Endocrine Physiology: comprehensive lecture

a concise review on part of endocrinology that can bring about a useful re-cap of our lectures in preparation for exams

1. ENDOCRINOLOGY AJAO D.I ( B.Tech , MSc, physsiology)

2. The endocrine system, like the nervous system, is important in regulating organ and cell function. These two systems provide communication between cells in an organized manner. The nervous system uses electrical signals (nervous impulses) to communicate while the endocrine system uses hormones circulating in blood to provide communication . Not an anatomically connected system but it is still functionally a connected system.

3. They accomplish their functions by secreting Intercellular chemical messengers (hormones), which travel through the blood stream to affect target cells/organs . The endocrine glands secrete a major class of chemical messengers called the “hormones”, and in practical usage the term “endocrine gland” has come to be synonymous with “hormone-secreting gland.” Endocrine gland, or ductless gland, secretions are released directly into the interstitial fluid surrounding the gland cells from where they are transported into the bloodstreams

4. However, there are “ductless glands” that secrete nonhormonal , organic substances into the blood. i.e the liver secretes glucose, amino acids, fats, and proteins into the blood . The substances secreted by such nonendocrine glands serve as nutrients for other cells or perform special functions in the blood, but they do not act as messengers and therefore are not hormones.

5. The exocrine type of glands secrete through the ducts and are discharged into the lumen of an organ or, in the case of the skin glands, onto the surface of the skin Sweat glands and salivary glands are examples of exocrine glands

6. The target cell/organ is the cell that responds to the intracellular chemical messenger. As with all such signaling mechanisms, if the target cell does not have a receptor for the signaling molecule, it will not respond to the signal. In addition, there are many interactions which occur between endocrine glands (such as between the pituitary and gonads).

7. Some endocrine hormones affect most cells of the body; e.g. growth hormone causes growth in most parts of the body, and thyroxine increases the rate of many chemical reactions in almost all the body's cells. Hormones are chemical messengers secreted into the circulation by ductless glands. Hormones are grouped into two: Local e.g. Ach, secretin, cholecystokinin have specific local effects General: by specific endocrine glands to exert effect at distant point of the body

8. The general hormones are: Anterior Pituitary Hormones Posterior pituitary hormones Adrenocortical hormones cortisol and aldosterone Thyroid hormones T 4 , T 3 , Calcitonin Pancreatic hormones insulin, glucagon Ovarian hormones oestrogens , progesterone Testicular Hormones testosterone Parathyroid hormones parathormone Placental hormones HCG, oestrogens , progesterone

9. Classification of hormones There are three general classes of hormones: 1. Proteins and Polypeptides Most of the hormones in the body are polypeptides and proteins. These range from the ultrashort nonpeptides like vasopressin (ADH) to much larger proteins, like insulin. Polypeptides with 100 or more amino acids are called proteins, and those with fewer than 100 amino acids are referred to as peptides. They includes hormones secreted by the anterior and posterior pituitary gland, the pancreas (insulin and glucagon), the parathyroid gland (parathyroid hormone) etc

10. They are hydrophilic and lipophobic thus they have their receptors on the cell surface. Mechanisms of synthesis They are synthesized in the rER, packaged in the Golgi, and stored in secretory granules. Modes of action Most use the second messenger system, such as cAMP few bind with the target cell’s surface receptors and alter the cell’s permeability to one or more ions by opening or closing ion channels.

11. 2. Steroids All are derived from cholesterol. They are hydrophobic and lipophilic, and so mostly require carrier proteins so their receptors are cytoplasmic. Secreted by the adrenal cortex (cortisol and aldosterone), the ovaries also the placenta (estrogen and progesterone), the testes (testosterone).

12. Modes of action All lipophilic hormones produce their effects on the target cells by enhancing the synthesis of new enzymes or new structural proteins. These effects are the result of activating genes within the nucleus: The free hormone diffuses through the plasma membrane and binds to its specific cytoplasmic receptor the hormone-receptor complex binds to the DNA at a specific DNA attachment site This promotes the activation of the particular genes, resulting in transcription of the gene into mRNA.

13. 3. Amines (d erivatives of the amino acid tyrosine) Secreted by the thyroid (thyroxine and triiodothyronine) and the adrenal medulla (epinephrine and norepinephrine). The catecholamines are synthesized in the cytosol and stored in chromaffin granules. The thyroid hormones are synthesized and stored within the colloid inside the follicles

14. Regulation of hormonal action Negative Feedback: It prevents Overactivity of Hormone Systems. After a stimulus causes release of the hormone, conditions or products resulting from the action of the hormone tend to suppress its further release. Positive feedback: When the biological action of the hormone causes additional secretion of the hormone. E.g. the surge of luteinizing hormone (LH) that occurs as a result of the stimulatory effect of estrogen on the anterior pituitary before ovulation. …….physiologically relevant hormone

15. Cyclical-variations: Super­imposed on the negative and positive feedback control of hormone secretion are periodic variations in hormone release influenced by seasonal changes, aging, the diurnal (daily) cycle, or sleep. Measurement of hormones, their precursors, and their metabolic end products are done using the method of radioimmunoassay.

