Health Outcomes After Stopping Estrogen Alone Hormone Replacement Therapy Among Postmenopausal Women With Prior Hysterectomy

Follow up results from the Women’s Health Initiative

Study Design: Women’s Health Initiative (WHI) Estrogen-Alone Trial was a double-blind, placebo-controlled randomized trial of conjugated equine estrogens (CEE) versus placebo.

Study Eligibility: Postmenopausal women aged 50-79 years who had a prior hysterectomy, were not taking hormone therapy and had had an anticipated 3-year survival or more. Women with prior breast cancer or other cancer or venous thromboembolism within 10 years were excluded.

Enrollment: 10,739 – 5,310 in CEE arm and 5,429 in placebo group. Follow-up continued after the trial completion date among 7,645 surviving participants (78%).

Research Question: Does CEE impact long-term health outcomes among women with a prior hysterectomy?

The Women’s Health Initiative (WHI) Estrogen-Alone Trial was a double-blind, placebo-controlled randomized trial evaluating the effects of conjugated equine estrogens (CEE) on chronic disease incidence among 10, 739 postmenopausal women aged 50-79 with prior hysterectomy. 5,310 women were randomized to receive CEE and 5,429 received the placebo. Study participants were recruited from 1993 to 1998, with a median of 5.9 years of CEE use, and the trial was stopped 1 year early because of an increased risk of adverse events (i.e. stroke). This extended follow-up reports on outcomes through a mean of 10.7 years of follow-up to assess the long-term health effects of CEE.

The researchers compare events in the intervention phase (when patients were taking CEE or placebo) to the post-intervention phase when treatment was complete. After the additional years of follow-up, the risk of cardiovascular events (CHD, stroke, deep vein thrombosis, and pulmonary embolism) was no difference between the CEE group and the patients taking a placebo (HR=1.06, 95% CI = 098 – 1.15). The cumulative breast cancer incidence in the CEE group was 23% lower relative to the placebo group, and there were fewer invasive breast cancers in the CEE group compared with the placebo group for all ages.

Younger postmenopausal women (ages 50-59) who took CEE had a lower risk of death (all causes) compared to women taking a placebo (HR=0.73, 95% CI=0.53-1.00), while the risk of death was no difference between groups for women in their 60s. On the other hand, women in their 70s taking CEE had a slightly increased risk of death compared to their counterparts taking a placebo. A similar age pattern was observed for the global index of chronic diseases (including CHD, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, and death), with the oldest on CEE at a greater risk and the youngest on CEE with a lower risk compared to their respective placebo group.

In summary, several health risks and benefits observed during CEE treatment do not persist with treatment cessation, and older women tend to have greater risks compared to younger women. For example, the increased risk of stroke seen among women randomized to CEE during the intervention period, which led to early closure of the trial, dissipated during follow-up. CEE use was not associated with an increased or decreased risk of cardiovascular events or total mortality and was associated with a decreased risk of invasive breast cancer after 10.7 years of follow-up in this WHI study.

Accompanying editorial cautions that other studies have found an increased risk of breast cancer with prolonged use of estrogen alone hormone replacement therapy, and points out that there was enough evidence for the International Agency for Research on Cancer to conclude that both estrogen alone HRT and combination HRT are carcinogenic. “The lack of an adverse effect of unopposed estrogen when used for a short period in the WHI does not counter the larger body of evidence of an elevated risk of breast cancer with increasing duration of use, the greater adverse effect among leaner women, and the greater randomized controlled trial evidence that estrogen agonist/antagonists (eg, tamoxifen) reduce the incidence of estrogen receptor-positive breast cancer by more than 50%,” they say.

Citations

LaCroix AZ, Chlebowski RT, Manson JE, et al. Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy. JAMA. 2011 Apr 6;305(13):1305-1314.

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