for the release of gonadotropins (FSH, LH) from the pituitary. Continuous administration inhibits gonadotropin release. Continuous administration inhibits gonadotropin release. 16

17. Synthetic forms of gonadorelins Leuprolide Leuprolide Nafarelin Nafarelin Buserelin Buserelin Goserelin Goserelin Histrelin Histrelin 17

18. 18 ROUTE : I V, I M, S C, NASAL ROUTE : I V, I M, S C, NASAL Pulsatile IV administration Pulsatile IV administration FSH & LH secretion stimulation FSH & LH secretion stimulation Continuous GnRH administration Continuous GnRH administration Inhibition of Gonadotropin release Inhibition of Gonadotropin release

19. 19 Therapeutic Applications: GnRH Stimulation: pulsatile admin. To treat Infertility and hypogonadism in males and females To treat Infertility and hypogonadism in males and females Inhibition: Continuous admin. Prostate cancer, Prostate cancer, Uterine fibroids, Endometriosis Uterine fibroids, Endometriosis Precocious puberty Precocious puberty

20. 20 adverse effects: GnRH adverse effects: GnRH Dermatitis, hypersensitivity and headache. Dermatitis, hypersensitivity and headache. In women: hot flushes, sweating, diminished libido, depression and ovarian cyst In women: hot flushes, sweating, diminished libido, depression and ovarian cyst In men: bone pain, edema, gynecomastia and diminished libido In men: bone pain, edema, gynecomastia and diminished libido Contraindicated in pregnancy and breastfeeding. Contraindicated in pregnancy and breastfeeding.

21. 21 Gonadotropins Gonadotropins hMG - - Menotropins hMG - - Menotropins FSH -- Urofollitropin FSH -- Urofollitropin hCG – LH agonist hCG – LH agonist LH LH

22. Therapeutic uses of gonadotropins Infertility in men and women Infertility in men and women 22

23. 23 Toxicity: Gonadotropins Toxicity: Gonadotropins Hyperstimulation syndrome Hyperstimulation syndrome Ovarian Hyper Stimulation syndrome (OHSS) Ovarian Hyper Stimulation syndrome (OHSS) hMG -induced ovarian enlargement hMG -induced ovarian enlargement Hemoperitoneum (secondary to ruptured ovarian cyst) Hemoperitoneum (secondary to ruptured ovarian cyst) Arterial thromboembolism Arterial thromboembolism Multiple births Multiple births In men: gynecomastia In men: gynecomastia

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25. prolactin Similar in structure to GH Similar in structure to GH Secreted by the ant. Pituitary whose secretion is inhibited by dopamine and stimulated by TRH Secreted by the ant. Pituitary whose secretion is inhibited by dopamine and stimulated by TRH FUNCTION: to stimulate and maintain lactation FUNCTION: to stimulate and maintain lactation Decreases sexual drive and reproductive function Decreases sexual drive and reproductive function 25

26. 26 Prolactin Abnormal prolactin levels: Deficiency: hypoProlactinemia--Manifestations: Deficiency: hypoProlactinemia--Manifestations: lactation failure lactation failure Excess: hyperProlactinemia Galactorrhea Galactorrhea Hypogonadism Hypogonadism Amenorrhea Amenorrhea

27. 27 Bromocriptine and cabergoline - Dopamine Agonists Actions Dopamine-like action Dopamine-like action Used to treat hyperprolactinemic states Used to treat hyperprolactinemic states as well as microadenomas and macroprolactinomas as well as microadenomas and macroprolactinomas

28. 28 Side effects GI side effects: constipation, dyspepsia, symptoms of reflux esophagitis constipation, dyspepsia, symptoms of reflux esophagitis peptic ulceration with bleeding peptic ulceration with bleeding Psychiatric problems Psychiatric problemsCVS: Common: postural/orthostatic hypotension Common: postural/orthostatic hypotension Arrhythmias Arrhythmias

29. Posterior pituitary hormones Release of these hormones are not regulated by the releasing hormones of the hypothalamus Release of these hormones are not regulated by the releasing hormones of the hypothalamus Are instead synthesized in the hypothalamus and stored in the post. Pituitary till when needed in response to signals such as Are instead synthesized in the hypothalamus and stored in the post. Pituitary till when needed in response to signals such as High urine osmolality or parturition. High urine osmolality or parturition. 29

30. 30 Posterior Pituitary Hormone Oxytocin : Uses : stimulate uterine contraction to induce labor Uses : stimulate uterine contraction to induce labor Milk ejection Milk ejection SE: HTN crisis, Uterine rupture Uterine rupture Fetal death Fetal death CI: premature delivery, Abnormal fetal presentation, fetal distress Abnormal fetal presentation, fetal distress

31. 31 Vasopressin Actions : has both antidiuretic and well as vasopressor effects V 1 recep – found in the liver and vascular smooth muscle (vasoconstriction) V 1 recep – found in the liver and vascular smooth muscle (vasoconstriction) V 2 recep – renal system, water reabsop. V 2 recep – renal system, water reabsop. SE: Water intoxication, hyponatremia, headache, tremor. Care : CAD, asthma, epilepsy. Uses: Diabetes insipidus Diabetes insipidus Nocturnal enuresis Nocturnal enuresis To control bleeding due to esophageal varices and colonic diverticular To control bleeding due to esophageal varices and colonic diverticular

32. desmopressin Synthetic form of vasopressin Synthetic form of vasopressin Has minimal to no activity on V1 receptor resulting in minimal to no pressor effect Has minimal to no activity on V1 receptor resulting in minimal to no pressor effect It is now preferred for diabetes insipidus and nocturnal enuresis It is now preferred for diabetes insipidus and nocturnal enuresis Treatment of Von-Willibrand Disease Treatment of Von-Willibrand Disease Longer acting than vasopressin Longer acting than vasopressin Administered intranasally Administered intranasally 32

