HYPOTHALAMIC AND PITUITARY HORMONES [Autosaved].pptx

A brief description of the hormones of the hypothalamus as well as the pituitary gland (that is, both anterior and posterior)

1. HYPOTHALAMIC AND PITUITARY HORMONES DR. E. T. OJUGBELI

2. OUTLINE HYPOTHALAMIC HORMONES INTRODUCTION PITUITARY HORMOMES

3. INTRODUCTION The pituitary gland is often portrayed as the "master gland”. This is because, the posterior and anterior pituitary secrete an array of hormones that collectively influence the activitive of all cells and affect virtually all physiologic processes in the body

4. HYPOTHALAMIC AND PITUITARY HORMONES The pituitary gland may be king, but the power behind the throne is clearly the hypothalamus.  The hypothalamus contains neurosecretory neurons which secrete hormones that strictly control the secretion of hormones from the anterior pituitary. The hypothalamic hormones are referred to as  releasing  and  inhibiting hormones , reflecting their influence on the anterior pituitary hormones.

5. HYPOTHALAMIC HORMONES Hypothalamic releasing and inhibiting hormones are carried directly to the anterior pituitary gland via  hypothalamic- hypophyseal portal veins . Specific hypothalamic hormones bind to receptors on specific anterior pituitary cells, modulating the release of the hormone they produce It also secret oxytocin and ADH which are stored in the posterior pituitary

6. HYPOTHALAMIC HORMONES CONT… Hypothalamic Hormones Effect on Ant. Pituitary TRH Stimulates secretion of TSH and PRL GHRH GH release GnRH Stimulate FSH and LH, spermatogenesis, ovulation and testoterone secretion CRF Release ACTH, inhibited by cortisol Somatostatin Inhibits secretion of GH, TSH, GUT hormones, pancreatic and gastric secretions Prolactin inhibitory factor (Dopamine) Inhibits prolactin release

7. POSTERIOR PITUITARY NEUROHYPOPHYSIS Secrets ADH (vasopressin) and oxytocin It is derived from neuroectoderm in the floor or the forebrain It is made up of axons and nerve terminals from the hypothalamus The nerve terminals from the paraventricular nucleus secret oxytocin and the axons from the supraoptic nucleus secrets ADH.

8. ANTIDIURETIC HORMONE ADH  is also called arginine vasopressin. It's a  hormone  made by the hypothalamus in the brain and stored in the posterior pituitary gland. ADH release is controlled by Plasma  osmotic pressure , and volume status . Other factors include exercise, angiotensin II, and emotional states such as pain.

9. ACTION OF ADH The kidney is the effector organ of ADH. It regulates the volume and osmolarity of the urine via the  distal convoluted tubule  (DCT) and  collecting ducts  (CD). ADH acts through a G-protein coupled receptor to increase the transcription and insertion of  Aquaporin – 2  channels to the apical membrane of the DCT and CD cells. In high concentrations, ADH can also act on the blood vessels to increase  peripheral vascular resistance , the result of which is increased blood pressure. This mechanism is useful in restoring blood pressure during hypovolemic shock.

10. DIABETES INSIPIDUS It is characterised by excessive thirst and production of large amounts of dilute urine. DIAGNOSIS ; Is by   high plasma osmolality   low urine osmolality , and a positive water deprivation test .

11. TYPES OF DIABETE INSIPIDUS Cranial diabetes insipidus – occurs due to a lack of secretion of ADH from the posterior pituitary gland. This could be idiopathic, or possibly due to damage to the pituitary gland by tumours , infection or trauma. It is treated with ADH analogues. Nephrogenic diabetes insipidus  – The kidney is unable to respond to the ADH. Causes include genetic predisposition, electrolyte disturbances and some medications (e.g. lithium). Management of the condition is difficult, but methods such as high dose ADH analogues, thiazide diuretics, amiloride and NSAIDs can be trialled .