16. Measurement of Hormone Concentration Plasma analysis Provides information at the time of sampling only and may not reflect the overall secretion rate When hormone secretion is episodic, single sampling may reflect peaks (erroneous hyperfunction ) or nadirs (erroneous hypofunction ). Pulsatile secretion, diurnal and cyclic variation, age, sleep entrainment, and hor m one antagonism must all be considered in evaluating circulating levels. Two important methods have been employed Radio-immunoassay RIA: the principle behind the RIA is the competitive binding of a radiolabeled antigen, hormone, to an antibody (immunoglobulin G class) by an unlabeled antigen (hormone in sample)

17. Immunometric assay: The principle behind immunometric assay is the binding of the hormone by a monoclonal antibody followed by binding of the hormone to a different antigenic site in the hormone, ‘sandwiching’ the hormone. The second antibody is labeled and is fixed to a solid phase to allow separation. This assay has greater sensitiviity for the hormone because the antibodies recognize 2 antigenic sites of the hormone. And circulating hormone antibodies do not interfer with measurements

18. Urine analysis Restricted to the measurement of catecholamines , steroid hormones, and water-soluble hormones such as hCG and LH. A distinct advantage of urine analysis is that it provides an integrated sample. – A “24-hour urine free cortisol” is often necessary to pick up a low-level Cushing’s syndrome and to eliminate the highs and lows of the normal circadian rhythm

19. Hypothalamic Control of the Anterior Pituitary The hypothalamus is composed of a number of groups of nerve cells Situated below and in front of the thalamus Situated immediately above the pituitary gland Usually delineated into nuclei and areas; The median eminence is generally defined as the portion of the ventral hypothalamus from which the portal vessels arise. This region is outside the blood–brain barrier . Regulates anterior pituitary secretion.

20. Hypothalamic Control of the Anterior Pituitary Anterior pituitary secretion is controlled by chemical agents carried in the portal hypophysial vessels from the hypothalamus The portal hypophysial vessels form a direct vascular link between the hypothalamus and the anterior pituitary T hese substances used to be called releas i ng and inhibiting factors, but now they are commonly called hypophysiotropic hormones.

21. Hypothalamic Control of the Anterior Pituitary Thyroid stimulating hormone releasing hormone (TRH) or thyrotropin (TSH) releasing hormone causes release of TSH Corticotropin releasing hormone (CRH): causes release of ACTH ( adrenocorticotropin ) Growth hormone Releasing Hormone (GHRH) causes the release of GH Growth H. Inhibitory Hormone (GHIH) or Somatostatin: inhibits the release of GH Gonadotropin releasing hormone ( GnRH ): Causes the release of LH and FSH Prolactin inhibitory hormone (PIH): Inhibit prolactin secretion

22. The hormones of the posterior pituitary gland are synthesized in the cell bodies of the magnocellular neurons in the supraoptic and paraventricular nuclei. It is transported down the axons of these neurons to their endings in the posterior lobe, where they are secreted in response to electrical activity in the endings . The posterior pituitary is made up in large part of the endings of axons that arise from cell bodies in the supraoptic and paraventricular nucle . it passes to the posterior pituitary via the hypothalamohypophysial tract .

23. Pituitary Gland The pituitary gland, also known as the hypophysis is sometimes called the "master" gland of the endocrine system, because it controls the functions of the other endocrine glands. It is a roundish organ no larger than a pea, and is located at the base of the brain ( immediately beneath the hypothalamus) . It sits in the sella turcica (a depression in the sphenoid bone of the skull).

24. Physiological the pituitary gland is divided into 2 distinct portion: - the anterior pituitary or adenohypophysis and - the posterior pituitary or neurohypohysis Inbetween these two is a small relatively avascular zone known as the pars intermedia or intermediate lobe (rudimentary in human)

25. The anterior pituitary p roduces 6 main hormones: TSH (thyroid-stimulating hormone) ACTH ( adrenocorticotropic hormone) Growth hormone LH (luteinizing hormone) FSH (follicle-stimulating hormone) Prolactin Pars intermedia or intermediate lobe p roduces Melanocyte stimulating hormone The posterior pituitary p roduces : ADH ( antidiuretic hormone) Oxytocin

26. Hormones of the adenohypophysis : Thyroid-stimulating hormone (TSH): Also known as thyrotropin is a glycoprotein produced by the thyrotropes which forms 5% of the secetory cells in the ant. Pit. Actions: It increases the secretion of T3 ( triiodothyronine) and T4 ( thyroxine) from the thyroid follicular cells by increasing all the known secretory activities of the thyroid glandular cells.

27. Its specific effects on the thyroid gland are as follows: I. Increased proteolysis of the thyroglobulin that has already been stored in the follicles, with resultant release of the thyroid hormones into the circulating blood. 2. Increased activity of the iodide pump, which in­creases the rate of "iodide trapping" in the glandular cells. 3. Increased iodination of tyrosine to form the thyroid hormones. 4. Increased size and secretory activity of the thyroid cells. 5. Increased number of thyroid cells.

