Endocrine Physiology summarised lecture notes

Endocrine physiology

1. ENDOCRINE SYSTEM Abednego M utuku

2. Introduction Hormones are the chemical messenger produced in small amount by endocrine glands, secreted into blood stream to control metabolism and biological activities in target cell or organs.

3. Introduction This is an interconnected network of glands that is closely linked with the nervous and immune systems The endocrine system involves the release of chemical substances known as hormones to regulate and integrate body functions. Hormones are produced mainly by endocrine organs. Endocrine glands secrete most hormones directly into the bloodstream. Exocrine glands , such as sweat glands, secrete their products through ducts onto epithelial surfaces or into the GI tract.

4. Characteristics or properties of hormone: Low molecular weight Small soluble organic molecules Rate of diffusion is very high and are readily oxidized but the effect does not remains constant It is effective in low concentration Travels in blood It has its target site different from where it is produce and is specific to a particular target Hormones are non- specific for organisms and may influences body process of other individuals

5. Feedback Mechanism Negative Feedback- a build up of the product will eventually reduce further production eg FT3/FT4 build up will stop TSH production Positive Feedback – a build up of the product further enhances production eg. During labour – increase in production of oxytocin, Bleeding – more platelets are recruited

6. FUNCTIONS The endocrine system plays a vital role in: Growth and development, The metabolism of energy, Muscle and adipose tissue distribution, Sexual development, Fluid and electrolyte balance, Inflammation and immune responses

7. Classification of Hormones Hormones are classified ①On the basis of chemical nature ②On the basis of mechanism of hormone action Group I hormone Group II hormone

8. 1. On the basis of chemical nature

9. 2. On the basis of mechanism of hormone action 1. Group I hormone (lipophilic hormone): These hormones are lipophilic in nature. They are mostly derivatives of cholesterol. These hormones binds to intracellular receptors Example: Steroid hormones, Estrogen, androgen, glucocorticoids, cholcalciferol, thyroxine etc 2. Group II hormones (water soluble hormone): These hormones binds to cell surface receptors and stimulates the release of certain molecules (secondary messengers) to perform biochemical functions

10. 3. On the basis of secondary messengers group II hormones are of 3 types; i. Secondary messenger is cAMP: eg. Adrenocorticotropic hormone, FSH, LH, PTH,ADH, calcitonin, glucagon, ii. Secondary messenger is phosphotidylinocitol/calcium or both: eg. Acetylcholine, vasopressin, cholecystokinin, gastrin, gonadotropin releasing hormone, thyrotropin releasing hormone, Insulin, chorynoic somato mamotropin, epidermal growth factors, fibroblast growth factors, GH, prolactin iii. Secondary messenger is cGMP: Atrial natriuretic peptide (ANP)

11. Mechanism of Action ① Hormones can alter the function of the target tissue by interacting with chemical receptors located either on the cell membrane or in the interior of the cell . Peptide and protein hormones interact with receptor sites on the cell surface, resulting in stimulation of the intracellular enzyme adenyl cyclase . This causes increased production of cyclic AMP. The cyclic AMP inside the cell alters enzyme activity. ② Some protein and peptide hormones also act by changing membrane permeability and act within seconds or minutes. ③ Steroid hormones, because of their smaller size and higher lipid solubility, penetrate cell membranes and interact with intracellular receptors. The steroid–receptor complex modifies cell metabolism and the formation of messenger ribonucleic acid (mRNA) from deoxyribonucleic acid (DNA ). The mRNA then stimulates protein synthesis within the cell. Steroid hormones require several hours to exert their effects, because they exert their action by the modification of protein synthesis.

12. Endocrine Organs Pineal Gland Hypothalamus Pituitary Anterior Posterior Thyroid Gland Parathyroid Glands Thymus Adrenal Glands Cortex Medulla Pancreas Gonads Kidney/adipocytes/ small intestine

13. Major Endocrine Glands

14. Other organs Producing Hormones GI mucosa produces hormones (eg, gastrin, enterogastrone, secretin, cholecystokinin ) that are important in the digestive process; The kidneys produce erythropoietin - erythropoesis The white blood cells produce cytokines (hormonelike proteins) that actively participate in inflammatory and immune responses. Chemicals such as neurotransmitters (eg, epinephrine) released by the nervous system can also function as hormones when needed.

