Harvard-MIT Division of Health Sciences and Technology HST.071: Human Reproductive Biology Course Director: Professor Henry Klapholz HST 071 IN SUMMARY OVARIAN FAILURE OVARIAN FAILURE Possible Menstrual Changes During the Perimenopause – Cycle shorter than 28 days – Bleeding for more days than usual – Bleeding for fewer days than usual – Heavier bleeding – Lighter bleeding – Skipped periods Causes of Ovarian failure Genetic factors� - e.g. micro deletions X-chromosome, mosaic 45X0/46XX - e.g. mutation in FSH receptor gene Viral factors - e.g. mumps Iatrogenic factors - surgery (e.g. oophorectomy, hysterectomy) - chemotherapy (e.g. for breast cancer, lymphoma) - radiotherapy (e.g. for cervix cancer, Hodgkin’s) Life style factors - e.g. cigarette smoking, vegetarian diet Other factors - e.g. autoimmune diseases (myasthenia gravis) e.g. low body weight Menopause Three phases over about 10 years – Perimenopause (mid forties) • Irregular cycles • Hot flushes • Mood changes • Sleep disturbance – Menopause • 12 months without a period • Not pregnant • Age 48-55 – Postmenopause • No periods • Onset of menopause determined by the ovary • Other functional body changes secondary • Loss of the capacity of the ovary to sustain ovulation • Nearly complete loss of ovarian follicles • Minimum 1000 follicles has to be present for ovulation • Birth -a few million primordial follicles are present • Menarche -around 250,000 folliclesIN SUMMARY HST 071 OVARIAN FAILURE •� 500 will reach the stage of a Graafian follicle •� Process of apoptosis and atresia •� 38 years -disappearance of follicles becomes accelerated •� Mid-thirties -the duration of the menstrual cycle gradually declines •� 4 to 6 years before menopause -women start to notice changes in their menstrual cycle •� Accompanied by o� night sweats o� hot flushes o� vaginal dryness •� Ovulatory cycle remains intact until the mid-forties, •� 5 years before menopause -three-quarters of all women, mean cycle length Gradually increases from 28 days (range 26 -32 days) to 60 days (range 35 ->100 days) •� Hormone levels may fluctuate -highly variable between cycles •� Estradiol tends to stay within the normal fertile range (400 -600 pmol/L) •� Levels below 200 pmol/L at one year after menopause •� Postmenopausally -non-ovarian tissues o� fat o� liver o� kidney •� Peripheral conversion of androgens •� Obese postmenopausal women o� Higher circulating estradiol o� Less oestrogen bound to SHBG •� Estrone may rise •� Secretion of androgen by the ovary is reduced •� Decline of peripheral androgen levels by 20 -40 percent •� Increased androgen to estrogen ratio o� Androgen-associated facial hair pattern o� Deepening of the voice The hypothalamic-pituitary-ovarian axis •� Growing hypothalamic-pituitary stimulation •� Early follicular phase FSH levels (cycle day 3 FSH) o� Rise typically 10 years before the menopause •� Ovaries become also progressively less responsive to exogenous �gonadotrophins�•� Refractory to stimulation with exogenous gonadotrophinsIN SUMMARY HST 071 OVARIAN FAILURE • Secretion of FSH is influenced o Estradiol o Inhibin  Products of the ovarian granulosa cells • Both suppress the pituitary secretion of FSH • LH serum levels remain unchangedIN SUMMARY HST 071 OVARIAN FAILURE Symptoms of Menopause • Hot flush – 30-80 percent of postmenopausal women – Sudden sensation of heat rising to the top of one’s body – Shiver at conclusion – Disruptive to sleep patterns – Cross-cultural differences May last from 1 month to 7 years What’s Hot Flush Really About ? – 75% of women experience hot flushes – 10-15% seek physician help for this – Highest during first 2 years – 85% for more than 1 year – 20-50% for up to 5 years – Oophorectomy flashes are more severe and frequent – 2/3 premenopausal women – May continue to have periods Description of Hot Flush • Visible redness of upper chest, neck, face • Perspiration in that area • Finger temperature rises p to 6 degrees C. • Temperature drops after sweating • Night sweats – More severe – Awaken from sleep • Fatigue, irritability, inability to concentrate, Awakened before temperature changes Ovarian function reduced – 6AM to 8 AM & 6 PM to 10 PM – Most women have one a day – Some have many or a few as one weekly – Triggers o Stress o Warm weather o Hot drinks, alcohol o Aura • Anxiety attack impaired memory • Uniformity of Experience But not FrequencyIN SUMMARY HST 071 OVARIAN FAILURE Treatment • Evaluate severity -keep a chart • Pinpoint triggers • Evaluate therapy • ESTROGEN WITHDRAWL IS TRIGGER • 90+% effective – Pills – Patches – Creams – May take up to four weeks • Other Causes – Thyroid – Carcinoid – Diabetes – Alcoholism Vaginal Dryness – Gradual process – May take years to develop – Estrogen replacement – Systemic – Local – Topical lubricants – Uncomfortable Linked to “decline” in sexual functioning Menopausal Therapeutics • 35%-40% of women ever start conventional ERT • Conventional ERT Benefits – Osteoporosis risk reduced 50% – Cardiovascular disease reduced ??? – Reduced menopausal symptoms – Memory loss – Alzheimer’s disease – Tooth loss – Colon cancer reduction • Conventional ERT Risks – Breast cancer – Vaginal bleeding – Endometrial cancer (negated by progesterone)IN SUMMARY HST 071 OVARIAN FAILURE Bone Density Evaluation *� DXA (Dual Energy X-ray Absorptiometry) measures the spine, hip or total body; *� pDXA (Peripheral Dual Energy X-ray Absorptiometry) measures the wrist, heel or finger; *� SXA (single Energy X-ray Absorptiometry) measures the wrist or heel; *� QUS (Quantitative Ultrasound) uses sound waves to measure density at the heel, shin bone and kneecap. *� QCT (Quantitative Computed Tomography) most commonly used to measure the spine, but can be used at other sites; *� pQCT (Peripheral Quantitative Computed Tomography) measures the wrist; *� RA (Radiographic Absorptiometry) uses an X-ray of the hand and a small metal wedge to calculate bone density; *� DPA (Dual Photon Absorptiometry) measures the spine, hip or total body (used infrequently); *� SPA (Single