28. Regulation: Anterior pituitary secretion of TSH is controlled by a hypothalamic hormone, thyrotropin-releasing hormone (TRH) or TSH-RH , which is secreted by nerve endings in the hypothalamus.

29. One of the best-known stimuli increasing the rate of TRH secretion by the hypothalamus and therefore TSH secretion by the anterior pituitary gland, is exposure of an animal to cold. Various emotional reactions can also affect the output of TRH and TSH and therefore indirectly affect the secretion of thyroid hormones. Excitement and anxiety conditions that greatly stimulate the sympathetic nervous system cause an acute decrease in secretion of TSH.

30. 2. Adrenocorticotropic hormone (ACTH): Also called corticotropin or adrenocorticotropin is a large polypep­tide produced by the corticotropes which forms 10% of the secetory cells in the ant. Pit. Actions: ACTH stimulates Cortisol secretion and also enhances the production of adrenal androgens. How? It stimulate secretion and growth of zona fasciculata and reticularis of the adrenal cortex. Thus activating these adrenocortical Cells to produce steroids.

31. Regulation: ACTH Secretion Is Controlled by Corticotropin-Releasing Factor from the Hypothalamus. In the same way that other pituitary hormones are controlled by releasing factors from the hypothalamus. The anterior pituitary gland can secrete only minute quantities of ACTH in the absence of CRF. Any type of physical or mental stress can lead within minutes to greatly enhanced secretion of ACTH. Pain stimuli caused by any type of physical stress or tissue damage are also stimulate release.

32. 1.Gluconeogenesis 2 . Protein mobilization 3. Fat mobilization 4. Stabilizes Iysosomes Stress Relieves Excites

33. 3.Gonadotropins ( Luteinizing and Follicle Stimulating Hormones ). They are known as glycoproteins produced by the gonadotrophs which forms 20% of the secetory cells in the ant. Pit. Most gonadotrophs secrete only LH FSH, but some appear to secrete both hormones . .

34. Physiologic Effects of Gonadotropins Physiologic effects of the gonadotrophins are known only in the Ovaries and testes. Together, then regulate many aspects of gonadal function in both males and females. Luteinizing Hormone In both sexes, LH stimulates secretion of sex steroids from the gonads. In the testes, LH binds to receptors on Leydig cells, stimulating synthesis and secretion of testosterone. In females, it stimulates ovulation and luteinization of ovarian follicles

35. Follicle-Stimulating Hormone As its name implies, FSH stimulates the maturation of ovarian follicles. FSH is also critical for sperm production (spermatogenesis). It supports the function of Sertoli cells, which in turn support many aspects of sperm cell maturation.

36. Control of Gonadotropin Secretion The principle regulator of LH and FSH secretion is gonadotropin-releasing hormone (GnRH, also known as LH-releasing hormone). GnRH is a peptide that is synthesized and secreted from hypothalamic neurons and binds to receptors on gonadotrophs. Numerous hormones influence GnRH secretion. The gonads secrete at least two additional hormones - inhibin and activin - which selectively inhibit and activate FSH secretion from the pituitary .

37. Disease States Hypogonadism: Failure of gonadal function. This condition is typically manifested in males as failure in production of normal numbers of sperm. - In females, cessation of reproductive cycles is commonly observed. Hypergonadism Elevated blood levels of gonadotropins usually reflect lack of steroid negative feedback. Removal of the gonads from either males or females leads to persistent elevation in LH and FSH Excessive secretion of FSH and/or LH most commonly the result of pituitary tumors. In general, elevated levels of gonadotropins per se have no biological effect.

38. 6. Prolactin Produced by the lactotropes which forms 10-30% of the secetory cells in the ant. Pit. Actions: Causes milk secretion from the breast after estrogen and progesterone priming. Promote dev of female breast Inhibit actions of gonadotrophins thus preventing ovulation in lactating ovary.

39. Control of Prolactin Secretion Tonically inhibited by the hypothalamus. Hypothalamic inhibitory factors (PIH) Hypothalamic PRL stimulates pituitary Lactotrophs to produce Prolactin while hypothalamic Dopamine is inhibitory

40. Factors that increase secretion are: - exercise, - Surgical and psychological stress, - stimulus to the nipple. Disorders: hypoprolactinemia : chromophobe adenoma due to tumor or damage to portal system. May cause galactorrhea

41. END OF LECTURE 1

42. Growth hormone (GH): Also known as Somatotropin is a protein hormone produced by the somatotropes which forms 50% of the secetory cells in the ant. Pit. Growth Hormone (GH) is a peptide hormone secreted by the anterior pituitary and is critical for normal growth to adult size and functions by coordinating multiple metabolic processes

43. Actions: Essential, but not the only hormone responsible for growth Stimulates growth of bones and soft tissues Have metabolic effects which include glucose sparing, fat mobilization and protein anabolism The effects of GH on protein and lipid metabolism result in GH being a key factor maintaining lean body mass Stimulates somatomedin secretion by liver

44. GH induces growth in nearly any tissue that can possibly grow and is required for reaching full size and weight of a variety of organs. However, its most important growth-promoting effect is on cartilage and bone which occurs with cooperation from Thyroid Hormones. Together, these hormones are critical for proper linear growth.

