Menopause Basics Physiology, Perimenopause and Menopause

1. Menopause BasicsPhysiology, Perimenopause and Menopause 2007 JoAnn V. Pinkerton, MD Director, Midlife Health Center Professor of Ob/Gyn University of Virginia

2. Menopause BasicsLearning Objectives: • Describe the hypothalamic-pituitary-ovarian axis • Differentiate between Perimenopause and Menopause • Learn physiologic and anatomic changes at menopause • Describe typical menopausal symptoms • Perform focused history +physical for menopausal woman • Interpret selected laboratory tests to evaluate menopause. • Counsel patients regarding female sexuality and aging • physical, emotional, and relationship-based issues

3. What does menopause mean to women? • Cessation of menstrual periods • End of reproductive capacity • Hormonal changes • Change of life, a life stage • End of prior symptoms • Beginning of new symptoms • Changing emotions • Changing body • Aging process • Disease risks • Medical care needs Woods et al. Menopause 1999.

4. Menopause: The Reality Clinical diagnosis Permanent cessation of menses following the loss of ovarian activity Lack of menses for 12 months Mean age in US is 51 (45-55 years) Women will spend one-third to one-half of their lives postmenopausally Katz VL, Lentz GM, Lobo RA, Gershenson DM. Comprehensive Gynecology. 5th ed. Philadelphia, PA: Mosby; 2007

5.  Menopause STRAW “The anchor point that is defined after 12 months of amenorrhea following the final menstrual period (FMP), which reflects a near complete but natural diminution of ovarian hormone secretion.” Soules et al. Menopause 2001.

6.  Natural (spontaneous) menopause CAMS “Occurs after 12 consecutive months of amenorrhea, for which there is no other obvious pathologic or physiologic cause.” (Average age in Western world is 51 years) Utian. Climacteric 1999.

7.  Premature menopause CAMS “Menopause that occurs in women at or under40 years old.” Utian. Climacteric 1999.

8. Premature ovarian failure • Hypergonadotropic amenorrhea ≥ 40 years old • Associated with many other health conditions (eg, autoimmune, toxic, genetic) • May not be permanent • Is not the same as premature menopause

9. Premature ovarian failure(continued) • Ovarian insufficiency leading to amenorrhea that occurs in women ≥ 40 • Can be transient (eg, from over-exercising, eating disorders, high stress levels • Can be permanent (eg, from autoimmune disease or genetic abnormalities) and equivalent to premature menopause

10. STRAW reproductive aging system Length decreases -2 days Stages of Reproductive Aging Workshop. Menopause 2001.

11. “Symptoms” of perimenopause • Natural, normal changes, not a disease • Subtle hormonal changes during the 30s • Symptoms noticeable during the 40s • Disturbances may be acute or gradual • Not all midlife symptoms are attributable to menopause

12.  Induced menopause CAMS “Cessation of menstruation that follows bilateral oophorectomy (surgical menopause), iatrogenic ablation of ovarian function by chemotherapy or pelvic radiation therapy.” (No perimenopause transition for these women) Utian. Climacteric 1999.

13. Premature or induced menopause: complicating factors • Early loss of fertility • More severe symptoms • Greater risk of osteoporosis and CVD • Possibly complicated by sequelae of underlying disease • Little research regarding benefits/risks of treatment

14. Hypothalamic-pituitary-ovarian axis GnRH (+) Pituitary Hypothalamus LH FSH Inhibins Ovary Estradiol Progesterone

15. Reproductive aging • 1-2 million follicles at birth, only approximately 1,000 by menopause • Most follicular loss due to atresia, not ovulation • Atresia accelerates at around age 37 • Age-related uterine changes also contribute to decreased fertility

16. Ovarian function in perimenopause • Ovaries begin decreasing in size • Estradiol still dominant estrogen • Number of follicles decreases substantially • Production of inhibin decreases • Remaining follicles respond poorly to elevated FSH and LH • Erratic ovulation results in menstrual cycle irregularity

17. Decline in fertility • Fertility wanes starting at about age 37, before perimenopause signs occur • By age 45, risk of spontaneous miscarriage increases to 50% • Fertility-enhancing techniques available • Natural pregnancy still possible until menopause is reached

18. Physiology: perimenopause • Estrogen and progesterone levels fluctuate erratically • Very high serum estrogen levels may result • Gradual decline in testosterone with age beginning mid-30s Zumoff et al. J Clin Endocrinol Metab 1995. Burger et al. J Clin Endocrinol Metab 2000.

