Ryan Klimczak Discussion 7 April 16th, 2007 Lectures 27,28,29-32

1. Ryan Klimczak Discussion 7 April 16th, 2007 Lectures 27,28,29-32

2. Hypophysiotopic hormones (A hormone secreted by the hypothalamus that stimulates or inhibits the adenohypophysis portion of the pituitary gland) CRH - corticotropic releasing hormone - released from the hypothalamus. It interacts with the pituitary to produce adrenocorticotropin hormone. Involved in the stress response. GHRH - growth hormone releasing hormone - The hormone released from the hypothalamus that causes the release of growth hormone from the pituitary gland GHIH - growth hormone inhibitory hormone - (somatostatin) - inhibits the release of GH and TSH, suppresses the release of gastrointestinal and pancreatic hormones and also suppressed the exocrine secretory function of the pancrease PRH - prolactin releasing hormone - A polypeptidehormone that originates in the hypothalamus and stimulates the secretion of prolactin in the pituitary gland. GnRH - gonadotropin releasing hormone - A hormone made by the hypothalamus (part of the brain). GnRH causes the pituitary gland to make luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These hormones are involved in reproduction TRH - thyrotopin-releasing hormone - hormone released by the hypothalamus that controls the release of thyroid-stimulating hormone from the anterior pituitary

3. Pituitary hormones ACTH - adrenocorticotropin hormone - Hormone produced by the pituitary gland, which stimulates the adrenal glands to produce cortisone LH - lutenizing hormone - A pituitary hormone that stimulates the gonads. In the man LH is necessary for spermatogenesis (Sertoli cell function) and for the production of testosterone (Leydig cell function). In the woman LH is necessary for the production of estrogen. When oestrogen reaches a critical peak, the pituitary releases a surge of LH (the LH spike), which releases the egg from the follicle. [Gonadotropin] FSH - follicle stimulating hormone - hormone secreted by the pituitary gland in the brain that stimulates the growth and maturation of eggs in females and sperm in males, and sex hormone production in both males and females. [Gonadotropin] Vasopressin: hormone secreted by the posterior pituitary gland and also by nerve endings in the hypothalamus; affects blood pressure by stimulating capillary muscles and reduces urine flow by affecting reabsorption of water by kidney tubules Oxytocin: involved in reproductive behaviour in both men and women, and apparently triggers "caring" behavior. It is also the hormone which allows contractions of the womb during pregnancy and labour

4. Pituitary hormones (con’t) PL - prolactin - hormone produced by the pituitary gland that stimulates breast development and milk production. TSH - thyroid stimulating hormone - Ahormone secreted by the anterior pituitary gland, that controls the production and release of the thyroid hormones (T4 and T3) GH - growth hormone - A peptide hormone, made in the anterior pituitary, that stimulates tissue and skeletal growth MSH - melanocyte stimulating hormone - stimulates the production and release of melanin (melanogenesis) by melanocytes in skin and hair. MSH is also produced by a subpopulation of neurons in the arcuate nucleus of the hypothalamus. MSH released into the brain by these neurons has effects on appetite and sexual arousal.

5. Adrenal hormones (glucocortocoids) Cortisol - One of the primary catabolic hormones in the body. It is typically secreted in response to physical trauma or prolonged stress. Its functions include controlling inflammation, increasing muscular catabolism and glycolysis, suppressing immune response, and maintaining normal vascular circulation and renal function, among others. Epinephrine (Adrenaline) - A hormone produced by the adrenal glands that also acts as a neurotransmitter for nerve cells. As part of the fight-or-flight response, epinephrine signals the heart to pump harder, increases blood pressure and has other effects on the cardiovascular system. It helps the liver release glucose (sugar) and limits the release of insulin. Norepinephrine (Noradrenaline) - A neurotransmitter and a hormone. It is released by the sympathetic nervous system onto the heart, blood vessels, and other organs, and by the adrenal gland into the bloodstream as part of the fight-or-flight response. Norepinephrine in the brain is used as a neurotransmitter in normal brain processes. DHEA - (dehydroepiandrosterone) steroid precursor produced by the adrenal gland and converted to testosterone or the estrogens by the body's tissues. Adequate DHEA levels give the body the building blocks necessary to produce these hormones.

6. Thyroid: Thyroxine: The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are tyrosine-based hormones produced by the thyroid gland. They act on the body to increase the basal metabolic rate, affect protein synthesis and increase the body's sensitivity to catecholamines (such as adrenaline). An important component in the synthesis is iodine. Sex hormones: Testosterone - the male sex hormone, secreted by the testes but also synthesised in small quantities in the adrenal glands. Testosterone is necessary in the foetus for the development of male genitalia, and increased levels of testosterone at puberty result in the further growth of genitalia and the development of male secondary sex characteristics such as facial hair. DHT - Dihydrotestosterone - The enzyme 5 alpha reductase converts testosterone into its more potent form DHT. considered to be an aging-bio-marker. Among its affects are the appearance of body-hair, the loss of scalp hair and the onset of prostate gland problems. Estrogen - The female sex hormone produced by the ovary. Estrogens are responsible for the development of secondary sexual characteristics and cyclic changes in the viginal epithelium and endothelium of the uterus.