45. Physiologic Effects of Growth Hormone It has two distinct types of effects: Direct effects are the result of growth hormone binding its receptor on target cells. Indirect effects are mediated primarily by a insulin-like growth factor-I (IGF-I) , a hormone that is secreted from the liver and other tissues in response to growth hormone. Majority of the growth promoting effects of growth hormone is actually due to IGF-I acting on its target cells. GH stimulates amino acid uptake and protein synthesis in muscle and other tissues.

46. Metabolic Effects:t Growth hormone has important effects on metabolism. Protein metabolism: In general it stimulates protein anabolism in many tissues. -This effect reflects increased amino acid uptake, -increased protein synthesis and -decreased oxidation of proteins. Fat metabolism: Growth hormone enhances utilization of fat by stimulating triglyceride breakdown and oxidation in adipocytes.

47. Carbohydrate metabolism: Growth hormone helps to maintain blood glucose within a normal range. It is often said to have anti-insulin activity, because: it suppresses the abilities of insulin to stimulate uptake of glucose in peripheral tissues and enhance glucose synthesis in the liver.

48. Regulation of Growth Hormone Secretion Production of growth hormone is modulated by many factors including: -stress -exercise -nutrition -sleep and -growth hormone itself. However, its primary controllers are: Growth hormone-releasing hormone (GHRH): a hypothalamic peptide that stimulates both the synthesis and secretion of growth hormone. Ghrelin: a peptide hormone secreted from the stomach. stimulates secretion of growth hormone.

49. Somatostatin (SS): a peptide produced by several tissues in the body, including the hypothalamus. It inhibits growth hormone release. However, a variety of acute inducers of GH release are known with the most influential being hypoglycemia although stress and protein-energy malnutrition can also result in increased GH release. Others: SEE DIAGRAM -

50. Disorders of Growth Hormones. Growth hormone disorders can reflect lesions in either the hypothalamus , the pituitary or in target cells . Clinically, deficiency in growth hormone or defects in its binding to receptor are seen as growth retardation or dwarfism. The manifestation of growth hormone deficiency depends upon the age of onset of the disorder.

51. Panhypopituitarism This means decreased secretion of all the anterior pituitary hormones. It may be congenital (present from birth), or it may occur suddenly or slowly at any time during the life of the individual, most often resulting from a pituitary tumor that destroys the pituitary gland.

52. Panhypopituitarism during childhood (Dwarfism) . Most instances of dwarfism result from generalized deficiency of anterior pituitary secretion. In general, all the physical parts of the body develop in appropriate proportion to one another, but the rate of development is greatly decreased. A child who has reached the age of 10 years may have the bodily development of a child of 4 to 5 years on reaching the age of 20 years may have the bodily development of a child of 7 to 10 years.

53. The panhypopituitary dwarf does not pass through puberty and never secretes sufficient quantities of gonadotropic hormones to develop adult sexual functions. In one third of such dwarfs, there is the deficiency of growth hormone alone; these persons do mature sexually and occasionally reproduce. In the Levi­Lorain dwarf, the rate of growth hormone secretion is normal or high, but there is a hereditary inability to form somatomedin C

54. Panhypopituitarism in the Adult. In adulthood frequently due to: tumors which may compress the pituitary gland until the functioning anterior pituitary cells are totally or almost totally destroyed. thrombosis of the pituitary blood vessels.

55. Effects in general are: (I) hypothyroidism, (2) depressed production of glucocorticoids by the adrenal glands, (3) suppressed secretion of t he gonadotropic hormones so that sexua l functions are lost. Except for the abnormal sexual functions, the patient can usually be treated satisfactorily by administration of adrenocortical and thyroid hormones.

56. Gigantism Excessive growth hormone secretion that begins in young children or adolescents. It is a very rare disorder, usually resulting from a tumor of somatotropes. All body tissues grow rapidly, including the bones. Because the condition occurs before the epiphyses of the long bones have become fused with the shafts, height increases so that the person becomes a giant as tall as 8 feet. The giant ordinarily has hyperglycemia. In about 10 per cent of giants, full-blown diabetes mellitus develops.

57. In most giants, panhypopituitarism eventually develops if they remain untreated, because the gigantism is usually caused by a tumor of the pituitary gland that grows until the gland itself is destroyed. This eventual general deficiency of pituitary hormones usually causes death in early adulthood. However, once gigantism is diagnosed, further effects can often be blocked by microsurgical removal of the tumor from the pituitary gland or by irradiation of the gland.

58. Acromegaly Results from excessive secretion of growth hormone in adults (adolescence) after the epiphyses of the long bones have fused with the shafts. soft tissues continue to grow bones also grow in thickness. Clinical signs include: - overgrowth of extremities - Enlargement especially marked in the bones of the hands and feet and in the cranium, nose, the forehead, lower jawbone, and portions of the vertebrae (because their growth does not cease at adolescence).