15. Hypothalamus/ Pituitary Gland

16. Regulation of Endocrine System Figure 18–8a Feedback Control of Endocrine Secretion

17. Hypothalamus Communicates w/ anterior pituitary via hypothalamic- hypophyseal portal vein Dumps protein hormones into portal vein à ant. pituitary Releasing hormones stimulate hormone production in anterior pituitary Inhibiting hormones prevent hormone production in anterior pituitary

18. Hypothalamus/ Pituitary Gland

19. Anterior Pituitary Adenohypophysis Under hypothalamus rule via vein Releases six different hormones into the blood: Thyroid stimulating hormone (TSH) Adrenocorticotropic hormone (ACTH) Follicle stimulating hormone (FSH) Luteinizing hormone (LH) Prolactin (PRL) Growth hormone (GH)

20. Posterior Pituitary Neurohypophysis Communicates with hypothalamus via nerve axons from hypo to post. pit. Releases two different hormones into the blood: – Antidiuretic hormone (ADH) – Oxytocin

21. Posterior Pituitary and ADH Posterior pituitary will release antidiuretic hormone (ADH; vasopressin) into the blood when blood osmolarity is high Is this when you are hydrated or dehydrated? ADH target is kidney Reabsorb H 2 O back into body to decrease blood osmolarity (~ 300 mOsM) Less urine is formed

22. Regulation of Blood Osmolarity

23. Diabetes Insipidus Less water reabsorption and excessive urination Decrease in ADH due to damage to hypothalamus or post. pituitary (brain trauma; tumor) OR damage to kidney so water reabsorption is inhibited (inherited genetic mutation in males, drugs, infection, and hypercalcemia)

24. Thyroid gland

25. Thyroid Gland Regulates basal metabolic rate via thyroxine Regulates blood [Ca +2 ] with the parathyroid gland by releasing calcitonin when high blood [Ca +2 ] Basal Metabolic Rate: Follicular cells release thyroid hormones T3 (Triiodothyronine) & T4 (Thyroxine) These hormones increases metabolic rate, regulates body temperature

26. Mechanism of action Thyroid hormones enter cells and T3 binds to thyroid receptors (TR) in the nuclei. The hormone- receptor complex then binds to DNA via zinc fingers and increases (or in some cases, decreases) the expression of a variety of different genes that code for proteins that regulate cell function

27. Thyroid hormones circulate in the plasma predominantly in protein- bound forms. Only the free hormones are biologically active, and both feed back to reduce secretion of TSH. Thyroid hormones exert their effects by entering cells and binding to thyroid receptors. Thyroid hormones stimulate metabolic rate, calorigenesis, cardiac function, and normal mentation, and interact synergistically with catecholamines. Thyroid hormones also play critical roles in development, particularly of the nervous system, and growth.

28. Hypothyroidism (low thyroid hormone level) leads to weight gain, lethargy, and potential depression. Hyperthyroidism (oversecretion of thyroid hormones), or Graves ’ disease, leads to hyperactivity and insomnia; eyeballs tend to bulge and a goiter (enlarged thyroid gland) forms. – Removal of a part of the thyroid is the usual treatment Thyroid hormone Disorders

29. Thyroid Gland Blood Calcium Homeostasis Thyroid gland releases calcitonin when high blood [Ca +2 ] Parathyroid gland releases parathyroid hormone when low blood [Ca +2 ] Considered a humoral mediated response

30. http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/thyroid/pth.html

31. Assessment of Thyroid Serum TSH Serum FT3, FT4, T3 and T4 levels Radioactive Iodine uptake Thyroid antibodies Fine Needle Aspiration Biopsy Thyroid Ultrasound

32. Adrenal Gland

33. Adrenal Gland Two separate portions with different functions: Adrenal cortex Adrenal medulla

34. Adrenal Gland Adrenal Cortex (outer/glandular) Glucocorticoids (cortisol) Released from zona fasciculata when under stress ( ACTH) Causes tissues to increase blood glucose, liver storage of glucose (glycogen) and decrease inflammation/ immune response Mineralcorticoids (aldosterone) Released from zona glomerulosa when blood volume is low Increases blood volume by increasing Na + / H 2 O reabsorption & K + excretion from kidneys Androgens (zona reticularis) Sex hormones

35. Significance of Hypothalamic-Pituitary- Adrenal Axis to adapt to Climate Change in Livestock T. K. Binsiya,

36. Circadian rhythm of ACTH production

37. Cushing ’ s syndrome - hypercortisolism Cushing ’ s patients have very high glucocorticoid levels caused by adrenal or pituitary disease or an excess of glucocorticoid drugs. Cushing ’ s patients store fat in cells (face and midsection) that only respond to high levels of insulin, and they have a high risk of type- 2 diabetes. Stress Response

