1. David Barad, MD CHR Grand Rounds April 14, 2009

2.  1940: DES used for “healthy pregnancy”  1966: Feminine Forever published by Dr. Wilson  1976: Unopposed estrogen linked to endometrial cancer  1980s: Estrogen and Progestin given  1993 to Present: WHI

3.  Occur in 60 - 80%  Severe in 15%  Worse in iatrogenic menopause  Primary reason for starting or restarting HRT  Primary SE of stopping HRT

4.  Multifactorial: Stress, empty nesters, fatigue  The gamut of tears, laughter, depression  Estrogen/ Serotonin receptor association  Often reported by significant others

5.  Vaginal dryness and burning  Thinned mucosa  May complain of pain with intercourse  Increased microhematuria

6.  After menopause, cardiac risk approaches that of men  Cardiac disease is #1 killer of women

7. CHD Mortality in Men and Women by Age Myth and paradox of coronary risk and menopause

8. Case-Control Studies Psaty, 1994 Mann, 1994 Rosenberg, 1993 Thompson, 1989 Cohort Studies Falkeborn, 1992 Clinical Trial 0.01 0.11 Estrogen+ Progestin 0.01 0.1 1 10 Cohort Studies Falkeborn, 1992 Wolf, 1991 Henderson, 1991 Sullivan, 1990 Avila, 1990 Criqui, 1988 Petitti, 1987 LRC Prevalence Study: Bush, 1987 Framingham: Wilson, 1985 Nurses Health Sutdy: Stampfer, 1985 Angiographic Studies McFarland, 1989 Sullivan, 1988 Gruchow, 1988 Case-Control Studies Mann, 1994 Rosenberg, 1993 Croft, 1989 Beard, 1989 Szklo, 1984 Ross, 1981 Bain, 1981 Adam, 1981 Rosenberg, 1980 Pfeffer, 1978 Talbott, 1977 Rosenberg, 1976 Summary Relative Risk Estrogen Only Barrett-Connor. Annu Rev Public Health. 1998;19:55-72

9.  Addressed etiology and prevention of major causes of morbidity and mortality in  Postmenopausal Women  aged 50-59 enrolled 1993-1996  aged 60-79 enrolled 1993-1998  Three clinical trials (N=68,133)  Hormone Therapy (HT) to prevent CHD  Diet Modification (DM) to prevent cancer  Calcium/Vitamin D (CaD) to prevent hip fractures  Large observational study (N=93, 676)  Planned duration 8.4 years (average) www.whi.org www.whiscience.org

10. Event Primary Secondary Tertiary Health Promotion RehabilitationAcute care

11. Disease Event Primary Secondary Tertiary Health Promotion RehabilitationAcute care

12. CHD Mortality in Men and Women by Age Myth and paradox of coronary risk and menopause

13. CHD Mortality in Men and Women by Age Myth and paradox of coronary risk and menopause

14. Heart Disease - Not for Secondary Prevention AHA Position (HERS) Primary Prevention - believed favorable Stroke - NOT for 2ndary Prevention; primary, unknown VTE (blood clots: lungs, PE; legs, DVT)- unfavorable Breast Cancer - believed unfavorable Hip Fractures - believed favorable Vertebral Fractures - favorable? Memory, AD - believed favorable Gallbladder Disease - unfavorable? Urinary Incontinence - favorable? Postmenopausal Hormone Therapy for Aging NOT KNOWN:

15. Hysterectomy CEE 0.625 mg/d + medroxyprogesterone acetate (MPA) 2.5 mg/d E Alone N = 10,739 YES NO Placebo Conjugated equine estrogens (CEE) 0.625 mg/d Placebo E + P N=16,608

16. Stroke? Threshold Level Early STOPPING for HARM Threshold Level Early STOPPING for BENEFIT Coronary Artery Disease (Heart Attacks) Breast Cancer Anticipated RiskExpected Benefit Plan to follow to 2005 (average 8.5 years) Additional Benefits: Hip (Bone) Fractures Overall Mortality Additional Risks: Blood Clots, VTE Lungs=PE; Legs=DVT Colon Cancer Global Index: overall balance of benefits and risks Earliest occurrence of CHD, Stroke, PE, Breast Cancer, Hip Fracture, Colorectal Cancer, Death from other causes, Endometrial Cancer

17. 26% Increase Breast Cancer Also: DVTs STOPPED Early, Clear Harm Threshold Level Risks Benefits *Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333 Stopped 3.3 yrs early * had 0.4 more yrs of data Other Fractures

18. 26% Increase Breast Cancer Also: DVTs 33% Decrease Hip Fracture STOPPED Early, Clear Harm Threshold Level 29% Increase CHD (Coronary Heart Disease) 41% Increase Stroke Risks Benefits *Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333 Stopped 3.3 yrs early * had 0.4 more yrs of data 113% Increase Pulmonary Emboli Other Fractures Decreased Colorectal Cancer