59. Consequently, the lower jaw protrudes forward, fingers become extremely thickened so that the hands develop a size almost twice normal. In addition to these effects, changes in the vertebrae ordinarily cause a hunched back, which is known clinically as kyphosis. - many soft tissue organs, such as the tongue, liver, and especially the kidneys, become greatly enlarged.

60. intermediate lobe: melanocyte-stimulating hormone - control skin pigmentation B-lipotropin. Corticotropes. 10% of the cells Actions unknown .

61. THE POSTERIOR PITUITARY GLAND Also called the neurohypophysis, is composed mainly of glial-like cells called pituicytes. The pituicytes do not secrete hormones but act as a supporting structure. the supraoptic and para ventricular nuclei of the hypothalamus secretes two posterior pituitary hormones: (1) antidiuretic hormone (ADH), also called vasopressin, and (2) oxytocin. The tracts pass to the neurohypophysis through the pituitary stalk (hypophysial stalk).

62. ADH acts on collecting duct of the kidney, increases water retention Control: Stimulate secretion - increase osmotic press., decrease ECF vol, pain, emotion, stress etc inhibit secretion- decrease osmotic press., increase ECF vol, alcohol etc

63. Diabetes insipidus: Damage to the pituitary gland may result in decreased ADH and therefore the production of large amounts of urine up to 20-30 liters per day. Neurogenic Diabetes insipidus kidney fail to resond to ADH - Polyuria - polydipsia

64. Oxytocin Action primarily on : - breast contraction of myoepithelia cells to squeeze milk out of alveoli - uterus to cause contraction of smooth muscle - facilitate sperm transport in non-preg. Uterus - propel sperm toward the urethra

65. THYROID GLAND

66. Physiological Anatomy: Located below the larynx on either side and anterior to the trachea. Consists of two lobes joined by an isthmus Normal adult thyroid gland weighs about 15 - 20grams. Highly vascularized. Made up of numerous Acini or Follicles. Follicles are spherical in shape and lined by single layer of cuboidal epithelium. Follicles are filled with colloid.

67. Follicular cells Synthesize Thyroxine (T4) & Triiodothyronine (T3). Colloid is made up manly of the large glycoprotein called thyroglobulin synthesized and secreted by the ER and golgi complex. Thymoglobulin Has a mol. wt. of 660,000 and contains 140 tyrosine a. a.

68. Iodine is essential for synthesis of thyroid hormones. Minimum daily intake in food & water 100-150mg Iodine is converted to iodide in gut and absorbed into blood & ECF. About 1/3 of absorbed iodide is taken up by the thyroid and 2/3 excreted by kidney SYNTHESIS OF THYROID HORMONES

69. 1. Iodide trapping :- This is the specific ability of the thyroid cells to actively pump iodide into the cell. 2. Synthesis and secretion of thyroglobulin. 3. Oxidation of iodide ion in the presence of enzyme peroxidase and hydrogen peroxide.

70. 4. Organification of thyroglobulin : Binding of iodine with a.a. thyrosine in the thyroglobulin.

71. Release Thyroglobulin itself is not released but T4 & T3 are cleaved from the thyroglobulin molecule and released into the blood. Transport 67% bind with TBG 20% bind with TBPA 13% with serum albumin <0.1% in free form Albumin has largest capacity to bind T4 & TBG the smallest. TBG has the greatest affinity to bind T4

72. Secretion Normal human thyroid secretes about: 80mg of T4/day 4mg of T3 ,, 2mg of RT3 ,, Control of secretion TSH - ses TH secretion. T4 – feedback at pituitary or hypothalamic level to control TSH release. Cold – stimulate TSH Warmth – reduces TSH stress – reduces TSH Glucocorticoids inhabit TRH

73. Functions of Thyroid Hormones It activates nuclear transcription of genes. Increases Na,K-ATPase Increase number and activity of mitochondria. Promote growth of the brain during fetal life and first few years of postnatal life.

74. Thyroid hormone on specific bodily mechanisms 1. carbohydrate metabolism - rapid uptake of glucose by cells - glycolysis - gluconeogenesis - rate of absorption from GIT - Insulin secretion. 2. Fat metabolism - mobilization of lipid from fat tissue - Accelerates the oxidation of free fatty acids by the cells. 3. Vitamin metabolism - demand for vitamins Vitamin deficiency in the presence of thyroid hormone secretion. 4. BMR

75. 5. Body weight (Do not occur). 6. CVS: - Blood flow C.O. * - HR due to direct effect on its excitability - strength of heart muscle but this is depressed with marked increase TH - MAP is unchanged, as systolic BP slightly while diastolic BP is correspondingly reduced.