7. Sex hormones (con’t) Progesterone: A female hormone secreted by the corpus luteum after ovulation during the second half of the menstrual cycle (luteal phase). It prepares the lining of the uterus (endometrium) for implantation of a fertilized egg and allows for complete shedding of the endometrium at the time of menstruation. In the event of pregnancy, the progesterone level remains stable beginning a week or so after conception. Inhibin: Peptide that is an inhibitor of FSH synthesis and secretion and participates in the regulation of the menstrual cycle.

10. Table 10.1 Factors Influencing Evaluation of Endocrine Function in Aging Physiologic Factors Metabolic rate, body composition, dietary regimen, physical exercise, exposure to stress (environmental and psychosocial) Relations with other endocrines and body systems Secretory cells and their rates of secretion Transport of the hormones to target cells • Metabolism of the secreted hormones • Metabolites may be more or less biologically active than the • secreted hormones (e.g. more active, conversion of T to DHT) Number and affinity of hormone receptors Intracellular postreceptor molecular events Occurrence of disease and use of medications

11. Gene expression & new protein synthesis • Relatively long latency of onset • Medium & long term cell program • Organization of cell networks for complex functions • Activation/repression of pre-existing cell proteins • Rapid onset of action • Rapid adaptation to changes in the milieu • Dynamic modifications of long term cell programs

13. Changes with Aging in the Hypothalamo-Pituitary-Adrenal Axis No significant changes in healthy, non-stressed, elderly The few changes that occur are rapidly compensated for (e.g. decreased secretion of GCs from the adrenal cortex) but also less rapid metabolism in the liver & less urine excretion Therefore the circulating levels remain constant Also, normal ACTH & cortisol responses to CRH administration Some alterations of the circadian rhythm

14. Exposure to Stress Generates: • Specific responses: vary with the stimulus (specialized responses) and generate different responses with each different stimulus. • Nonspecific responses: (also called non- specialized) are always the same • regardless of the stimulus • mediated through stimulation of neural, endocrine, and immune axis

15. HomeostasisFrom Walter B. Cannon (1871-1945)Wisdom of the Body, 1932 From Greek: homeo “the same” stasis “state” Indicates that for optimal function of the organism, a steady state (or equilibrium) must be achieved This “constancy” of the internal environment allows survival despite continuing changes in the external environment (stress)

16. Homeodynamics A constant environment obtained through a series of dynamic adjustments This continual need for adjustment is implicated in the term “allostasis” (From Greek allo “different” stasis “state”) Emphasizes the dynamism of adaptive responses to stress This adaptation to stress is often achieved with a price -- a declining ability to adapt and/or an increased pathology and disease *Prof. T. Seeman, Geriatrics, UCLA (UCB alumna)

17. Table 10.6 glucagon secretion

18. Table 10.6

19. Beneficial effects of Hormesis may be due to: DNA repair Immune competence Neurologic acuity Neuromuscular activity Better memory Resistance/ adaptation to stress

20. Several lines of investigations have shown that manipulation of the genome will result in changes of the phenome. These changes involve alteration of the endocrine signaling with a shift From To • High energy consumption • Active growth & development • Active reproductive function • Reduce energy • consumption • Arrest of growth, • development, • reproductive function • High resistance to stress

21. Shift in HPA secretory priorities during stress

22. Suppressing signaling from hormones such as: insulin, growth hormone, insulin-like growth hormone and others by constructing mutants with lack of the hormone or the hormone receptors can prolong the lifespan as much as six times the lifespan in C. Elegans,delaying the aging process

23. “I cannot, and should not, be cured of my stress but merely taught to enjoy it” Hans Selye, l950 Responses to stress are indispensable to our survival as they allow us to maintain the internal equilibrium necessary for optimal function Responses to stress are multifactorial (depend on interactions of several systems)

24. If response to stress is severe & prolonged it may represent a major risk for the “diseases of adaptation” (e.g. cardiovascular, cognitive, emotional, metabolic diseases) & shorten the lifespan • If the response to stress is moderate & of short duration, it may stimulate hormesis: • the functions of alertness, vigilance & motivation • a greater availability & utilization of metabolic energy • favor DNA repair • improve protein folding (chaperone stimulation) • prevent/decrease free radical accumulation • promote survival and may delay aging

25. ON FLIES, WORMS, RODENTS: LONGEVITY is associated With stimulation (up-regulation) Of genes involved in response to stress including those of HSP HSPs act as chaperones and promote greater tolerance/resistance to stress (thermic and others) Hence, increased longevity and hormesis may depend on Increased HSPs and their actions as chaperones

26. With Age: • Incidence of Diabetes Mellitus Type 2 (late onset diabetes, non-insulin dependent diabetes) increases considerably • Diabetes Mellitus Type 2 is the most common form of diabetes • Onset occurs years before symptoms are appreciated • therefore, it is important to screen high risk individuals

28. Morphologic Changes • A certain degree of atrophy • An increased incidence of tumors • Presence of amyloid material & lipofuscin granules (signs of abnormal cellular metabolism)

29. Pancreatic endocrine functions •  cells: insulin (stores glucose) •  cells: glucagon (mobilizes glucose) •  cells: Somatostatin (regulatory, inhibits endocrine pancreas) • PP cells: pancreatic polypeptide (regulatory, inhibits exocrine pancreas) • The pancreas also has exocrine functions, secreting enzymes needed in digestion (pancreatic amylase, trypsin, chymotrypsin, etc.)