38. Aldosterone 52 Regulates blood volume Secretion by the adrenal cortex triggered by angiotensin II Promotes sodium reabsorption by the kidney tubules Na + moves back into the blood H 2 O follows by osmosis

39. Adrenal Medulla

40. Adrenal Gland Adrenal Medulla (inner/nervous) CNS synapses directly with adrenal medulla (neural response) Adrenal medulla releases Epinephrine (adrenalin) & NorEpinephrine (noradrenalin) during your fight or flight mechanism Stimulates use of glucose and glycogen and release of lipids from adipocytes Increases HR, BP and vasoconstricts blood vessels Stress and low blood glucose can increase Epi and NE

41. Pancreas

42. The Pancreas

43. The pancreas, located in the upper abdomen, has endocrine as well as exocrine functions The exocrine functions include secretion of pancreatic enzymes into the gastrointestinal (GI) tract through the pancreatic duct. The enzyme secretions include amylase, which aids in the digestion of carbohydrates; trypsin, which aids in the digestion of proteins; and lipase, which aids in the digestion of fats. The endocrine functions include secretion of insulin, glucagon, and somatostatin directly into the bloodstream. The islets of Langerhans , the endocrine part of the pancreas, are collections of cells embedded in the pancreatic tissue.

44. They are composed of: ①Alpha (glucagon) , ②Beta (Insulin) , ③Delta cells (Somastostatin) and ④ F-cells (Pancreatic polypeptide.

45. Physiology of Glucose metabolism

46. Glucose regulation cycle

47. Biosynthesis and secretion Insulin is synthesized in the rough endoplasmic reticulum of the B cells It is then transported to the Golgi apparatus, where it is packaged into membrane- bound granules. These granules move to the plasma membrane by a process involving microtubules, and their contents are expelled by exocytosis Insulin is synthesized as part of a larger preprohormone

48. Yanwu Yang, Qing- xin Hua, Jin Liu, Eri H. Shimizu, Meredith H. Choquette, Robert B. Mackin, Michael A. Weiss, Solution Structure of Proinsulin: CONNECTING DOMAIN FLEXIBILITY AND PROHORMONE PROCESSING*, Journal of Biological Chemistry, 2010,

49. Physiology of glucose metabolism

50. Mechanism of action Insulin works via Insulin receptors in all tissues. Binding of insulin triggers the tyrosine kinase activity of the β subunits, producing autophosphorylation of the β subunits on tyrosine residues The growth- promoting protein anabolic effects of insulin are mediated via phosphatidylinositol 3- kinase (PI3K)

51. Cycling of GLUT 4 transporters through endosomes in insulin- sensitive tissues.

52. Consequences of Insulin deficiency Type 1 DM (Formerly IDDM) – autoimmune β- cell destruction, leading to absolute insulin deficiency Type 2 DM (Formerly NIDDM) – progressive loss of β-cell insulin secretion, Insulin resistance Gestational Diabetes Mellitus – 90% progresses into Type II DM

53. Pathophysiology - Ominus octet of Diabetes Defronzo, Ralph. (2009). From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus. Diabetes. 58. 773-95. 10.2337/db09-9028.

54. Risk Factors

55. Risk factors for T2DM

56. Types of Insulin

57. Types of Insulin continued

58. Calcium hemostasis

59. Introduction The majority of the calcium in the body is stored in the bones but it is the free, ionized calcium in the cells and extracellular fluids that fulfills physiological roles in cell signaling, nerve function, muscle contraction, and blood coagulation, among others. Phosphate is likewise predominantly stored in the bones and regulated by many of the same factors that influence calcium levels. The three major hormones regulating calcium and phosphate homeostasis are ① 1,25- dihydroxycholecalciferol (a derivative of vitamin D) ② Parathyroid hormone; ③ Calcitonin 1,25- dihydroxycholecalciferol acts to elevate plasma calcium and phosphate by predominantly transcriptional mechanisms Parathyroid hormone elevates calcium but decreases phosphate by increasing the latter’s renal excretion. Calcitonin lowers both calcium and phosphate levels.

60. Summary of Ca 2+ regulation PTH ① Increases plasma Ca2+ by mobilizing this ion from bone. ② Increases Ca2+ reabsorption in the kidney ③ Increases the formation of 1,25- dihydroxycholecalciferol. 1,25-Dihydroxycholecalciferol ① Increases Ca2+ absorption from the intestine ② Increases Ca2+ reabsorption in the kidneys. Calcitonin ① inhibits bone resorption ② Increases the amount of Ca2+ in the urine.