76. 7. Respiration: - Rate & depth of respiration 8. GIT - Appetite – food intake - Secretion of digestive juices - Gastric motility – diarrhea 9. CNS - Extreme nervousness - Anxiety - Extreme worry 10. Muscles - Slight increase in thyroid hormone – muscle reacts with vigor - Excessive muscle become weakened because of excess protein catabolism. * Fine muscle tremor

77. 11. Sleep - Difficult to sleep 12. Other endocrine glands Thyroid hormone – rate of secretion of most other endocrine glands 13. Effect on sexual function In men: Lack of thyroid hormone – loss of libido Excess thyroid hormones impotence

78. END OF LECTURE 2

79. In women - Lack of thyroid hormones leads to excessive & frequent menstrual bleeding - Irregular period and occasionally Amenorrhea. Hyperthyroid woman - Greatly reduced bleeding and occasionally amenorrhea

80. Endemic Goiter:

81. Infantile form of hypothyroidism is cretinism In adult it is called myxedema. Hypersecretion of TH: Grave disease or toxic goiter Thyroid adenoma Symptoms: exopthalamus

82. Diagnosis: BMR TSH

83. THE ADRENAL GLAND

84. There are 2 endocrine organs in the adrenal gland. INNER Adrenal medulla ---> secretes adrenaline, noradrenalin & dopamine. OUTER Adrenal cortex secretes steroid hormones

85. Divided into 3 zones-: 1. zona glomerulosa , forms 15% of the gland. Only one capable of secreting aldostorone in significant amount. 2. zona fasciculata forms 50% of the gland mass. secrete mainly cortisol but also small androgens and estrogens. 3. zona reticularis form 7% of the gland mass. secrete mainly the androgens, small estrogens and glucocorticoids . Adrenal cortex

86. Biosynthesis of adrenal cortex hormones .

87. Mineralocorticoids (Aldosterone) Functions: Renal tubular reabsorption of Na+ & secretion of k+. Na+ reabsorption from saliva, sweat & GIT Thus ECF volume Regulation of alsodsterone secretion: Its regulation is intertwined with regulation of ECF volume. K+ stimulate aldosterone secretion. activity of renin-angiotensin system. Na+ conc. in ECF slightly secretion. ACTH. From ant. Pit.

88. Glucocorticoids (cortisols, Hydrocortisone& corticosterone,) CHO metabolism: - stimulate gluconeogenesis - Glucose utilization by the cell. Can cause “adrenal diabetes”. Protein metabolism: – protein store in the body except the liver due to catabolism protein synthesis. Fat metabolism: - promotes fat mobilization of fatty acids from adipose tissue. Other effects : - provides resistance to stress. - have anti-inflammatory effects - eosinophils and lymphocytes in blood. - Suppresses immunity.

89. Regulation of cortisol secretion: Controlled entirely by ACTH (adrenocorticotropic hormone). Other stimuli: any type of physical or mental stress.

90. Adrenal Androgens has masculinizing effect it is anabolic Control: by ACTH.

91. Abnormalities of Adrenal cortex hormones Addison’s disease: failure of secretion of cortex hormones due to atrophy of the cortex. Characteristics: - Weight loss. - chronically hypotensive leading to shock (addisonian crisis) - - ACTH level elevated. Secondary adrenal insufficiency: pituitary disease causing decrease ACTH secretion. Tertiary adrenal insufficiency: hypothalamic disorder that disrupt CRH Secretion.

92. Cushing's syndrome: Prolonged in plasma cortisol. ACTH dependent- Cushing's disease due to ACTH secreting tumors of the ant. Pituitary gland or hypothalamus that secretes CRH. ACTH independent – due to tumor of glucocorticoid secreting adrenal tumors.

93. Characteristics: Protein depletion due to excess catabolism except in plasma & liver. Skin very thin. Muscles poorly developed. Wounds heal poorly. Thin hair but hair in face & acne due to androgen. Fat distribution is such that extremities are - thin but fat deposition on face (moon face). - Upper back “ buffalo hump” - Abdominal wall (pendulous abdomen)

94. Hyperglyceamia (b-cells usually burn-out can cause diabetes mellitus) hight cortisol may cause mineralocorticoid’s action i.e. water & salt retention K+ depletion Osteoporosis

95. Primary aldosteronism: tumor of z. glomerulosa resulting in excess aldosteone. - Hypokalemia - Slight in ECF vol. and blood vol. - Hypertension - Renin can be due to feedback suppression on its secretion as a result of excess ECF.

96. THE ADRENAL MEDULLA It is a sympathetic ganglion in which the postganglionic neurons have lost their axons and become secretory cells. The cells secrete when stimulated by the pregaglionic nerve fibres that reach the gland through the splanchnic nerves. Adrenal medullary hormones are not essential to life although they help prepare the individual for emergencies.

97. PHYSIOLOGICAL EFFECT OF CATECHOLAMINES Effect are exerted on target tissues by binding to a receptor site on cell membrane influencing the activity of adenyl cyclase Β- adrenergic agents increase cyclic Amp levels while a-adrenergic agents decrease it. Adrenaline & noradrenaline have both –a and Β- Adrenergic effects..

98. Exert metabolic effects – glycogenolysis in liver & skeletal muscles via Β-receptor. mobilization of FFA prompt metabolic rate force & rate of heart contraction, myocardial excitability.

99. NE- vasoconstriction via a-receptor. E- dilation of blood vessels in liver & muscles via Β2-receptor. Alertness. Cause inital plasma K+, then prolong fall in plasma K+ as K+ entry into cell is increased.