19. Serum hormone levels at menopause Circulating estrogens Ratio of estrogen to androgen Sex hormone-binding globulin secretion Peripheral aromatization of DHEA to estrone Reversal of E2 to E1 ratio No significant change in testosterone levels •

20. E, FSH, and inihibins prior and following FMP Burger et al. J Clin Endocrinol Metab 1999.

21. Health evaluation at perimenopause • Determine the primary complaint(s) • Medical, psychological, and social history • Family history • Complete physical examination • Determine quality of life • Laboratory tests • For differential diagnosis of problems • Screening tests for specific chronic conditions

22. Routine screens • Standard blood screens • Periodic serum cholesterol (total, HDL, LDL, TG) • Fasting glucose • Thyroid screen • Annual Pap test • Periodic stool guaiac test, sigmoidoscopy, colonoscopy • Annual mammogram • Urine screen, when indicated • Sexually transmitted infections, when indicated • Bone density, when needed

23. Evaluate need for contraception Proportion of all US unintended pregnancies by age: 1994 Unintended pregnancies Unintended pregnancies ending in abortion Henshaw. Fam Plann Perspect 1998.

24. Confirming menopause • Age, medical/menstrual history, and symptoms usually sufficient • Rule out other causes of symptoms (eg, thyroid disorder) • Consistently elevated FSH (> 30 mIU/mL) diagnostic, but rarely necessary except with nonsurgically induced menopause • Serum estradiol testing may be of value; value of salivary levels unproven

25. Evaluate risk for specific conditions and diseases • Vasomotor symptoms/sleep disturbance • Vulvovaginal health • Psychological health • Cardiovascular disease • Diabetes • Osteoporosis • Cancer • Sexual function • Sexually transmitted infections • Urinary incontinence • Alcohol/drug use/abuse • Domestic abuse/violence risk

26. Assess all women for alterable risk factors • Smoking • Poor diet • Obesity • Lack of exercise • Stress • Habit-forming drugs • Unsafe sex • Excess alcohol • No seat belts

27. Therapeutic options • No intervention/treatment • Lifestyle modification • Nonprescription remedies • Complementary and alternative medicine (CAM) approaches • Prescription drugs • Surgical procedures

28. Write a lifestyle Rx • Stop smoking • Have a nutritionally sound diet • Achieve and maintain healthy weight • Reduce stress • Avoid excess alcohol • Say no to drugs and unsafe sex • Wear seat belts • Exercise regularly

29. Benefits of regular exercise • Decreases hot flashes • Improves mood and sleep • Decreases/maintains weight • Supports joint/muscle flexibility • Prevents bone loss • Decreases risk of many other diseases

30. “Improved control of behavioral risk factors, such as use of tobacco, alcohol, and other drugs, lack of exercise, and poor nutrition, could prevent half of premature deaths, one-third of all cases of acute disability, and all cases of chronic disability.” US Preventive Services Task Force. Guide to Clinical Preventive Service 1989.

31. Vasomotor symptoms • One of the hallmarks of perimenopause • Includes hot flashes and night sweats • Recurrent, transient episodes of flushing, perspiration, and intense warmth on upper body and face • Skin temperature increases 1-7 ºC, returns to normal gradually • Chill often follows

32. Causes of hot flashes • Precise cause is unknown • Estrogen levels alone not predictive of hot flash frequency or severity • Other conditions: thyroid disease, epilepsy, infection, insulinoma, carcinoid syndromes, leukemia, pancreatic tumors, autoimmune disorders, mast-cell disorders

33. Number of years women report having hot flushes as estimated by a survey of 501 untreated women who experienced hot flushes Hot Flushes May Continue Years After Menopause Ages 29 to 82 Years Mean age of natural menopause was 49.5 years; mean age of surgical menopause was 43.7 years. Kronenberg F. Ann NY Acad Sci. 1990;592:52-86. Used with permission. 33

34. Causes of hot flashes(continued) • Drugs: tamoxifen, raloxifene • Lifestyle factors: warm ambient air temperature, higher BMI, cigarette smoking, less physical activity

35. Hot Flashes: Demographics, Lifestyle, Health Symptoms vary by race/ethnicity More African Americans and Hispanics than Caucasians affected Fewer Chinese than Caucasian affected Significant association with BMI Passive smoke exposure History of premenstrual symptoms Use of OTC pain medication History of comorbidities Perceived stress Age Gold EB et al. Am J Epidemiol. 2004;159(12):1189-1199

36. Alternative Approaches for Vasomotor Symptoms: Lifestyle AdaptationsGuidelines from NAMS • Limited effectiveness • Cooling body core temperature • Exercise • Paced respirations (catecholamine control) • Relaxing activities • yoga, massage, meditation, paced respiration, leisurely bath • Avoid Triggers • spicy food, hot drinks, caffeine, alcohol NAMS Position Statement (Treatment of menopause-associated vasomotor symptoms) Menopause. 2004;11:11-33; Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137:805-813 Huntley AL, Ernst E. Menopause. 2003;10:465-76.

37. Non-Prescription RemediesSide effects and drug interactions clearly occurLack long-term safety and efficacy data • Phytoestrogens/isoflavones • Dietary or supplements (soy-derived) • Red clover • Black cohosh • Vitamin E - not clinically significant • Studies show no effect compared with placebo • Dong quai • Ginseng • Evening primrose oil NAMS Position Statement (Treatment of menopause-associated vasomotor symptoms). Menopause. 2004;11:11-33; Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137:805-813; Huntley AL, Ernst E. Menopause. 2003;10:465-76.

