Menopausal Estrogen-Alone Therapy and Health Outcomes in Women With and Without Bilateral Oophorectomy: A Randomized Trial

JoAnn E Manson, Aaron K Aragaki, Shari S Bassuk, Rowan T Chlebowski, Garnet L Anderson, Jacques E Rossouw, Barbara V Howard, Cynthia A Thomson, Marcia L Stefanick, Andrew M Kaunitz, Carolyn J Crandall, Charles B Eaton, Victor W Henderson, Simin Liu, Juhua Luo, Thomas Rohan, Aladdin H Shadyab, Gretchen Wells, Jean Wactawski-Wende, Ross L Prentice, WHI Investigators, Shari Ludlam, Joan McGowan, Leslie Ford, Nancy Geller, Andrea LaCroix, Charles Kooperberg, Rebecca Jackson, Marian Limacher, Robert Wallace, Lewis Kuller, Sally Shumaker, JoAnn E Manson, Aaron K Aragaki, Shari S Bassuk, Rowan T Chlebowski, Garnet L Anderson, Jacques E Rossouw, Barbara V Howard, Cynthia A Thomson, Marcia L Stefanick, Andrew M Kaunitz, Carolyn J Crandall, Charles B Eaton, Victor W Henderson, Simin Liu, Juhua Luo, Thomas Rohan, Aladdin H Shadyab, Gretchen Wells, Jean Wactawski-Wende, Ross L Prentice, WHI Investigators, Shari Ludlam, Joan McGowan, Leslie Ford, Nancy Geller, Andrea LaCroix, Charles Kooperberg, Rebecca Jackson, Marian Limacher, Robert Wallace, Lewis Kuller, Sally Shumaker

Abstract

Background: Whether health outcomes of menopausal estrogen therapy differ between women with and without bilateral salpingo-oophorectomy (BSO) is unknown.

Objective: To examine estrogen therapy outcomes by BSO status, with additional stratification by 10-year age groups.

Design: Subgroup analyses of the randomized Women's Health Initiative Estrogen-Alone Trial. (ClinicalTrials.gov: NCT00000611).

Setting: 40 U.S. clinical centers.

Participants: 9939 women aged 50 to 79 years with prior hysterectomy and known oophorectomy status.

Intervention: Conjugated equine estrogens (CEE) (0.625 mg/d) or placebo for a median of 7.2 years.

Measurements: Incidence of coronary heart disease and invasive breast cancer (the trial's 2 primary end points), all-cause mortality, and a "global index" (these end points plus stroke, pulmonary embolism, colorectal cancer, and hip fracture) during the intervention phase and 18-year cumulative follow-up.

Results: The effects of CEE alone did not differ significantly according to BSO status. However, age modified the effect of CEE in women with prior BSO. During the intervention phase, CEE was significantly associated with a net adverse effect (hazard ratio for global index, 1.42 [95% CI, 1.09 to 1.86]) in older women (aged ≥70 years), but the global index was not elevated in younger women (P trend by age = 0.016). During cumulative follow-up, women aged 50 to 59 years with BSO had a treatment-associated reduction in all-cause mortality (hazard ratio, 0.68 [CI, 0.48 to 0.96]), whereas older women with BSO had no reduction (P trend by age = 0.034). There was no significant association between CEE and outcomes among women with conserved ovaries, regardless of age.

Limitations: The timing of CEE in relation to BSO varied; several comparisons were made without adjustment for multiple testing.

Conclusion: The effects of CEE did not differ by BSO status in the overall cohort, but some findings varied by age. Among women with prior BSO, in those aged 70 years or older, CEE led to adverse effects during the treatment period, whereas women randomly assigned to CEE before age 60 seemed to derive mortality benefit over the long term.

Primary funding source: The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and U.S. Department of Health and Human Services. Wyeth Ayerst donated the study drugs.