1. Menopause-Clinical Considerations Esther Eisenberg, M.D., M.P.H. Professor, Obstetrics and Gynecology Vanderbilt University Medical Center

2. "The desire to take medicine is perhaps the greatest feature which distinguishes man from animals." Sir William Osler

3. Learning objectives –To discuss the role of HRT in the menopausal woman –To compare findings of WHI study in women with natural vs. surgical menopause –To discuss alternatives for HRT in the treatment of menopausal problems

4. MENOPAUSE Permanent cessation of mensesPermanent cessation of menses Ovarian follicular depletionOvarian follicular depletion Marked by last menstrual periodMarked by last menstrual period Clinical definition – no menses x 1 yearClinical definition – no menses x 1 year

5. Age-related decrease in total number of primordial follicles from birth to menopause. Lobo, RA, Clin Obstet Gynecol, 1998

7. Stages of Reproductive Aging ASRM Committee Opinion 2001

8. Signs of Menopause Menstrual cycle changes- Oligomenorrhea, amenorrheaMenstrual cycle changes- Oligomenorrhea, amenorrhea Vasomotor symptoms- hot flashes, night sweatsVasomotor symptoms- hot flashes, night sweats Vaginal drynessVaginal dryness Depression (if prone)Depression (if prone) Low libidoLow libido

9. Vasomotor sxVasomotor sx – Hot flashes – Sleep disturbance Urogenital atrophyUrogenital atrophy –Vaginal dryness Low libidoLow libido OsteoporosisOsteoporosis Skin changesSkin changes ?CVD, ?Dementia?CVD, ?Dementia Brain Eyes Vasomotor Heart Breast Colon Urogenital Tract Bone Consequences of Estrogen Loss on Target Tissue

10. Years BeforeYears After Menopause Prevalence of Hot Flashes 321123 Prevalence of Vasomotor Symptoms > 75% of women report hot flashes within the 2-year period surrounding their menopause> 75% of women report hot flashes within the 2-year period surrounding their menopause Primary reason women seek medical treatmentPrimary reason women seek medical treatment 25% remain symptomatic for > 5 years25% remain symptomatic for > 5 years Kronenberg F. Ann N Y Acad Sci. 1990;592:52-86.

11. History Of HRT 1965Dr. Robert A Wilson publishes “Feminine Forever”, ERT = “fountain of youth” 1975ERT associated with  risk of endometrial cancer 1980Nachtigall & Gambrell pioneer HRT-add MPA 1980s Continuous combined HRT regimen developed to reduce uterine bleeding and increase adherence 1990s New and more HRT products developed 1992 ACP, ACFP and USPS Task Force endorse guidelines for Rx of HRT for prevention of heart disease and osteoporosis-WHI trial is conceived.

12. History Of HRT 1998HERS Trial - 2° prevention - no difference in fatal or nonfatal CHD 2001AHA advises against prescription of HRT for secondary prevention of CHD 2002 HRT arm of WHI trial stopped; Global index - risks outweigh benefits. Events occurred in fewer than 1% of WHI women 2003 ACOG, NAMS, FDA, USPSTF revise recommendations for HRT 2004WHI hysterectomy trial stopped. Increased risk of stroke. No effect on CHD risk. Decreased fracture risk. Breast Ca risk increase in HRT, not ERT.

13. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333. WHI Clinical Trial Multi-center double-blind randomized placebo controlled trialMulti-center double-blind randomized placebo controlled trial --HRT Arm-mean age 63.3 years. Intact uterus –Average follow-up = 5.2 years; –Regimen: CEE 0.625 mg/d + MPA 2.5 mg/d (n = 8506) or placebo (n = 8102) --ERT Arm-All with hysterectomy -Average follow-up = 6.8 years -Regimen: CEE 0.625 mg/d (n = 5310) or placebo (n = 5429) Primary outcome: Nonfatal MI and CHD deathPrimary outcome: Nonfatal MI and CHD death Primary adverse outcome: Invasive breast cancerPrimary adverse outcome: Invasive breast cancer Global index: Summary measure of risks and benefitsGlobal index: Summary measure of risks and benefits

14. WHI Combined HRT Age at screening Prior hormone use BMI (kg/m 2 ) Never smokers DiabetesHypertension Statin use at baseline Family Hx Breast Ca History of MI History of CABG/PTCA 63.226.128.549.64.435.76.916.01.61.163.325.628.550.04.436.46.815.31.91.5‡ Baseline HRT Placebo Characteristics n=8506 (%) n=8102 (%)