12. Syndrome of Inappropriate ADH (SIADH) secretion Syndrome of inappropriate ADH (SIADH) secretion is characterised by  hyponatraemia  secondary to excessive retention of free water. Symptoms can be mild, but in severe cases cerebral oedema and resultant neurological dysfunction can occur.

13. Syndrome of Inappropriate ADH (SIADH) secretion CONT… Common causes of SIADH include: Malignancy e.g. small cell lung cancer Brain injury e.g. stroke or subarachnoid haemorrhage Infections e.g. atypical pneumonia, meningitis Drugs e.g. carbamazepine , sulfonylureas

14. Syndrome of Inappropriate ADH (SIADH) secretion CONT… When treating SIADH, care must be taken to correct Na +  slowly, to avoid precipitating a severe neurological sequalae –  Cerebral Pontine Myelinolysis (‘locked in’ syndrome).  The mainstay of management is  fluid restriction , although in some cases  demeclocycline  may be used.

15. OXYTOCIN Oxytocin is a hormone produced by the paraventricular nuclei of the hypothalamus, stored and secreted by the posterior pituitary gland. It plays an important role in childbirth process and also helps with milk letdown . Afferent fibers in nipple are stimulated during suckling and the signal sent to spinal cord Triggers release of oxytocin from the posterior pituitary Oxytocin causes contraction of the myoepithelial cells in the breast milk letdown

16. OXYTOCIN cont … Oxytocin also helps with uterine contraction to aid delivery Its receptors are upregulated in the uterus near term Application Pictocin -synthetic oxytocin used for induction of labour and management of post partum haemorrhage .

17. ANTERIOR PITUITARY HORMONES Cell Type Hormone Secreted Corticotrophs Adenocorticotropic hormone (ACTH) Thyrotrophs Thyroid stimulating hormone (TSH) Gonadotrophs Leutinizing hormone (LH) and Follicle stimulating hormone (FSH) Somatotrophs Growth hormone lactotrophs Prolactin

18. ANTERIOR PITUITARY HORMONES CONT… The ant. Pituitary gland is derived from the rathke’s pouch. An outgrowth of the oral cavity. It contains five cell types that secrets five different hormones . The blood supply is via the hypothalamic portal system

19. PROLACTIN Prolactin is a peptide hormone secreted by the lactotrophs of the adenohypophysis It functions induce milk secretion in an estrogen primed breast The secretion of prolactin is stimulated by TRH and vaso active intestinal peptide and inhibited by Dopamine(via D2 receptors) and GABA from the hypothalamus Prolactine secretion is pulsatile with its highest level during REM sleep. NB- dopamine will lead to prolactin levels.

20. TRH AND PROLACTIN TRH from the hypothalamus is the stimulatory factor for prolactin release from the ant. Pituitary. TRH is also the stimulatory hormone for TSH which modulate the secretion of the thyroid gland and as such, under feedback regulation from the hormones of the gland. As a result, hypothyroidism gives rise to hyperprolactinemia hyperprolactinemia is a differential of hypothyroidism and pituitary enlargement.

21. PROLACTIN, AND PREGNANCY Serum estrogen and progesterone are very high during pregnancy Estrogen stimulate prolactin release by stimulating prolactin gene transcription and Prolactin release from lactotrophs in the ant. Pituitary. As a result, there is hyperplasia of the lactotrophs which causes increase in prolactin levels and the size of pituitary gland during pregnancy.

22. PROLACTIN AND PREGNANCY CONT… The high prolactin level stimulates the growth of the mammary gland. However, there is no milk production; because the high level of estrogen and progesterone block the effect of prolactin on milk production. This effect is removed after childbirth due to fall in estrogen and progesterone levels A lso, during pregnancy, the high levels of serum prolactin inhibits GnRH (stimulates production of LH & FSH). This effect continues for a while after delivery and is the basis of lactational amenorrhia

23. Hyperprolactinemia H igh serum prolactin Causes include 1. Pituitary adenomas invoving the lactotrophs ; this accounts for approx. 40% of all pituitary adenomas (most common). 2. Hypothyroidism; via negative feedback effect on TRH. 3. Medications- dopamine antagonists ; haloperidol , resperidone , metoclopramide.

