Common Questions
What did the Women's Health Initiative (WHI) reveal about the risks of menopausal hormone therapy (HT)?
The HT portion of the WHI studied outcomes in postmenopausal women (average age 62) for ~5 years after initiation of conjugated estrogen 0.625 mg + medroxyprogesterone acetate 2.5 mg daily, conjugated estrogen 0.625 mg (for women who had had hysterectomy), or placebo (1,2).
Estrogen plus progestin Results
Coronary Heart Disease (CHD): In WHI, the risk for CHD was 24% higher among the HT-treated women (HR = 1.24; 95% CI, 1.00 - 1.54) (3). This increased risk was seen in women with and without prior CHD diagnosis and was independent of other factors influencing CHD risk (e.g. use of aspirin or statins). The increased risk of CHD was most marked in the first year of use but persisted through year 5.
Stroke: Risk of stroke was 31% in HT-treated women compared with women on placebo (4). Prior stroke and other risk factors (e.g., blood pressure, use of aspirin, smoking, diabetes) did not influence the relative risk.
Breast cancer: Combination HT increased the risk of total and invasive breast cancer by 24% compared to women taking placebo (HR 1.24; 95% CI 1.00 - 1.59). The cancers were diagnosed at a more advanced stage on HT compared to placebo and there were more abnormal mammograms with HT. Subgroup analysis showed risk increased with duration of HT use. For women with no prior HT use, there was no significant increase in breast cancer rates over the 5 years of the study (5).
Venous Thromboembolic Disease (VTD-deep vein thrombosis and pulmonary embolism): Multiple studies have shown the risk of VTD to be two- to three-fold higher in women on estrogen or combination HT, with highest risk occurring in the year after initiation. In the WHI study, the risk of VTD in treated women was double that of control women (HR 2.06; 95% CI 1.57 - 2.7) (6). The risk increased with age, Factor V Leiden, and being overweight.
Estrogen Only Results
Stroke and Pulmonary Embolism: There was a 39% increase in the risk of stroke and a 34% increase in the risk of pulmonary embolus (2).
| Outcome | ||
|---|---|---|
|
WHI CEE + MPA* N = 16,608Duration = 5.2 yrs |
WHI CEE N = 10,739Duration = 6.8 yrs |
|
| Hazard Ratio (95% Confidence Interval) | ||
| CHD events | 1.24 (1.00 - 1.54) | 0.91 (0.75 - 1.12) |
| Stroke | 1.31 (1.02 - 1.68) | 1.39 (1.10 - 1.77) |
| Pulmonary Embolism | 2.13 (1.39 - 3.25) | 1.34 (0.87 - 2.06) |
| Breast Cancer | 1.24 (1.00 - 1.59) | 0.77 (0.59 - 1.01) |
| Death | 0.98 (0.82 - 1.18) | 1.04 (0.88 - 1.22) |
| Global Index** | 1.15 (1.03 - 1.28) | 1.01 (0.91 - 1.12) |
* CEE=conjugated equine estrogen, MPA=medroxyprogesterone acetate
**Global Index: first event for each participant in each of the major categories (including fracture)
- Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative Randomized Controlled Tria. JAMA 2002; 288: 321-33.
- Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCro. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004; 291: 1701-12.
- Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, et al.; for the Women’s Health Initiative Investigators. Estrogen plus Progestin and the risk of coronary heart disease. NEJM 2003; 349: 523-534.
- Wassertheil-Smoller S, Hendrix S, Limacher M, Heiss G, Kiiperberg C, Baird A, Kotchen T, et al.;for the WHI Investigators. Effect of Estrogen Plus Progestin on Stroke in postmenopausal women. JAMA 2003; 289: 2673-2684.
- Chlebowski RT, Hendrix SL, Kanger RD, Stefanick ML, Gass M, Lane D; for the WHI Investigators. Influence of Estrogen plus Progestin on breast cancer and mammography in Healthy Postmenopausal Women. JAMA 2003; 289: 3243-3253.
- Cushman M, Kuller LH, Prentice R, Rodabough RJ, Psaty BM, Stafford RS, Sidney S, Rosendaal FR; for the Women’s Health Initiative Investigators. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA 2004; 292: 1573-1580.