61. Calcium hemostasis

62. http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/thyroid/pth.html

63. Disorders Osteopetrosis Osteoporosis Hypercalcaemia Hypocalcaemia

64. Gonads and Reproductive System

65. Gonads Differences between males and females depend primarily on a single chromosome (the Y chromosome) and a single pair of endocrine structures (the gonads); testes in the male and ovaries in the female The gonads have a dual function: ①The production of germ cells (gametogenesis) ②The secretion of sex hormones. The testes secrete large amounts of androgens, principally testosterone, but they also secrete small amounts of estrogens. The ovaries secrete large amounts of estrogens and small amounts of androgens.

66. Testosterone is the principal hormone of the testis. It is synthesized from cholesterol in Leydig cells. The secretion of testosterone from Leydig cells is under control of luteinizing hormone at a rate of 4 to 9 mg/day in adult males. Most testosterone is bound to albumin or to gonadal steroid- binding globulin in the plasma. Testosterone plays an important role in the development and maintenance of male secondary sex characteristics, as well as other defined functions. Ovaries also secrete progesterone, a steroid that has special functions in preparing the uterus for pregnancy. During pregnancy the ovaries secrete relaxin, which facilitates the delivery of the fetus. In both sexes, the gonads secrete other polypeptides, including inhibin B, a polypeptide that inhibits FSH secretion.

67. Testosterone

68. Actions Secondary sex characteristics - The widespread changes in hair distribution, body configuration, and genital size that develop in boys at puberty. Exert an inhibitory feedback effect on pituitary LH secretion Androgens increase the synthesis and decrease the breakdown of protein, leading to an increase in the rate of growth. Maintain spermatogenesis – along with FSH.

69. Actions of testosterone

70. Abnormalities of testicular functions Cryptorchidism Hypogonadism ① Testicular disease - circulating gonadotropin levels are elevated (hypergonadotropic hypogonadism); ② Secondary to disorders of the pituitary or the hypothalamus (eg, Kallmann syndrome), circulating gonadotropin levels are depressed (hypogonadotropic hypogonadism). Eunuchoidism - when the Leydig cell deficiency dates from childhood

71. Female reproductive System

72. Gonads- Menstrual cycle

73. Ovarian Hormones

74. ESTROGEN The naturally occurring estrogens are ① 17β- estradiol – E 2 ② Estrone – E 1 ③ Estriol – E 3 Their biosynthesis depends on the enzyme aromatase (CYP19), which converts testosterone to estradiol and androstenedione to estrone Theca interna cells have many LH receptors, and LH acts via cAMP to increase conversion of cholesterol to androstenedione.

75. Effects of Estrogen Estrogens decrease FSH secretion. Estrogens cause increased secretion of angiotensinogen and thyroid- binding globulin. They exert an important protein anabolic effect in chickens and cattle, possibly by stimulating the secretion of androgens from the adrenal Estrogens facilitate the growth of the ovarian follicles and in- crease the motility of the uterine tubes. They cause epiphysial closure in humans The estrogens are responsible for estrous behavior in animals, and they increase libido in humans.

76. Estrogens produce duct growth in the breasts and are largely responsible for breast enlargement at puberty in girls They are responsible for the pigmentation of the areolas, Estrogens cause some degree of salt and water retention. Female Secondary sex characteristics - enlargement of breasts, uterus, and vagina— are due in part to estrogens “Feminizing Hormones” Estrogens have a significant plasma cholesterol- lowering action, and they rapidly produce vasodilation by increasing the local production of NO.

77. Abnormalities of Ovarian Function Amenorrhea is the absence of menstrual periods ^ Primary or Secondary Hypomenorrhea - too scanty Menorrhagia - abnormally profuse flow, Metrorrhagia is bleeding from the uterus between periods Oligomenorrhea is reduced frequency of periods. Dysmenorrhea is painful menstruation. Premenstrual syndrome (PMS) - irritability, bloating, edema, decreased ability to concentrate, depression, headache, and constipation during the last 7 to 10 d of their menstrual cycles. These symptoms of the have been attributed to salt and water retention.

78. Pineal & Thymus Glands Pineal Gland (Endocrine & CNS) Melatonin Target: Hypothalamus Action: Sets Diurnal Clock/Circadian rhythm & promotes sleep Thymus (atrophies at puberty) Thymosins Target: T cells of immune system Action: T cell maturation (immunocompetence)

79. Figure 16.13

80. Thank You