24. Hyperprolactinemia cont … Signs and Symptoms include Women; galactorrhea , oligomenorrhea , amenorrhea, infertility, fractures, headache and visual field defects . Men; headache, visual problems and sexual dysfunction; hypogonadotropic hypogonadism , low libido, impotence, gynacomastia . Diagnosis ; serum prolactin levels and CNS imaging

25. Hyperprolactinemia cont … Treatment ; depends on the cause and symptoms; Symptomatic treatment. for medication, withdrawal of the drugs improves symptoms Dopamine agonists- bromocriptine , cabergoline . surgery

26. PITUITARY ADENOMAS Tumors of any cells of the anterior pituitary They may result in increase/decrease secretion of hormones The most common are prolactinomas (40%) Cell Type Disease condition lactotrophs Hyperprolactinemia Thyrotrophs Hyperthyroidism Corticotrophs Cushings disease Somatotrophs Gingatism /acromegaly

27. GENERAL SYMPTOMS OF PITUITARY ADENOMAS Headache and bitemporal hemianopia due to compression of the optic chiasm

28. HYPOPITUITARISM Fall in pituitary hormones Causes include Mass; non functional adenoma, craniopharyngioma , hemorrhage Ischemia Brain injury Radiation therapy ACTH deficiency Low cortisol- shock No salt wasting because the renin- angiotensin & aldosterone system is not affected TSH deficiency-hypothyroidism FSH/LH- hypogonadism

29. EMPTY SELLE SYNDROME It is characterized by empty sella tucica partially filled with CSF It can rarely cause pressure effect giving rise to hypopituitarism It is more common in women with obesity and hypertension

30. CRANIOPHARYNGIOMA It is a benign tumor derived from the remainant of the Rathke’s pouch. Usually occur in children of age 10-14 years. Symptoms are usually as a result of pressure effects and they include Hypogonadism Headaches Visual field defects and Behavioural changes

31. PIYUITARY APOPLEXY Sudden bleeds into the pituitary gland from a pre-existing adenoma Other risk factors include blood thinning medications (warfarin) and bleeding disorders Symptoms include Sudden headaches, Diplopia (pressure effect on oculomotor nerve) And hypopituitarism which manifest as shock due to loss of cortisol

32. SHEEHAN SYNDROME Sheehan syndrome is cause by infarction of the pituitary gland as a result of hypovolemia following post partum haemorrhage . It can manifest as shock after delivery if cortisol levels are very low And failure to lactate in the post partum period.

33. TREATMENT OF HYPOPITUITARISM Hormone replacement therapy

34. GROWTH HORMONE Also known as somatotropin Is a protein hormone that stimulates  growth , cell reproduction, and cell regeneration It is important for linear growth in children It is released in pulses and maybecome undetectable between pulses

35. GROWTH HORMONE cont … GH has a short half life; 10-20 mins Stimulants of GH release include GHRH Exercise and sleep Inhibitors of GH include Glucose Somatostatin (in response to IGF-1 and GH) IGF-1

36. GROWTH HORMONE cont … MOA; GH receptor is a 638 amino acid long homodimeric receptor. It is a membrane bound receptor It acts via janus kinase 2 (JAK 2) enzyme- an intracytoplasmic tyrosine kinase JAK2 phosphorylates tyrosine residues on itself and on the GH receptors. This forms binding sites for many signal molecules which result in gene expression, transcription and protein synthesis.

37. GROWTH HORMONE cont … The liver contains many GH receptors. Binding of GH to these receptor induce synthesis of IGF-1. IGF-1 or somatomedin is the main hormone that mediate the many effects of GH It can be measured in serum clinically as an indicator of GH function hence, it is use for monitoreing GH activities IGF-1 is also produced in peripheral tissues and has paracrine effects on nearby sites.