30. Table 14-2 Major actions of insulin Glucose transport into muscle & adipose cells overall body growth (general effect) • intracellular metabolic use of glucose blood glucose intracellular transport of amino acids & lipids & protein and triglyceride synthesis glycogen synthesis in liver and muscle cells gluconeogenesis (in liver)

31. When blood glucose is high (hyperglycemia), glucose balance is maintained by: Glucose cellular uptake (in muscle) Insulin secretion Endogenous production of glucose Storage of glucose (in liver as glycogen), fat & amino Acids arriving in the blood form GI tract Utilization of glucose (muscle & adipose cells)

33. How does glucose cause insulin release? How does insulin lower blood sugar? Glucose from blood vessel Insulin primarily targets muscle cells / adipocytes

35. Table 14-7 Characteristics of Diabetes Mellitus glucose uptake Hyperglycemia glycogenesis hepatogluconeogenesis Glycosuria Polyuria Polydipsia Polyphagia protein catabolism plasma amino acid gluconeogenesis Weight loss, growth inhibition Negative nitrogen balance lipolysys free fatty acids Ketosis Acidosis Vascular changes Microangiopathies

36. Theories of Complications • High levels of glucose lead to formation of Advanced Glycosylation End products (AGEs). They cross-link proteins and accelerate atherosclerosis, kidney damage, artery wall damage • Excess Glucose is metabolized through a different pathway, the sorbitol pathway which more readily forms reactive oxidative species • Excess glucose activates Protein Kinase C and alters other cellular pathways, leading to deleterious changes in transcription/translation and thus causing damage • ?

37. Table 14-8 • Diabetes and Accelerated Aging • DIABETESAGING • Microangiopathy --- • Cataracts Cataracts • Neuropathy Neuropathy • Accelerated Atherosclerosis Atherosclerosis • Early decreased fibroblast Decreased fibroblast • proliferation proliferation • Autoimmune involvement Autoimmune involvement • Skin changes Skin changes

39. Anatomy of the Male Reproductive Tract • In humans the principal reproductive organ is the brain • In addition to the brain, the male reproductive system consists of the: TESTIS Primary sex organ suspended outside of the body in the scrotum Secondary male sex organs include: EPIDIDYMIS, VAS DEFERENS, EJACULATORY DUCTS which carry sperm to the urethra SEMINAL VESISCLES, PROSTATE, & BULBOURETHRAL GLANDS which secrete seminal fluid PENIS with URETHRA through which flow both urine and semen

40. A simplified version of the male reproductive endocrinology: The hypothalamus releases GnRH into the circulatory system and, through blood, directly into the pituitary. GnRH triggers the release of the pituitary LH and FSH that stimulate the testes to testosterone secretion and sperm production.

42. The testis, the male primary reproductive organ, contains three types of cells, all necessary for reproduction: the GERM CELLS or GAMETES, involved in fertilization. the INTERSTITIAL CELLS of LEYDIG that secrete testosterone, the major androgen the SERTOLI CELLSwith secretory and reproductive functions

43. With Age: • On the average, the male reproductive function remains normal (or only slightly diminished in some individuals) until advanced old age (80+ years) when itdecreases • Subtle changes include: GnRH Sensitivity of androgen secretion to LH Sensitivity of negative feedback between GnRH and LH

44. Table 19-13 • Normal Aging of the Prostate • After age 40: • Outer regions: • Atrophy of smooth muscle and proliferation of connective tissue • Flattening of secretory epithelium • Inner region: • Increase in the number of cells present (hyperplasia) • After age 60: • Slower, but more uniform atrophy of the prostate • Accumulation of prostate concretions

45. Table 19-12 • The Prostate and Testosterone • The healthy prostate is dependent on androgens for growth • In the prostate: testosterone  dihydrotestosterone (DHT) • The enzyme catalyzing this reaction is 5--reductase • DHT stimulates growth of the prostate

48. Treatment of Prostate Cancer Depends on Life expectancy Overall health status Personal preferences Size of the prostate State of disease Treatments include: Watchful waiting Surgery Radiation Therapy Hormonal Therapy Cryotherapy **PSA controversary pp. 353, 354**

49. Ovary Characteristics • Ovaries • Contain germinal cells • Contain endocrine producing cells • Thecal • Granulosa • Determine secondary structures and sexual characteristics

50. Hypothalamus GnRH Pituitary FSH, LH Ovaries E2, P