19. Risks Benefi ts

20.  Total: 52.9/10,000 E+P vs 52.3/10,000  Breast Cancer: Increase in E+P arm reason for stopping trial  Not statistically significant, but exceeded preset threshold by DSMB  Colon Cancer: Decrease in E+P arm  Endometrial Cancer: No difference

21.  No increased risk for breast cancer during the first 2 years of combined estrogen and progesterone (E+P)  potentially identifying a "safe" period.  Marked drop in the risk for breast cancer 2 years after postmenopausal women stopped taking the hormones.  Cancer. Published online before print January 20, 2009. Abstract N Engl J Med. 2009 :360:573-587.Abstract

22.  CAD: Overall 29% higher rate in E+P  Equal number of revascularization procedures and cardiac deaths  Excess events in non-fatal MI group  Stroke:  Equal number of fatal strokes  DVT/PE:  10 x number reported by USPSTF

23.  T score > 2.5 SD below young adults  10 million Americans  1.5 million fractures annually  Hip fractures  1 out of 6 women  1/2 can not walk without assist  1/4 die within one year of fracture

24.  Hip fractures reduced by 34%  Vertebral fractures reduced  Only 40% symptomatic  No routine radiographs to screen for vertebral fractues  Patients with osteoporosis excluded from enrollment

26.  Enrolled 4500 women 65 – 79  Participants memory and cognitive functions were tested yearly  Tested rate of memory decline and for presence of dementia  Outcomes:  E+P does not protect from normal decline  E+P showed increase in dementia

27. HR, 2.05 95% CI, 1.21 __ 3.48 WHIMS E+P: Probable Dementia Hazard Ratio 4532 women, aged 65-79; followed for 4.1 years E+P Placebo No. at Risk E+P Placebo 2229 2112 2026 1915 1325 401 2303 2200 2125 1984 1392 477 0 1 2 3 4 5 Years Since Randomization Cumulative Hazard

28.  Enrolled 10,739 women, aged 50 -79, and treated with estrogen or placebo  Average follow-up of 6.8 years  Tested primary prevention/safety estrogen  Outcomes:  Increased risk in stroke, decreased hip fx  No change in breast CA, CAD, colon CA

29. STOPPED - Increased Stroke No CHD Benefit Threshold Level 37% Increase Stroke (55% Increase Ischemic Stroke) RisksBenefits *Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333 Stopped 1.5 yrs early * had 0.3 more yrs of data N.S. 37% Increase Pulmonary Emboli 47% increase DVTs Other Fractures 33% Decrease Hip Fracture No Effect on CHD No Increase Breast Cancer No Effect on Colorectal Cancer

30. Summary: WHI E+P* vs. E-Alone** Trial published: *July 2002 **April 2004  Concordant results n Heart Disease – no benefit (for E+P, early harm) n Strokes, Blood Clots – harmful n Fractures – beneficial n Dementia (if ≥ 65 yrs of age) – harmful  Disparate Results n Breast Cancer n Increased in E+P Trial (women with a uterus) n Not increased in E-Alone Trial (women with prior hysterectomy) n Increased breast cancer risk in women with highest baseline risk n Global Index n Increased in E+P (CEE + MPA) Trial n Neutral in E-Alone (CEE) Trial

31. JAMA 2003; 289:2651-2662 JAMA 2004; 291:2947-2958 N=4,532; 4.1 yrs follow-up N=2,947; 5.2 yrs follow-up 49% (NS) 34% (NS) 105%

32. Risks Benefi ts RiskBenefit Risk? Benefit?

33. HERS WHI E+P WHI E only Hersh AL, Stefanick ML, Stafford RS JAMA 291: 2004; 291: 47-53

34. % of Enrolled Population 5522 33.3% 7510 45.2% 3576 21.5% 12,304 74.1% 3262 19.6% 1035 6.2% 5058 30.6% 5826 35.3% 5636 34.1% Mean =63.3 yrs Mean =28.5 kg/m 2 JAMA. 2002;288: 321-333 N Age (yrs) Prior HT Use Body Mass Index

35. % of Enrolled Population JAMA. 2004;291: 1701-1712 3310 30.8% 4852 45.2% 2577 24.0% 2206 20.7% 3707 34.7% 4759 44.6% Mean =63.6 yrs Mean =30.1 kg/m 2 5539 51.6% 3819 35.6% 1377 12.8% N Age (yrs) Prior HT Use Body Mass Index