15. WHI CEE Alone Baseline CEEPlacebo Characteristics(n=5310)(n=5429) Age at hysterectomy < 402100 (39.8)2149 (39.8) < 402100 (39.8)2149 (39.8) 40-492281 (43.2)2275 (42.2) 40-492281 (43.2)2275 (42.2) 50-54 501 (9.5) 566 (10.5) 50-54 501 (9.5) 566 (10.5) > 55 401 (7.6) 404 (7.5) > 55 401 (7.6) 404 (7.5) BSO 1938 (39.5)2111 (42.0) Fam hx/Breast ca 893 (18.0) 870 (17.1) Fracture age > 55 676 (14.0) 643 (13.2)

16. WHI CEE Alone BaselineCEEPlacebo Characteristics(n=5310)(n=5429) Hormone use Never 2769 (52.2)2770 (51.1) Never 2769 (52.2)2770 (51.1) Past1871 (35.2)1948 (35.9) Past1871 (35.2)1948 (35.9) Current*669 (12.6) 708 (13.0) Current*669 (12.6) 708 (13.0) Duration of prior hormone** < 51352 (53.2)1412 (53.1) < 51352 (53.2)1412 (53.1) 5 - < 10469 (18.5) 515 (19.4) 5 - < 10469 (18.5) 515 (19.4) > 10720 (28.3) 732 (27.5) > 10720 (28.3) 732 (27.5) BMI 30.1 30.1 Smoking Never2723 (51.9)2705 (50.4) Never2723 (51.9)2705 (50.4) Past1986 (37.8)2089 (38.9) Past1986 (37.8)2089 (38.9) Current542 (10.3) 571 (10.6) Current542 (10.3) 571 (10.6) *Required 3-month washout JAMA 2004; 291: 1704 ** Among women reporting hormone use JAMA 2004; 291: 1704

17. WHI Disease Rates for Women on Combination HRT or Placebo Adapted from WHI HRT Update, June 2002.

18. WHI: Relative and Absolute Risk or Benefit of CEE plus MPA at 5.2 Yrs Cases Risk Ratio Changes/10,000 Cases Risk Ratio Changes/10,000 OutcomeHRT Placebo Women Breast Ca1661241.26(1.0-1.59)+ 8 MI/CVD1641221.29(1.02-1.63)+ 7 Stroke127 851.41(1.07-1.85)+ 8 VTE151 672.11(1.58-2.82) +18 PE 70 312.14(1.39-3.25)+ 8 Colon Ca 45 670.63(0.43-0.92) - 6 Hip Fx 44 620.66(0.45-0.98) - 5 Vertebral Fx 41 600.66(0.44-0.98) - 5 Death2312180.988(0.82-1.18)

19. WHI Results CEE Alone Health EventRisk Ratio vs. Nominal CI Placebo (6.8 yrs) CHD (nonfatal MI or death) 0.910.75-1.12 Stroke 1.391.10-1.12 VTE 1.330.99-1.79 Breast Cancer 0.770.59-1.01 Colorectal Cancer 1.080.75-1.55 Hip Fracture 0.610.41-0.91 Global Index 1.010.91-1.12

20. Kaplan-Meier Estimates of Cumulative Hazards for Selected Outcomes (JAMA 2004; 291:1707)

21. Estrogen plus Progestin Increases Breast Cancer Risk in Postmenopausal Women EPT use increased breast cancer risk by 24% (p <.001)EPT use increased breast cancer risk by 24% (p <.001) Invasive breast CA risk (↑ 24%, p = 0.003)Invasive breast CA risk (↑ 24%, p = 0.003) –Tumors were larger and at more advanced stage in EPT users EPT users were more likely to have abnormal mammograms (9.4% vs. 5.4%, p < 0.001)EPT users were more likely to have abnormal mammograms (9.4% vs. 5.4%, p < 0.001)

22. Higher Levels of Exercise Reduce Breast Cancer Risk JAMA 2003; 290: 1331-1336 Reduced risk of breast cancer was seen across all categories including women who took estrogen and progestinReduced risk of breast cancer was seen across all categories including women who took estrogen and progestin Greatest reduction in women with BMI < 24Greatest reduction in women with BMI < 24

23. Hazard Ratios from 3 Hormone Therapy Trials Hazard Ratio (95% C.I.) JAMA 2004; 291; 1770

24. Complexity of WHI Trial 1. Participants - “healthy” postmenopausal women - asymptomatic Some participants have relative contra- indications to HRT - smokers (10.5%), history of MI (7.7%), Stroke, DVT, PE or BMI > 30 Kg/m 2Some participants have relative contra- indications to HRT - smokers (10.5%), history of MI (7.7%), Stroke, DVT, PE or BMI > 30 Kg/m 2 Trial is applicable to general population - more generalizable and external validityTrial is applicable to general population - more generalizable and external validity

