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

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

Anatomy: Female Reproductive Tract

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

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

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

Normal Female Hormone Patterns

Hormonal Changes From Aging 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 Gonadotropins: LH Change to pulsatile pattern: Duration, Frequency FSH “Monotropic FSH ” 1st Noticed prior to any change in cycle length

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

Ovarian Structural Changes 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

Menopause Symptoms Hot Flashes Symptoms 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

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

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

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

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

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”

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?

Aging of the Male Reproductive System

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

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.

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 CELLS with secretory and reproductive functions

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 it decreases Subtle changes include: GnRH Sensitivity of androgen secretion to LH Sensitivity of negative feedback between GnRH and LH

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

Aging of the Prostate

The Prostate and Testosterone 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

Normal Aging of the Prostate 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

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**

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?

Hormone Replacement Therapy

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

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

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

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

DHEA and Aging DHEA Replacement beneficial in: 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?

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

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

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

Types of Hormones Used in Post-Menopause 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

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

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

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.

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