38. GROWTH HORMONE cont … Direct effect of GH It decrease glucose uptake by cells Anti-insulin effect Hyperinsulinaemia Peripheral tissues become insulin resistant Other hormones that opposes insulin effect include Glucagon Cortisol and Epinephrine

39. GROWTH HORMONE cont … Other direct effect of GH include Lipolysis via activation of hormone sensitive lipase Production of IGF-1 from the liver. Indirect effects of GH are via IGF-1 Stimulation of chondrocyte increase linear growth Stimulate muscle growth to increase lean muscle mass Increase organ size

40. GROWTH HORMONE cont …

41. GROWTH HORMONE cont … GH DEFICIENCY In children Failure to grow; DWAFISM In adult Increase fat Decrease in lean body mass Low energy GH deficiency is most commonly caused by mass effect from a pituitary tumor. It may also be a consequence of surgery/radiation therapy. Treatment is with synthetic GH.

42. GROWTH HORMONE cont … GH excess is most commomly caused by pituitary adenoma of the somatotrophs Features High GH and IGF-1 Low GHRH High somatostatin May also present with headaches and visual deffects Rare causes Hypothalamic tumors Small cell lung CA Carcinoid tumors GHRH will be high

43. GROWTH HORMONE cont … Giangatism ; GH excess in children Acromegaly GH excess in adult Hard to diagnose- insidious onset, appxt 12 years Present with coarse facial features like enlarge jaw, nose and frontal bone enlarged hands and feet Joint pains Diabetes (10-15%) Viceral organ enlargement Cardiovascular disease

44. GROWTH HORMONE cont … Diagnosis Serum IGF-1 concentration OGTT CNS imaging Treatment Octreotide – somatostatin analogue Surgery Radiation

45. MSH Melanocyte stimulating hormone Proopiomelanocortin ; A precursor of ACTH and MSH MSH stimulate melanocytes to produce melanin Causes hyperpigmentation in C ushing’s disease

46. THYROID HORMONES The  thyroid gland  uses iodine from food to make two thyroid hormones: triiodothyronine (T3) and thyroxine (T4 ) The activity of the thyroid gland is under the regulation of the   hypothalamus  and the  pituitary gland The hypothalamus releases thyrotropin -releasing hormone (TRH), which stimulates the pituitary gland to release thyroid-stimulating hormone (TSH).

47. THYROID HORMONES cont … The secretions of the thyroid gland also negatively feed back to regulate the secretions of the hypothalamus and pituitary gland, such that, when the thyroid hormone levels are low, the hypothalamus and pituitary are stimulated to secrete more TRH and TSH, which in turn, stimulate the thyroid galnd to make more hormones . And thyroid hormone levels are too high , they secrete less TRH and TSH, which reduces hormone production by the thyroid gland.

48. THYROID HORMONES cont …

49. THYROTROPIN RELEASING HORMONE (TRH) Thyrotropin -releasing hormone (TRH) is a hypophysiotropic hormone produced by neurons in the hypothalamus. The half-life of TRH in the blood is approximately 6 minutes . It is synthesized in the paraventricular nucleus of the hypothalamus TRH travels to the anterior pituitary via the hypophyseal portal system where it binds to the TRH receptor stimulating the release of thyroid-stimulating hormone from thyrotropes and prolactin from lactotropes .

50. THYROID STIMULATING HORMONE ( TSH) TSH is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body . It is a glycoprotein hormone produced by thyrotroph cells in the anterior pituitary gland. TSH functions to regulates the endocrine secretion of the thyroid

51. THYROID STIMULATING HORMONE (TSH ) cont … TSH is a glycoprotein hormone and consists of two subunits, the alpha and the beta subunit . The α (alpha) subunit (i.e., chorionic gonadotropin alpha) is nearly identical to that of human chorionic gonadotropin ( hCG ), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). The α subunit is thought to be the effector region responsible for the stimulation of adenylate cyclase (involved the generation of cAMP ). The α chain has a 92-amino acid sequence .