100. Synthesis, Storage, Release And Metabolism of Catecholamines (READ UP)

101. Action of Dopamine Physiological function in circulation unknown but its injection: Produces renal vasodilatation & elsewhere vasoconstriction. Positive inotropic effect on heart. Systemic B.P with no change in diastolic Press. thus used in treating traumatic & cardiogenic shock.

102. Control Under neural control. Secretion is provoked by emergency stimulation causing sympathetic discharge. Hypoglycemic is a potent stimulus.

103. DISOEDER OF ADRENOMEDULLARY FUNCTION. Functioning tumors arising from pheochromocytes. catecholamine hypersecretion. Hypertension Excessive sweating Flushing Palpitations Tremor Headaches Nausea Vomiting Nervousness Weakness

104. CALCIUM HOMEOSTASIS

105. Physiological importance of calcium:- ca2+ salts in bone provide the structural integrity of the skeleton. Ca2+ in cellular and extracellular fluids is essential to the normal functioning of a number of biochemical processes (neuromuscular excitability, blood coagulation, enzymatic regulation etc. The biochemical role of ca2+ requires that ICF and ECF conc. be maintained within a narrow range and this is achieved by an elaborate system of hormonal controls.

106. Daily net changes in calcium are as follows: About 1000mg ca2+ ingested per day. Only 1/3 of this is absorbed from the intestine (360mg) and enters ECF. Part of ca2+ in ECF is lost through enteric secretion (190mg) back into the gut. 99% of calcium is in skeleton

107. Total serum ca2+ btw 8.5 -10.5mg/dl Ca2+ is constantly entering and leaving blood through exchange btw 3main target organs: kidney, intestine and bone. The movement or interaction is controlled by: a. Parathyroid hormone (PTH). b. Calcitonin c. 1,25, dihydroxycholecalciferol.

108. Parathyroid hormone (PTH): Produced by the parathyroid gland which are 2 pairs. Situated behind the thyroid glands. Each parathyroid measures 6×4×2mm and weighs 30-50mg. The chief cell, principal parenchyma parathyroid cell is responsible for synthesis and secretion of PTH .

109. PTH- increases blood ca2+ by: 1. resorption of bone by mobilizing ca2+ from bone; stimulating osteoclastic activity. 2. Promoting ca2+ reabsorption from the glomeration filtrate and reducing urinary loss. 3. Absorption of ca2+ from G.I.T. in presence of VIT D. Regulation: level of ionized ca2+.

110. Pathophysiology: Hypofunction i.e. plasma ca2+ level leading to: - Neuromuscular Hyperexcitability and - Tetany. Early signs of tetany: - chvostek’s sign – tapping the facial nerves on the jaw causes contraction of facial muscles. - Trousseau’s sign – sphygmomanometer on arm, if inflated or tourniquet application causes carpal spasm.

111. Hyperfunction: PTH – bone fragility, osteoporosis - Hypercalcemia. - Hypophosphtemia. - Deminiralization of bones - hypercalciurea - Formation of calcium-containing kidney stones.

112. 1, 25(OH)2 vit D Produced from vit D by hydroxylation in the liver of (25 OH) and in the 1, 25(OH)2 vit D. Actions Promotes ca absorption by small intestine and kidney. On bone, mobilizes Ca2+ & PO4 transport out of osteoblasts into ECF. ( bone resorption). Facilitates action of PTH in renal tubules.

113. THYROCALCITONIN OR CALCITONIN Produced from the Para follicular or c-cell of thyroid gland. Calcitonin (by RIA) fluctuates btw 5 and 100pg/ml in human serum and has a 1/2life of 5minutes Action : inhibit bone resorption by inhibiting osteoclasts and lowering of serum calcium level

114. Main stimuli for secretion of calcitonin is an elevated serum ca2+. Acute administration of calcitonin cause hypocalcaemia and hypophoshatemia

115. Effects of other hormones Glucocorticoids- plasma ca2+ by inhibiting osteoclast formation & activity. Over long periods it cause osteoporosis by bone formation and bone reasorption. Absorption of ca2+& po4 from intestine by an anti-Vit D action and by their renal excretion. Growth hormone ca2+ excretion in urine - intestine absorption (this may be greater than the first). . Effect = +ve ca2+ balance Thyroid hormones- hypercalcaemia hypercalciuria Osteoporosis Insulin – bone formation Estrogens – prevent osteoporosis by a direct effect on osteoblasts.