25. Complexity of WHI Trial 2. High drop out rate in treatment (42%) and placebo groups (38%) - unanticipated 3. Unblinding in 40.5% of treatment group compared with 6.8% in placebo group 4. Adjusted confidence intervals are more valid when making multiple comparisons; but in WHI study, there are seven variables - very conservative CI after adjustment. Level of uncertainly, probably somewhere in between

26. Age is an Effect Modifier NEJM 2003; 348:1836

27. WHI Summary 1.WHI combined EPT – risks outweigh benefits for prevention 2.WHI ET – risks and benefits are balanced 3.When quality of life and menopausal symptoms are issues – EPT and ET are most effective treatment and risks are low 4.Age is an effect modifier; the younger the woman, the lower the absolute risk

28. JAMA 2003; 289:3241

29. Hersh AL, et al. JAMA, 2004; 291: 51. Number of and Percentage Change in US Prescriptions for Hormone Therapy Between January-Jane 2002 and January-June 2003 by Formulation

30. Predictors of Inability to Stop HRT 377 women; Kaiser Health Plan; age 50-69377 women; Kaiser Health Plan; age 50-69 All tried to discontinue HRTAll tried to discontinue HRT 74% successfully stopped; 26% resumed HT74% successfully stopped; 26% resumed HT Predictors-Troublesome sxs (OR: 8.8; CI: 4.9, 16)Predictors-Troublesome sxs (OR: 8.8; CI: 4.9, 16) Flushes (88%)Flushes (88%) Excessive sweating (54%)Excessive sweating (54%) Difficulty sleeping (54%)Difficulty sleeping (54%) Fatigue (39%)Fatigue (39%) Depression (38%)Depression (38%) Vaginal dryness (38%)Vaginal dryness (38%) Grady D, et al. Obstet Gynecol 2003;102: 1233-9.

31. Predictors of Inability to Discontinue PMP Hormone Therapy Grady D, et al. Obstet Gynecol 2003; 102: 1233-9. Troublesome symptoms

32. Predictors of Inability to Stop PMP Hormone Therapy Predictors (cont.)Predictors (cont.) –Hysterectomy (OR: 1.9; CI: 1.1, 3.6) –HRT prescribed by nongynecologist (OR: 2.2; CI: 1.2,4.0) –High risk for fracture (OR: 1.4; CI: 1.1, 1.8) Grady D. Obstet Gynecol 2003; 102: 1233-9

33. Menopausal Hormone Therapy Other Issues EPT – Route of deliveryEPT – Route of delivery –Transdermal patch –Drops/Oil/Gel –Vaginal ring Choice of estrogenChoice of estrogen Progesterone vs progestinProgesterone vs progestin ?Androgen?Androgen

34. ESTHER Trial Scarabin PY, Oger E, Ply-Bureau G ESTHER Study Group Lancet 2003; 362: 428-32. Oral and transdermal EPT have different effects on risk of thromboembolismOral and transdermal EPT have different effects on risk of thromboembolism 155 Women155 Women –Age 45-70 –Cases – Diagnosed with VTE 318 Women 318 Women –Matched controls

35. ESTHER Case Control Study of Estrogen & VTE RX CasesControlORCT Oral EPT 21% 7%3.51.8-6.8 Transdermal 19% 24% 0.90.5-1.6 EPT EPT

36. Menopausal Sexual Concerns Lack of desire (low libido)Lack of desire (low libido) –?Androgen deficiency –?Other relationship issues; Life stress Vaginal drynessVaginal dryness –?Estrogen deficiency

39. Adapted from: Simon JA. Fert Steril. 2002;77:S77-S82. Source of Androgens in Naturally Postmenopausal Women

41. Menopausal Therapy- Other Considerations Prevention and treatment of osteoporosisPrevention and treatment of osteoporosis BMD testing-timingBMD testing-timing Adequate calcium (1200 mg/d) and Vitamin D (800 IU/d)Adequate calcium (1200 mg/d) and Vitamin D (800 IU/d) Anti-resorptive RxAnti-resorptive Rx

42. Prescribing HRT –HRT is best treatment for menopausal symptoms and quality of life issues –HRT should not be continued or started to prevent heart disease –For osteoporosis prevention, the benefits should be weighed vs. individualized risks for MI, stroke, VTE, and breast cancer. Other anti-resorptive agents should be considered. National Institutes of Health. National Heart, Lung, and Blood Institute. New Facts About: Estrogen/Progestin Hormone Therapy. July 9, 2002.

43. Clinical Considerations for HRT *Approximately 25% of women who discontinue HRT are unsuccessful – most common reason for restarts is menopausal symptoms *Approximately 25% of women who discontinue HRT are unsuccessful – most common reason for restarts is menopausal symptoms *If a woman successfully discontinues hormone therapy, consider her risk for osteoporosis – use other agents for prevention