52. THYROID STIMULATING HORMONE (TSH ) cont … The β (beta) subunit (TSHB) is unique to TSH, and therefore determines its receptor specificity. The β chain has a 118-amino acid sequence . The TSH receptor is a G-protein coupled membrane-bound receptor found mainly on thyroid follicular cells Binding of TSH to its receptor on the thyroid follicular cells triggers a signal transduction whis result in the synthesis of thyroglobulin

53. Function of TSH Production of thyroglobulin ( a precursor protein of thyroid hormone) in the thyroid follicular cells Stimulation of the receptor up-regulate the activity of the sodium-iodide symporter (NIS) on the basolateral membrane of thyroid follicular cells, thereby increasing intracellular concentrations of iodine (iodine trapping ). Stimulating iodination of thyroglobulin in the follicular lumen

54. Function of TSH cont … Stimulating the conjugation of iodinated tyrosine residues. This leads to the formation of thyroxine (T4) and triiodothyronine (T3) that remain attached to the thyroglobulin protein. Increased endocytosis of the iodinated thyroglobulin protein across the apical membrane back into the follicular cell . Stimulation of proteolysis of iodinated thyroglobulin to form free thyroxine (T4) and triiodothyronine (T3).

55. Secretion of thyroxine (T4) and triiodothyronine (T3) across the basolateral membrane of follicular cells to enter the circulation. Specifically , TSH activates a Gs -coupled receptor on the follicular cells which leads to activation of Adenyl cyclase resulting in increased c-AMP production and PKA (Protein Kinase-A) activation . The cascade results in gene transcription and translation for the synthesis of thyroglobulin molecule

56. THYROID HORMONE

57. THYROID HORMONE cont.. The thyroid secretes about 80mg of T4 and only 5mg of T3 per day However, T3 has a much greater biological activity (X10)than T4. As a result, an additional 25mg/day of T3 is produced peripherally from T4 by 5´monodeiodinase

58. THYROID HORMONE cont.. Thyroid hormones are unique biological molecules that has iodine incorporated into their structure. And as such, adequate iodine intake either through diet or water is needed for normal thyroid hormone biosynthesis . Minimum requirement(RDA): 75 micrograms/day Sources of iodine include; iodized salt, dairy products shellfish

59. THYROID HORMONE cont.. Dietary iodine is absorbed in the GI tract, then taken up and concentrated by the thyroid gland About 80% of the consumed iodine is excreted in urine where as only 20 % is taken up by the Thyroid follicular cells. The transport of iodide into follicular cells is dependent upon a Na ⁺ /I¯ symporter Iodide taken up by the thyroid gland is oxidized by the enzyme thyroperoxidase in the lumen of the follicle : I⁻ ―peroxidase―›I⁺

60. THYROID HORMONE BIOSYNTHESIS The synthesis of thyroid hormone begins with the binding of TSH to its receptors on the follicular cells of the thyroid gland The follicular cells produce thyroglobulin . Thyroglobulin is then, released into the colloid space , where its tyrosine residues are iodinated by I⁺ This results in formation of monoiodotyrosine or diiodotyrosine .

61. L-tyrosine 3-iodotyrosine 3-iodotyrosine 3,5-diiodotyrosine

62. THYROID HORMONE TRANSPORT Thyroid hormones are lipid-soluble . Thus, they are found Bound proteins in the circulation. Thyroid Hormone-Binding Globulin(TBG) (~70% of hormone) Pre-albumin( Transthyretin ) (~15%) Albumin (~15%) Less than 1% of thyroid hormone is found free in the circulation. And only free and albumin-bound thyroid hormone is biologically available to tissues .

