1. Menopause Paul Beck, MD, FACOG, FACS

2. What is Menopause  Loss of ovarian activity – loss of menses  Loss of estrogen-significant impact  Life span in menopause – 1/3 to ½

3. Menopause Demographics  42 million women over age 50  52 million by 2010  8.8 million women age 50 to 54  Average age at menopause 51.4 years (range – 45 to 55 years)

4. Epidemiology BornLife Span Years in Menopa use 1850450 1900500 19507019 19607322 19707524 19807928 19908030 20008030+

5. Primary Symptoms of Menopause  Cycle changes  Oligoamenorrhea – amenorrhea  Vasomotor  Vaginal dryness

6. Secondary Symptoms of Menopause  Urinary – stress/urge incontinence  Frequency – burning ( cystitis)  Psychophysiologic changes  Musculoskeletal pains  Decrease concentration  Decreased libido

7. Actions of Estrogen  Development of ovaries, tubes, uterus and vagina  Secondary sexual characteristics  HPO axis interaction  Proliferative changes in the endometrium  Increases fat deposition and vascular profusion of skin

8. Actions of Progesterone Specific  Interacts with hypothalmus and pituitary to regulate menstrual cycle  Produces secretory changes in the endometrium  Increases viscosity of cervical mucus  Prepares breast for lactation during pregnancy

9. Consequences and Impact of Estrogen Loss  Hot flashes  Sleep disturbance  Urogenital Atrophy  Osteoporosis  Skin Dryness  Aging

10. Managment  Hormone therapy  Alternative therapy  Grin and bear it

11. Estrogen/Progesterone Therapy Potential Risks and Concerns  Women’s health initiative study  Breast cancer  Cardio vascular disease  Venous thrombosis  Endometrial cancer  Compliance/therapy

12. WHI Objective  Assess benefits and risks of the most commonly used E/P combination in the US  16,608 women randomized  8, 506 – E+P (.625 CEE + 2.5 MP)  8, 102 – placebo  Planned duration 8.5 years  Post menopausal women age 50 – 79 years

13. WHI Main Outcome Measures  Primary outcome coronary heart disease (CHD): non-fatal myocardial infarction and CHD death  Primary adverse outcome invasive breast cancer  Secondary outcomes stoke pulmonary embolism endometrial cancer cholorectal cancer hip fracture death due to other causes

14. WHI Continued  No substantive difference between groups at baseline  Mean age 63.2 for E+P group  Mean age 63.3 for placebo group  2/3 between 60 and 79 years

15. WHI Status  E+P study stopped early – 531 2002, mean 5.2 years  Reason – increase in invasive breast cancer exceeded the safety boundary for harm  Evidence for some increase in CHD, stroke and pulmonary embolism  Outweighed evidence fracture decrease  Unopposed estrogen study continued

16. Women’s Health Initiative Clinical Outcomes OutcomePlaceboHRTAdditional (fewer) Cases Hazard Ratio CHD 3037+71.29 Stroke 2129+81.41 Pulmonary Embolism 816+82.13 Breast Cancer 3038+81.26 Hip Fracture 1510-50.66 Colon Cancer 1610-60.63

17. WHI Time Trends  CHD began to develop soon after randomization (first year)  Breast Cancer – comparable through first four years then curve for estrogen began to rise more rapidly then placebo  5.2 years sharper increase- more pronounced

18. Women’s Heath Initiative Primary Conclusion “The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regiment should not be initiated or continued for primary prevention of CHD.” Writing Group for the Women’s Health Initiative Investigators JAMA 2002;288:321-333

19. WHI Implications/Limitations  Absolute risks –small-previously described  E/PT for treatment of menopausal symptoms not evaluated  Only one drug used not comparable for other E/PTs

20. WHI Preliminary Findings for Estrogen Alone – As Reported by the NIH OutcomesChanges Vs Placebo after nearly 7 years CHDNo increased or decreased overall risk Breast CancerNo increased risk StrokeIncreased risk Hip FracturesDecreased risk Probable Dementia and Mild Cognitive Impairment Trend Toward Increased Risk

21. Summary (WHI Trials) E/PE/Only Breast CASignificant increased risk Did not detect increased risk Coronary heart disease events Significant increased risk Did not detect increased risk Hip fracturesDecreased risk Colon cancerDecreased risk StrokeIncreased risk

22. Alternative Measures Vasomotor Symptoms  Progesterone/oral and transdermal works/adverse affect on lipid profile  Micronized natural plant progesterone – no adverse effect on lipid profile – no trials regarding vasomotor symptoms  Exercise –beneficial (selection bias)  Soy – significant reduction in hot flashes- requires large amounts – lowers LDL

23. Vasomotor Symptoms (continued)  Black Cohosh: significant improvement  Dong Quai: no improvement when used alone  Evening Primrose Oil: no more effective than placebo  Antidepressants: SSRIs – 50% improvement  St. John’s Wort: use in mild depression beneficial – for menopausal symptoms – questionable efficacy  Other Herbal Supplements/Homeopathy: flaxseed oil, fish oil, omega 3, red clover, ginseng, rice bran oil, wild yam, calcium, gotukola, licorice root, sage, sarsaparilla, passion flower, ginkgo biloba and valerian root – no evidence

24. Menopause Preventing Cardiovascular Disease  Soy: claim based on lipid lowering effects  Vitamin C, E, and B Carotene: no good evidence  Fish Oil: Omega-3 fatty acids and N-3 polyunsaturated fatty acids – effective for secondary prevention of cardiac events – no large trials as a means of primary prevention in postmenopausal women who are at risk  Red Clover: does not improve plasma lipids- no long term studies

25. Menopause Preventing Bone Loss  Soy: (i.e., isoflavone) - small studies on postmenopausal women show increase in lumbar spine BMD – no difference in hip  Hip Fracture: no studies documenting reduction  Magnesium: deficiency may contribute to decreased BMD

26. Summary  Black Cohosh: good for vasomotor symptoms  Soy: good for VMS –bone – lowers lipid levels  Exercise: good for VMS  Fish Oil: good for secondary prevention of cardiac events, not VMS  Magnesium: good for bone density – no evidence of prevention of hip fractures