33. Thyroid hormones Secreted by the thyroid gland Secreted by the thyroid gland Facilitates normal growth and maturation in tissues that needs it for their normal function Facilitates normal growth and maturation in tissues that needs it for their normal function Secretes Two major thyroid hormones: T3 and T ₄ but can also secrete calcitonin Secretes Two major thyroid hormones: T3 and T ₄ but can also secrete calcitonin Not essential for life, but under and over secretion could result in disease state Not essential for life, but under and over secretion could result in disease state 33

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35. Symptoms of hypothyroidism Bradycardia Bradycardia Poor resistance to cold Poor resistance to cold Mental and physical slowing Mental and physical slowing In children can result in dwarfism and mental retardation In children can result in dwarfism and mental retardation Menstrual irregularities Menstrual irregularities Weigh gain despite decreased intake Weigh gain despite decreased intake Diagnosed by an ↑TSH & ↓T3, T4 Diagnosed by an ↑TSH & ↓T3, T4 35

36. Symptoms of hyperthyroidism Tachycardia Tachycardia Arrhythmias Arrhythmias Body wasting despite adequate intake Body wasting despite adequate intake Nervousness Nervousness Tremors Tremors Intolerance to heat Intolerance to heat Exolphthalmus Exolphthalmus Diagnosed by a ↓TSH & ↑ T3, T4 Diagnosed by a ↓TSH & ↑ T3, T4 36

37. pharmacokinetics T3 & T4 given orally T3 & T4 given orally IV-myxedema IV-myxedema T3 – the most active form T3 – the most active form Food, calcium preparations and aluminum antacids can decrease absorption of T4 but not T3 Food, calcium preparations and aluminum antacids can decrease absorption of T4 but not T3 Are metabolized via through microsomal P450 system. Are metabolized via through microsomal P450 system. Therefore inducers of P450 accelerates the metabolism of thyroid hormones. Therefore inducers of P450 accelerates the metabolism of thyroid hormones. 37

38. Treatment of hypothyroidism LEVOTHYROXINE, LIOTHYRONINE LEVOTHYROXINE, LIOTHYRONINE Given once daily Given once daily Toxicity manifests as: symptoms of hyperthyroidism. Toxicity manifests as: symptoms of hyperthyroidism. 38

39. Treatment of hyperthyroidism (thyrotoxicosis) Goal : Goal : Removing part or all of the thyroid gland Removing part or all of the thyroid gland Inhibiting synthesis of hormones Inhibiting synthesis of hormones Blocking release of hormones from the follicles Blocking release of hormones from the follicles 39

40. surgery Removal of part or all of the thyroid: done surgically or by destruction of the gland by radioactive iodine Removal of part or all of the thyroid: done surgically or by destruction of the gland by radioactive iodine 40

41. 41 Antithyroid Drugs Thioamides Thioamides Iodides Iodides Radioactive iodine Radioactive iodine Anion inhibitor Anion inhibitor

42. 42 Thioamides pharmacokinetics Propylthiouracil Propylthiouracil Methimazole Methimazole Carbimazole Carbimazole Both Crosses placenta but PTU is safer in pregnancy Both Crosses placenta but PTU is safer in pregnancy

43. Inhibition of thyroid hormone synthesis: using thioamides such as propylthiouracil (PTU)and methimazole Inhibition of thyroid hormone synthesis: using thioamides such as propylthiouracil (PTU)and methimazole PTU & methimazole inhibits the oxidation(peroxidase), iodination and coupling (condensation)step of tyrosine synthesis PTU & methimazole inhibits the oxidation(peroxidase), iodination and coupling (condensation)step of tyrosine synthesis PTU & propanolol can also block deiodinase in the conversion of T4 to T 3 PTU & propanolol can also block deiodinase in the conversion of T4 to T 3 43

44. SIDE EFFECTS OF THIOAMIDES Agranulocytosis: ↓neutrophil count(<500) Agranulocytosis: ↓neutrophil count(<500) Rash Rash edema edema 44

45. Iodide Used for treatment hyperthyroidism Used for treatment hyperthyroidism MOA: blocks the iodination of tyrosine as well as the release of the hormones into the blood MOA: blocks the iodination of tyrosine as well as the release of the hormones into the blood Used prior to surgery to decrease the vascularity of the gland Used prior to surgery to decrease the vascularity of the gland Not useful for long term therapy because thyroid gland ceases to respond after a few weeks Not useful for long term therapy because thyroid gland ceases to respond after a few weeks SE: sore mouth and throat, rashes, metallic taste in mouth SE: sore mouth and throat, rashes, metallic taste in mouth 45

46. 46 Anion Inhibitors Competitive inhibition: Competitive inhibition: Perchlorate Perchlorate Pertechnetate Pertechnetate Thiocyanate Thiocyanate Inhibits iodide uptake by thyroid Inhibits iodide uptake by thyroid

47. Thyroid storm A rare but severe complication of untreated hyperthyroidism in which the thyroid gland secretes excess thyroid hormones resulting widespread sympathetic symptoms A rare but severe complication of untreated hyperthyroidism in which the thyroid gland secretes excess thyroid hormones resulting widespread sympathetic symptoms Treatment: β-blockers such as propanolol Treatment: β-blockers such as propanolol Calcium channel blockers, diltiazem in pts suffering from severe heart failure and asthma Calcium channel blockers, diltiazem in pts suffering from severe heart failure and asthma 47