Today: 4/24/06

1. Today: 4/24/06 Female Reproductive System Aging Male Reproductive System Aging Hormone Replacement Therapy

2. Terminology • Menopause • Permanent Cessation of Menstruation • Permanent Loss of Ovarian Function • No reproduction • Functional consequences of low estrogens/progesterone • Perimenopause • 1 year before until 1 year after menopause • Postmenopause • From menopuase until death • Premenopause • Before menopause

3. Anatomy: Female Reproductive Tract

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

5. Cells in hypothalamus secrete GnRH (gonadotropin releasing hormone) • which reaches through the portal blood system the anterior pituitary where it stimulates the secretion of gonadotropins FSH & LH • FSH stimulates ovary to produce estrogens • LH stimulates release of the ovum in oviduct and production of estrogen and progesterone

6. Endocrinology • GnRH: Gonadotropin Releasing Hormone • Peptide • Hypothalamus • FSH, LH: Follicle Stimulating Hormone and Luteinizing Hormone • Peptides • Anterior pituitary gonadotrope cells • E, P: Estrogens and Progesterone • Steroids • E from follicle cells and corpus luteum • P from corpus luteum

7. Normal Female Hormone Patterns

8. Gonadotropins: LH Change to pulsatile pattern: Duration, Frequency FSH “Monotropic FSH ” 1st Noticed prior to any change in cycle length Ovarian Steroidal Hormones Estrone levels early in the cycle in older ovulatory women Possible due to LH/FSH alterations Eventually, H-P-G axis is unable to generate LH surge needed for ovulation Hormonal Changes From Aging

9. Fertility Changes and Perimenopause • Fertility and Fecundity Decrease • Ovulatory cycle continues after onset of perimenopause • Cycle length becomes more variable • Shortening of follicular phase • No change in luteal phase • Peak fecundity occurs at 24, with a gradual decrease to 35, and a rapid decrease after 35

10. Abnormalities in Older Oocyte Change in microtubule and chromosome placement at the second metaphase of meiosis May be linked to increased aneuploidy (unbalanced chromosomes) seen in offspring of older women Declining Follicular Reserve 2 Million Primordial Follicles during fetal development Declines to 1 million at birth and 250,000 by puberty Primordial Follicles develop to primary and secondary follicles independent of hormone status In the absence of LH/FSH, follicles undergo atresia Once follicles are depleted, ovarian hormone production declines Ovarian Structural Changes

11. Menopause Symptoms • Hot Flashes • Most common reported symptom: 70-80 % of women report signs of hot flashes • Asian women have much lower rate • 10-25 % Reported • Possibly due to genetics, diet, lack of reporting • Symptoms • Sweating • Increased Skin Conductance • Increased Core Body Temperature • Increased Metabolic Rate • Increased Skin Temperature • Hot flashes appear to be the result of noradrenergic control independent of estrogen regulation • ERT alleviates the symptoms of hot flashes • Adrenergic receptor agonists also show promise for treatment

12. Menopause Effects on the Reproductive Tract • Reproductive targets for steroidal hormones experience atrophy following menopause • In addition, these more specific changes are seen: • Vagina • Dryness • Decreased Vascularity • Decreased Secretions • Increased Risk of Infections • Ovaries • Become more fibrotic as follicles diminish • Uterus • Loses Weight and Volume

13. Effects on Non-Reproductive Steroidal Targets • Skin • Thinning of epidermis • Atrophy of sebaceous glands • Increased sensitivity to temperature, humidity, and trauma • Bladder • General Atrophy • Results in urinary incontinence • Hair • Body hair undergoes redistribution

14. Menopause and Non-reproductive Targets • Skeletal System • Osteoporosis • Decreased bone mass following menopause that appears to be the result of declining estrogen level • Central Nervous System • Psychological • Anxiety/Depression • Cognition/Memory • Cardiovascular System • Possibly due to role of estrogen in lipid metabolism

15. Osteoporosis • Cell Types: • Osteoblasts: form new bone (build) • Osteoclasts: resorption of old bone (chew) • Osteocytes: mature bone cells that maintain the bone matrix • Osteogensis is the formation of new bone

16. Why Menopause? • Life span of a species and survivability of offspring • Women have survived to an age where natural selection is no longer favored as the maintenance of the reproductive system • Menopause may be a pleiotropic effect of genes that had value earlier in life • Menopause may carry advantage for survival of species • Non-reproducing species members to care for young • “Surrogate Mothers”

17. Questions • What are the major female reproductive changes with aging? • What is menopause? • What are some of the non-reproductive effects of menopause? • What are the reproductive hormones in the female reproductive tract and how are they controlled?