38. Clinical Management Mild Vasomotor Symptoms • For mild vasomotor symptoms • Encourage lifestyle changes • Non-prescription remedies- tested short term with little efficacy over placebo but no evidence of harm • Dietary isoflavones • Black cohosh • Vitamin E

39. Clinical Management Mod-Severe Vasomotor Symptoms • Hormone therapy is only FDA approved treatment • “gold standard” • SSRI’s and gabapentin • have efficacy in early studies • Progestogens effective • however large doses required • Clonidine (oral or transdermal)

40. Lifestyle Issues in Menopause Vasomotor (hot flushes and night sweats) Low libido/painful intercourse Weight gain Memory problems, difficulty concentrating Mood swings Insomnia, fatigue Dizziness, rapid irregular heartbeat Atrophic vaginitis, bladder irritability Headaches Rapkin AJ. Am J Obstet Gynecol. 2007;196(2):97-106.

41. OCs: noncontraceptive benefits • Suppress vasomotor symptoms • Restore predictable menses • Decrease dysmenorrhea • Enhance BMD • Prevent endometrial and ovarian malignancies

42. OCs: when to stop • FSH testing not reliable in perimenopausal women or in those using OCs • If contraception needed, continuation to mid-50s reasonable • Otherwise, consider stopping early 50s • Low-dose OC has more hormone than EPT

43. Depression or Menopause? Depression Menopause Depressed1,2 Energy2 Irritable1,2 Hot flushes1 Concentration2 Anhedonia1,2 Perspiration1 Sleep2 Thoughts of death1,2 Vaginal dryness1 Weight change1 Libido1 Worthlessness1,2 1. Soares CN, Cohen LS. CNS Spectrums. 2001;6:167-174. 2. Joffe H et al. Psychiatr Clin North Am. 2003;26:563-580.

44. Sleep disturbances • 1/3 - 1/2 of US women aged 40-54 report sleep problems • Occur mainly in women with nighttime hot flashes • Most adults require 6-9 hr sleep nightly • Potential causes: ovarian hormone changes, advancing age, onset of sleep disorders (eg, apnea), stress, painful chronic illnesses (eg, arthritis), other conditions (eg, CVD, allergies), drugs (eg, thyroid medication) • Insomnia produces fatigue, irritability, chronic illness (eg, CVD), mood disorders (eg, depression)

45. Improve sleep hygiene • Lower light and noise • Adjust temperature (cool preferred) • Avoid heavy evening meals • Avoid alcohol, caffeine, nicotine throughout the entire day • Exercise daily, but not close to bedtime • Use bedroom only for sleep and sexual activities • Have a regular sleep schedule, even on weekends • Use relaxation techniques

46. ET effects on sleep • Decreases frequency of • Night sweats1-4 • Periods of wakefulness during the night 3,4 • Reduces sleep latency 1,2 • Improves sleep in menopausal women with insomnia, even in the absence of vasomotor symptoms4 • Increases the percentage of REM sleep 2,5 • For EPT, use bedtime dosage of progesterone, a mild soporific, to improve sleep 3Erlik et al. JAMA 1981.4Polo-Kantola et al. Am J Obstet Gynecol 1998. 5Antonijevic et al. Am J Obstet Gynecol 2000. 1Scharf et al. Clin Ther 1997. 2Schiff et al. Maturitas 1980.

47. Uterine bleeding changes during perimenopause • Strong predictor of perimenopause • About 90% of women have 4-8 years of cycle changes before reaching menopause • No universal definition of “irregular” but unique to each woman • Possible changes: • lighter bleeding (avg blood loss, < 20ml) • heavier bleeding (avg blood loss, > 40ml) • bleeding lasting for < 2 days or > 4 days • cycle length < 7 days or > 28 days • skipped periods

48. Bleeding during postmenopause • Must be assessed • Vaginal causes • Uterine fibroids • Endometrial or endocervical polyps • Uterine or cervical malignancy • EPT

49. Diagnostic workup for AUB • Comprehensive history and pelvic exam • Blood tests • Endometrial biopsy • Vaginal ultrasound • Additional tests, such as sonohysterogram or hysteroscopy

50. Presenting genital symptoms and physical signs of vaginal atrophy Symptoms Dryness Itching Burning Dyspareunia Burning leukorrhea Vulvar pruritus Feeling of pressure Yellow malodorous discharge Signs on physical exam Pale, smooth, or shiny vaginal epithelium Loss of elasticity or turgor of skin Sparsity of pubic hair Dryness of labia Fusion of labia minora Introital stenosis Friable, unrugated epithelium Pelvic organ prolapse Rectocele Vulvar dermatoses Vulvar lesions Vulvar patch erythema Petechiae of epithelium Bachmann et al. Am Fam Physician 2000.