Aging and ReproductionBIO 390P – Human Reproductive Biology

Reproductive Aging in the Female•Perimenopause or the female climacteric is a period surrounding menopause–A decline in the integrity of the HPO axis–Reproductive aging occurs much earlier than that of other body functions

•Reproductive changes surrounding menopause–Decreased fertility–Increased incidence of miscarriage and/or chromosomal abnormalities–Loss of menses

•Endocrinological changes surrounding menopause–Loss of follicular activity

•Progressive loss of granulosa cell function–Decrease in mean levels of estradiol

•especially during luteal phase–Increased gonadotropin levels

•FSH = 10-15X higher; LH = 3-4X higher•Due to decreased feedback of estrogen

•Why the changes?–Decline in follicular activity

•Perhaps caused by a depletion of primordial follicles below a critical value•Decline in granulosa cell competence

–Older women have fewer granulosa cells in each follicle

•Estrone becomes the primary estrogen after menopause–Derived from androstenedione (a weak androgen) in:

•Adipose tissue•Stromal (non-follicular) cells of the ovary•Adrenal glands

•Menopause seems to be unique to humans – Is there an evolutionary significance???–Simply a result of increased life expectancy–“Grandmother hypothesis”

•Ensuring maximal survival of genes•Aren’t fathers more important?

–Risks of child bearing at an older age?•Childbirth itself•Prolonged care…

The Medicalization of Menopause •The experience of menopause involves many possible symptoms

–Physical•Loss of skin texture, hair loss, growth of facial hair•Reduced breast size, Weight gain•Urogenital atrophy•Osteoporosis•Changes in metabolism and cardiovascular function

–Psychological•Hot flushes / cold sweats•Numbness, bloatedness•Backache, headache, dizzy spells•Bowel disorders•Rheumatic pains•Fatigue•Palpitations / panic attacks•Irritability, nervousness, depression•Excitability, loss of libido, insomnia

•If menopause is due to a loss of estrogen, then perhaps it can be treated…–ERT – estrogen replacement therapy–HRT – estrogen and progestin therapy

•Benefits–Protective effect for CHD

•Both ERT and HRT cause an increase in HDL, and decrease in LDL – protective effect•CHD accounts for 53% of all women’s deaths after age 50

–Osteoperosis•Bone health is a balance between osteoblast and osteoclast function •Influenced by physical activity, nutrition, and estrogen•Bone loss of 15% over 4-5 year period•ERT can stabilize bone mass irrespective of start time

–Maintains and enhances verbal memory –Relief of dry itch skin and urogenital atrophy

•Risks (do not apply to all women)–Long term ERT increases risks of endometrial cancer

•Addition of progestin (10-12 days/month) has a protective effect–Long term ERT increases risk for breast cancer

•30% increased risk (12.5 – 17%)•No protective effect from adding progestin•No Alcohol = no increased risk…

–Other side effects•Utrine bleeding•Venous thrombosis / pulmonary embolism•Breast soreness (early)•Exacerbation of migraines•Gallstones•Fluid retention

•Selective estrogen receptor modulators (SERMS) are alternatives to ERT–Maintains effects of estrogen, but reduces risks–Bind with different affinities to α and β forms of the estrogen receptor

•Some tissues have only α, others have only β–Three presently approved for human use

•Tamoxifen (tx of breast cancer)•Toremifene (tx of breast cancer)•Raloxifene (reduces the risk of breast and endometrial cancer as well as preventing osteoporosis and reducing risks of CHD)

•Bisphosphonates are used in treatment of osteoperosis–Aldronate –Inhibit osteoclast activity–Resulting in increased bone mass

Andropause: Male Menopause•Develops over a longer period of time than menopause (48-70 yrs)

–Remain fertile into the 70’s (paternity at 94)•Symptoms

–Decline in sexual activity–Erections take longer to achieve and require more stimulation–Changes in male sex characteristics

•Voice raises•Decrease in facial hair•Shrinkage of genitals and accessory structures

–Decreased muscle mass and strength –Osteoporosis–Depression and irritability –Impaired memory–Insomnia–Fatigue–Loss of concentration

•Potential Causes–Aging men experience declines in testosterone levels

•Higher blood testosterone levels in older men who are sexually active•Cause or effect???

–Does not seem to be a result of declines in HPT activity–Perhaps a decreased testicular response to pituitary gonadotropins–Higher estrogen levels???–Most likely a result of age related factors

•Treatment with androgen replacement therapy–Works for some–Increased risk of prostate cancer and CHD–Much more research needed in this area