18. Aging of theMale Reproductive System

19. 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

20. 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.

21. 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

23. 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

24. Young Older Young Older Serum LH concentration With aging, loss of high-amplitude LH pulsesdespite normal or increased pituitary LH stores Serum testosterone concentration With aging, decreased responsiveness of testis androgen secretion to LH

25. Aging of the Prostate

26. 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

27. 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

30. 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 controversy pp. 353, 354**

31. Questions • What are the male reproductive changes with aging? • What are the changes in the prostate with aging? • What are the hormones involved in the male reproductive tract and how is their release controlled?

32. Hormone Replacement Therapy

33. Hormone Replacement Therapy Involves the attempt to replace, or substitute, the lost constituent with a similar exogenous substance with comparable properties and actions • Dose, duration, metabolism, target cells, and side effects

34. Replacement Therapy Problems in Aging • Complexity of endocrine system • Loss or insufficiency of endogenous hormones • Target cells for hormones are themselves aging and this may effect their responsiveness • Changes in hormones and their targets due to disease and degenerative processes

35. Hormone Replacement Strategies • Adrenal Sex Steroids and DHEA • Growth Hormone • Insulin (as in Laura Epstein’s lecture 4/14) • Reproductive Hormones

36. Dihydroepiandrosterone (DHEA) • DHEA is the principal adrenal androgen • *Note-Does not bind androgen receptor • DHEA(S) concentrations change throughout the human life • DHEA(S) levels are lower in women than men • Increased mortality is associated in men with a lower DHEA(S) baseline, but not in women

37. Epidemiological Evidence (DHEA low levels) cardiovascular mortality Found in: Autoimmune diseases Dementia Breast cancer DHEA(S) levels may be indicative of a severe disease or predictive of a future disease DHEA Replacement beneficial in: Adrenal Insufficiency Healthy Elderly? No increase in well being, cognition, nor sexuality Elderly with impaired mood, cognition and sexual function? DHEA and Aging

38. Growth Hormone and Aging • Study in 1990 demonstrated in small group of elderly men that GH and IGF I levels were reduced: • 12 out of 21 men injected with hGH over a 6 month period showed small increases in muscle mass and bone density (10-14%) • Suggests that GH might be responsible in part for decreased muscle and bone in elderly

39. Role of GH in Aging • GH and IGF-I serum levels decrease in some elderly and nocturnal peak is lower or absent • Possibly due to: • Decreased GHRH • Increased GHIH (somatostatin) • Stress

40. Effects of GH Treatment • 1998 study of ICU patients found: • Mortality increased from 19% to 44% in patients having GH therapy for 7-14 days • Length of hospital stay was prolonged by GH therapy • Attributed to: • Decreased immune function • Increased insulin resistance • Multi-Organ Failure

41. Estrogens Alone or with progestin Types and route of administration Optimal dose is the lowest dose to treat symptoms over the shortest duration Progestins With Estrogen to reduce risk of endometrial cancer Cardiovascular risks outweigh benefits Other products for osteoporosis treatment Types of Hormones Used in Post-Menopause

42. Risks of HT • Estrogen + Progestin • Increases Risk of: • Breast Cancer • Heart Disease • Stroke • Blood Clots • Dementia • Decreased Risk of: • Hip Fractures (Osteoporosis) • Colon Cancer

43. Benefits of HRT • Relieves Short-Term Symptoms of Menopause: • Hot Flashes • Sweats • Disturbed Sleep • May also help prevent colon cancer and age-related vision loss

44. Alternatives to Hormone Therapy?(Recommendations from the Mayo Clinic) • Maintain a Healthy Heart: • Don't smoke. • Be physically active. • Eat a low-fat, high-fiber diet, plentiful in fresh fruits and vegetables. • Maintain a healthy weight. • Manage high blood pressure. • Keep cholesterol and triglyceride levels in check. • Control diabetes. • Avoid excess alcohol. • Healthy Bones • Calcium and vitamin D. Make sure you're getting enough of these nutrients in your diet to keep your bones strong. • Exercise. Regular physical activity — especially weight-bearing exercises such as walking or dancing — can help keep your bones strong and healthy.

45. Questions • What are the risks and benefits of post-menopausal hormone replacement therapy? • What are some of the challenges of hormone replacement therapy?