116. Summary of calcium Homeostasis

117. PANCREASE Exocrine (80% of whole volume) Endocrine or Islet of Langerhans (2% of whole volume). Ducts and blood vessels (18%)

118. An endocrine gland: - α or A cells (20-30% of the cells) secrete Glucagons (regulation of intermediary metabolism of CHO, proteins and fats). - β or B cells(60-80% of the cells) secrete Insulin (regulation of intermediary metabolism of CHO, proteins and fats). - Δσ or D cells (8% of the cells) secrete Somatostatin (regulates the secretions of islet of Langerhans). - F cells secrete Pancreatic polypeptide (primarily with gastrointestinal functions). Islet of Langerhans

119. INSULIN (mol.wt 5808) Biosynthesis and secretion: In the RER of B cells. preproinsulin (mol. wt. 11,500) ( a 23a.a signal peptide removed as enters ER). proinsulin (mol. Wt. 9000. 81-86 a.a with A & B chain with interconnecting c- chain). (protein bond protease ) cleavage occur in the golgi apparatus. zn + C peptide + insulin + proinsulin (equimolar amount) (90-97% of product)

120. Secretion: release by exocytosis when sugar level in blood rises to 90mg/100ml plasma Metabolism: half life of 5-6 minutes. 80% of secreted insulin is degraded in the liver and kidney by enzyme insulin protease. Control of secretion: Negative feedback with blood glucose. blood glucose insulin blood glucose (after a meal) Insulin

121. Actions of Insulin: CHO Metabolism: blood glucose and glycogen store How?: Increase glucose entry into adipose tissues and muscles (rapid) ‘’ ‘’ glucose utilization by muscle cells. ‘’ ‘’ glycogen synthesis and storage in muscle. Decrease glucose output due to glycogenolysis and gluconeogenesis. Protein Metabolism: Protein synthesis. How?: Increase a. a uptake in the muscle (rapid) (anabolic effect) ‘’ ‘’ protein synthesis in ribosome, liver (intermediate) (anabolic effect) Decrease protein catabolism (intermediate) (anabolic effect) ‘’ ‘’ gluconegenic amino acids.

122. Fat Metabolism: Fat store (fat sparer). How ? Increase F.A synthesis and storage in the adipose tissues. ‘’ ‘’ lipid synthesis in the liver (delayed) Decrease ketogenesis in the liver. ‘’ ‘’ Lipolysis Potassium Lowers ECF K ion conc. How? Increase k+ entrance into the cells by increasing the activities of Na+-K+ ATPase in cell membranes. (rapid) In general insulin increase cell growth. Atrophy of the Islet or destruction of B cells or inhibition of insulin secretion leads to insulin deficiency resulting in DIABETES MELLITUS.

123. Diabetes means production of large vol. of urine. 2 types of diabetes: “insipidus” and “mellitus” Diabetes Mellitus It is a disease characterized by a widespread biochemical abnormalities . The hallmark of this disease is chronic high blood glucose or hyperglycemia resulting from inadequate secretion or action of insulin. Xteristics: Polyuria Weight loss Ketosis Polydispia Hyperglycemia Acidosis Polyphagia Glycosuria coma All these are due to: 1. glucose entry into various peripheral tissues 2. glucose liberation into circulation from the liver. Thus , an increase EC glucose but a decrease IC glucose in most cells “STARVATION IN THE MIDST OF PLENTY” 3. Lipolysis 4. A.A entry into muscles

124. Types: IDDM (insulin-dependent) or Juvenile-onset or type I. Damage/autoimmune destruction of the B cells. NIDDM (non insulin dependent) or maturity or type II. Reduced tissue sensitivity to insulin effect/insulin resistance and insulin deficiency. - Exercise increases insulin sensitivity. - Obesity decreases insulin sensitivity. - An obese person need to secrete high amt. of insulin to maintain normal blood glucose level - Unlike IDDM, in NIDDM the insulin level may be normal or elevated, yet there will be hyperglycemia. - Over stimulation of the B cells with drugs may promote conversion from NIDDM to IDDM.

125. Physiology of diagnosis: Glucose in urine Fasting blood glucose and insulin level GTT

126. GTT: Used clinically to diagnose diabetes i.e. the response to a std. oral test dose of glucose.

127. Insulin Excess : Leads to direct or indirect hypoglycemia. Common in adults predispose to type II diabetes. After a CHO meal, there is exaggerated response from B cells. Symptoms include: palpitation/tremor Sweating Nervousness At very low level: Neuroglycopenic symptoms: Hunger confusion At lowest level: Coma Convulsion Death

128. GLUCAGON A linear polypeptide with 29 a.a. and mol wt. of 3,485 produced by the A cells. Synthesized from preproglucagon(179 a.a.) to proglucagon(37a.a.). Half life of 5-10 mins. Degraded in liver.

129. ACTIONS OF GLUCAGON: Primary action is to increase blood glucose level. How? Increases glycogen breakdown in liver (glycogenolytic) Increase hepatic glucose synthesis Increase lipolysis in adipose tissues Increase protein catabolism Decrease protein synthesis Actions mediated via cyclic AMP.

130. Secretion: release when sugar level in blood falls Control of secretion: Negative feedback with blood glucose. Blood glucose Glucagon inhibition Glycogen breakdown Blood sugar

131. Somatostatin A tetradecapeptide Involved in regulation of G.I. Functions. Plays a role as synaptic transmitter Inhibits insulin, glucagon and pancreatic polypeptide Secretion stimulated by glucose, a.a, cc

132. Pancreatic Polypeptide Closely related to polypeptide in Gut. Has 36 a.a residue No definite function, but slows food absorption in humans

133. Aging Growth Hormone is secreted throughout an individual's lifetime although levels increase throughout childhood, peak during puberty, and slowly decline with age