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 Born Life Span Years in Menopause 1850 45 1900 50 1950 70
1900 50
1950 70 19
1960 73 22
1970 75 24
1980 79 28
1990 80 30
2000
30+

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 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
Placebo
HRT
Additional
(fewer) Cases
Hazard
Ratio
CHD 30 37 +7
1.29
Stroke 21 29 +8
1.41
Pulmonary Embolism 8 16
2.13
Breast Cancer 38
1.26
Hip Fracture 15 10 -5
0.66
Colon Cancer -6
0.63
CHD events increased by 29%. Breast cancer increased by 26%. Hip fracture 1/3 less. A hazard ratio is the relative risk ( cumulative risk ratio of an end-point at any given time (and instantaneous risk ratio).

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:

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
Outcomes
Changes Vs Placebo after nearly 7 years
CHD
No increased or decreased overall risk
Breast Cancer
No increased risk
Stroke
Increased risk
Hip Fractures
Decreased risk
Probable Dementia and Mild Cognitive Impairment
Trend Toward Increased Risk

21. Summary (WHI Trials) E/P E/Only Breast CA Significant increased risk
Did not detect increased risk
Coronary heart disease events
Hip fractures
Decreased risk
Colon cancer
Stroke
Increased 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