63. THYROID HORMONE TRANSPORT T4 is approximately 95% and T3 is 5% of the total hoemone released. But biological active one is T3. so T4 is converted to T3 in peripheral tissues by the enzyme 5’monodeiodinase and become active. This conversion takes place mainly in the liver and kidneys. T3 formed is then released to the blood stream.

64. REGULATION OF THYROID HORMONE Thyroid hormone synthesis and secretion is regulated by two main mechanisms: - An “auto regulation” mechanism, which reflects the available levels of iodine. - Regulation by the hypothalamus and anterior pituitary.

65. IODIDE AUTO-REGULATION The rate of iodine uptake and incorporation into thyroglobulin is influenced by the amount of iodide available: - Low iodide levels increase iodine transport into follicular cells - High iodide levels decrease iodine transport into follicular cells Thus, there is negative feedback regulation of iodide transport by iodide .

66. REGULATION OF THYROID HORMONE cont … Other factors include; Diet : a high carbohydrate diet increases T3 levels, resulting in increased metabolic rate (diet-induced thermogenesis). Low carbohydrate diets decrease T3 levels, resulting in decreased metabolic rate. Cold Stress: increases T3 levels in other animals, but not in humans. Any condition that increases body energy requirements (e.g ., pregnancy , prolonged cold) stimulates hypothalamus TRH and pituitary TSH.

67. FUNCTIONS OF THYROID HORMONE Thyroid hormones are essential for normal growth of tissues, including the nervous system. Lack of thyroid hormone during development results in short stature and mental deficits (cretinism). Thyroid hormone stimulates or increase Basal Metabolic Rate(BMR)-increase glucose absorption from the GI tract, Increase carbohydrate, lipid and protein turnover, down-regulate insulin receptors and increase substrate availability

68. FUNCTIONS OF THYROID HORMONE cont … Effects on protein synthesis and degradation: Low thyroid hormone levels -› increased protein synthesis. That is, low metabolic rate; growth. High thyroid hormone levels -increased protein degradation. That is, high metabolic rate; catabolism, energy release. T3 increases the synthesis of Na ⁺ /K⁺ pumps, markedly increasing ATP consumption(BMR increases ). About 1/3rd of all ATP in the body is used by this pump.

69. FUNCTIONS OF THYROID HORMONE cont … Effects on carbohydrates: Low doses of thyroid hormone increase glycogen synthesis (low metabolic rate; storage of energy) High doses increase glycogen breakdown (high metabolic rate; glucose production) Effects on the CVS Increase heart rate Increase force of cardiac contractions Increase stroke volume Increase Cardiac output Up-regulate catecholamine receptors

70. FUNCTIONS OF THYROID HORMONE cont … Respiratory system Increase resting respiratory rate Increase minute ventilation Increase ventilatory response to hypercapnia and hypoxia Effect on UGS Increase blood flow Increase glomerular filtration rate(GFR ) etc

71. HYPOTHYROIDISM Early onset: Delayed/incomplete physical and mental development . Later onset(Youth): Impaired physical growth Adult onset(Myxedema) : Gradual changes occur. Tiredness, lethargy , decreased metabolic rate, slowing of mental function and motor activity, cold intolerance, weight gain, goiter, hair loss, dry skin. Eventually may result in coma. Causes : Insufficient iodine . Lack of thyroid gland. Lack of hormone receptors. Lack of TH binding globulin.

72. HYPOTHYROIDISM GOITRE During iodine deficiency, thyroid hormone production decreases . This results in increased TSH release (less negative feedback). TSH acts on thyroid, increasing blood flow, and stimulating follicular cells and increasing colloid production.

73. HYPERTHYROIDISM Emotional symptoms (nervousness, irritability), fatigue, heat intolerance , elevated metabolic rate, weight loss, tachycardia, goiter , muscle wasting, apparent bulging of eyes (exophthalmos ), may develop congestive heart failure . Women > Men Causes : Excessive TSH release. Autoimmune disorders . Medications Thyroiditis

74. ACTH

75. SOMATOSTATIN