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Menopause-Clinical Considerations

Menopause-Clinical Considerations. Esther Eisenberg, M.D., M.P.H. Professor, Obstetrics and Gynecology Vanderbilt University Medical Center. "The desire to take medicine is perhaps the greatest feature which distinguishes man from animals." Sir William Osler. Learning objectives.

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Menopause-Clinical Considerations

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  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 menses • Ovarian follicular depletion • Marked by last menstrual period • Clinical 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

  6. Stages of Reproductive AgingASRM Committee Opinion 2001

  7. Signs of Menopause • Menstrual cycle changes-Oligomenorrhea, amenorrhea • Vasomotor symptoms-hot flashes, night sweats • Vaginal dryness • Depression (if prone) • Low libido

  8. Consequences of Estrogen Loss on Target Tissue • Vasomotor sx • Hot flashes • Sleep disturbance • Urogenital atrophy • Vaginal dryness • Low libido • Osteoporosis • Skin changes • ?CVD, ?Dementia Brain Eyes Vasomotor Heart Bone Breast Colon Urogenital Tract

  9. Prevalence of Vasomotor Symptoms • > 75% of women report hot flashes within the 2-year period surrounding their menopause • Primary reason women seek medical treatment • 25% remain symptomatic for > 5 years Prevalence of Hot Flashes Menopause Years Before Years After 3 2 1 1 2 3 Kronenberg F. Ann N Y Acad Sci. 1990;592:52-86.

  10. History Of HRT 1965 Dr. Robert A Wilson publishes “Feminine Forever”, ERT = “fountain of youth” 1975 ERT associated with  risk of endometrial cancer 1980 Nachtigall & 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.

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

  12. WHI Clinical Trial • Multi-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 death • Primary adverse outcome: Invasive breast cancer • Global index: Summary measure of risks and benefits Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.

  13. WHI Combined HRT Baseline HRT Placebo Characteristics n=8506 (%) n=8102 (%) Age at screening Prior hormone use BMI (kg/m2) Never smokers Diabetes Hypertension Statin use at baseline Family Hx Breast Ca History of MI History of CABG/PTCA 63.2 26.1 28.5 49.6 4.4 35.7 6.9 16.0 1.6 1.1 63.3 25.6 28.5 50.0 4.4 36.4 6.8 15.3 1.9 1.5‡

  14. WHI CEE Alone Baseline CEE Placebo Characteristics (n=5310) (n=5429) Age at hysterectomy < 40 2100 (39.8) 2149 (39.8) 40-49 2281 (43.2) 2275 (42.2) 50-54 501 (9.5) 566 (10.5) > 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)

  15. WHI CEE Alone Baseline CEE Placebo Characteristics (n=5310) (n=5429) Hormone use Never 2769 (52.2) 2770 (51.1) Past 1871 (35.2) 1948 (35.9) Current* 669 (12.6) 708 (13.0) Duration of prior hormone** < 5 1352 (53.2) 1412 (53.1) 5 - < 10 469 (18.5) 515 (19.4) > 10 720 (28.3) 732 (27.5) BMI 30.1 30.1 Smoking Never 2723 (51.9) 2705 (50.4) Past 1986 (37.8) 2089 (38.9) Current 542 (10.3) 571 (10.6) *Required 3-month washout ** Among women reporting hormone use JAMA 2004; 291: 1704

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

  17. WHI: Relative and Absolute Risk or Benefit of CEE plus MPA at 5.2 Yrs Cases Risk Ratio Changes/10,000 Outcome HRT Placebo Women Breast Ca 166 124 1.26(1.0-1.59) + 8 MI/CVD 164 122 1.29(1.02-1.63) + 7 Stroke 127 85 1.41(1.07-1.85) + 8 VTE 151 67 2.11(1.58-2.82) +18 PE 70 31 2.14(1.39-3.25) + 8 Colon Ca 45 67 0.63(0.43-0.92) - 6 Hip Fx 44 62 0.66(0.45-0.98) - 5 Vertebral Fx 41 60 0.66(0.44-0.98) - 5 Death 231 218 0.988(0.82-1.18)

  18. WHI Results CEE Alone Health Event Risk Ratio vs. Nominal CI Placebo (6.8 yrs) CHD (nonfatal MI or death) 0 .91 0.75-1.12 Stroke 1.39 1.10-1.12 VTE 1.33 0.99-1.79 Breast Cancer 0.77 0.59-1.01 Colorectal Cancer 1.08 0.75-1.55 Hip Fracture 0.61 0.41-0.91 Global Index 1.01 0.91-1.12

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

  20. Estrogen plus Progestin Increases Breast Cancer Risk in Postmenopausal Women • EPT use increased breast cancer risk by 24% (p < .001) • 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)

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

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

  23. 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/m2 • Trial is applicable to general population - more generalizable and external validity

  24. 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

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

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

  27. JAMA 2003; 289:3241

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

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

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

  31. Predictors of Inability to Stop PMP Hormone Therapy • 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

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

  33. ESTHER TrialScarabin PY, Oger E, Ply-Bureau GESTHER Study GroupLancet 2003; 362: 428-32. • Oral and transdermal EPT have different effects on risk of thromboembolism • 155 Women • Age 45-70 • Cases – Diagnosed with VTE • 318 Women • Matched controls

  34. ESTHER Case Control Study of Estrogen & VTE RX Cases Control OR CT Oral EPT 21% 7% 3.5 1.8-6.8 Transdermal 19% 24% 0.9 0.5-1.6 EPT

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

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

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

  38. 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.

  39. Clinical Considerations for HRT *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

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