36. E-alone (32.7%) E+P (21.5%) 50-59 60-6970-79 0 5 10 15 20 25 Black Hispanic BlackHispanicBlackHispanic Hysterectomy (75.3% White)Uterus (84.0 % White ) E-alone (22.0%) E+P (12.5%) E-alone (13.9%) E+P ( 8.6%) Percent Minority Percent Ann Epidemiol 2003; 13: S78-S86

37. Arch Intern Med. 2006;166:357-365 Age 50-59 y Age 60-69 y Age 70-79 y P for interaction=0.07

39. Manson et al, NEJM 2007; 356: 2591-2602 l Women aged 50-59 at time of randomization into E-Alone trial (with prior hysterectomy) at 28 (of 40) WHI sites l After mean 7.4 years of treatment; 1.3 yrs after trial was completed - Did not study older women in E-only trial or women in E+P trial Baseline Characteristics (N=1064: 537 CEE, 527 Placebo) l Age: Mean 55 years (50-54, 39.5%; 55-59, 60.5%) l Age at Menopause: Mean 43.5 years l Age at Hysterectomy: < 35 (28%); 35-39 (25%); 40-44 (22.5%); ≥ 45 (23%) l Ethnicity: White, ~ 75% Black, 16.5% Hispanic, 6% Asian/PI, 0.3% American Indian, <1% l Body Mass Index: 30.5 kg/m2; Hypertension: 35.5%; Diabetes: 6.3%

40. CAC Categories Intent-to-Treat AnalysesAdherent Analyses Multivariate P=0.03Multivariate P=0.004 Manson et al, NEJM 2007; 356: 2591-2602

41.  Among women aged 50-59 in E-alone Trial calcified plaque burden in coronary arteries was lower in CEE group than placebo 1.3 yrs after 7.4 yrs of treatment. Did not study older women or E+P trial  WHI data do not suggest CHD harm for short-term therapy to relieve menopausal symptoms. HRT and the Young at Heart: Mendelssohn ME, Karas RH. NEJM 2007; 356: 2639-2641

42.  Timing Hypothesis: The beneficial effects of HRT in preventing atherosclerosis occur only when the therapy is initiated before advanced atherosclerosis develops.  Predicts that HRT is NOT beneficial when given to older women, because the underlying biologic characteristics of the vessel wall and vascular response to HRT are altered in older, more atherosclerotic vessels.  Age is a powerful risk factor for atherosclerosis; risk is low for majority of women aged 50-59.

43.  Women starting hormones close to the menopause may have fewer heart attacks and deaths due to HT compared to increases in women distant from the menopause  Provides some reassurance that younger women using hormones for the short term for relief of hot flashes and night sweats are not at increased risk of heart disease  Stroke increased irrespective of age or years since menopause (Breast cancer also increased in E+P only) Rossouw et al JAMA 2007;297:1465-1477

44.  Older women with moderate/severe hot flashes or night sweats appear to be at high risk if they start hormone therapy  In part explained by higher prevalence of risk factors (obesity, high blood pressure, high blood cholesterol, diabetes) in women with vasomotor symptoms Rossouw et al JAMA 2007;297:1465-1477

45.  “one estrogen and one estrogen/progestin”  Most commonly prescribed HT  “Women with moderate to severe menopausal symptoms discouraged”  Not a study of symptoms… symptomatic women were considered to have greater noncompliance  QOL measurement tools  Standardized and highly reliable, no QOL tool for menopause existed at the initiation of the WHI

47.  Estrogens and progestins should not be used for the prevention of cardiovascular disease.  Other doses of CEE and MPA and other combinations of estrogens and progestins were not studied in the WHI and, in the absence of comparable data, these risks should be assumed to be similar  Estrogens and progestins should not be used for the prevention of cardiovascular disease.  Other doses of CEE and MPA and other combinations of estrogens and progestins were not studied in the WHI and, in the absence of comparable data, these risks should be assumed to be similar

48.  HRT is not recommended for prevention of CAD  HRT is approved for treatment of moderate to severe menopausal sx  HRT is approved for osteoporosis prevention in certain patients  For approved conditions HRT should be used in the low dose for short duration

49.  Treatment of moderate to severe symptoms associated with menopause  Treatment of moderate to severe symptoms associated with vaginal and vulvar atrophy assoc. with menopause  Prevention of postmenopausal osteoporosis in women at significant risk, after considering non-hormonal rx

50.  www.menopause.org: NAMS www.menopause.org  http://www.cme.wisc.edu/online/menopaus e/sld001.htm: UW menopause review http://www.cme.wisc.edu/online/menopaus e/sld001.htm  www.4women.gov/owh: DHHS Office of Women’s Health www.4women.gov/owh  www.nhlbi.nih.gov/health/women/index.ht m: WHI website www.nhlbi.nih.gov/health/women/index.ht m