Background: The U.S. Women's Health Initiative (WHI) study closed prematurely when increased risk of stroke, pulmonary embolism, and breast cancer were reported in participants assigned to therapy with estrogen plus progesterone. An increased stroke risk, but no apparent effect on cardiovascular disease or breast cancer, was also reported in participants with previous hysterectomy who were taking estrogen only. Further analyses suggested that adverse effects predominantly occurred in women 70 to 79 years of age. The Women's International Study of long Duration Oestrogen after Menopause (WISDOM) trial aimed to study the effects of hormone therapy on women up to 69 years of age.

The Study: Postmenopausal women 50 to 69 years of age were recruited from more than 400 general practices in the United Kingdom, Australia, and New Zealand. After screening and physical examination to identify exclusions and contraindications to the study, participants were randomly assigned to combined hormone therapy (conjugated equine estrogen 0.625 plus medroxyprogesterone acetate 2.5 or 5 mg daily), estrogen therapy (conjugated equine estrogen 0.625 mg daily), or placebo. Follow-up visits were scheduled at four, 14, 27, 40, and 52 weeks after starting therapy and every six months thereafter.

Primary outcomes were major cardiovascular events, osteoporotic fractures, and breast cancer. Secondary outcomes included death from breast cancer, all-cause mortality, venous thromboembolism, cerebrovascular disease, and dementia. Any potential adverse event was investigated by a member of the research team who was not aware of treatment allocation. In addition, cardiovascular and cancer outcomes, as well as a sample of fractures, were reviewed by independent experts.

Results: Despite the intention to study younger postmenopausal women, older women were recruited first. Therefore, the mean age of the more than 5,000 participants was 62.8 years. The median follow-up was only 11.9 months because the study was closed prematurely following the publication of the WHI study results. The average participant started or restarted hormone therapy about 15 years after menopause. The study achieved 5,214 person-years of observation comparing participants randomized to combination therapy or placebo, and 1,688 person-years of observation on participants randomized to combination or estrogen-only therapy.

Compared with placebo, women in the combination group had more cardiovascular events (seven compared with zero) and thromboembolic events (22 compared with three). Despite the low incidence overall, these differences achieved statistical significance, indicating increased hazard risk from combination therapy. Rates for cerebrovascular disease, breast cancer, and all cancer did not differ significantly between the groups. The hazard ratios for cerebrovascular disease (0.73), osteoporotic fracture (0.69), and any cancer (0.88) showed lower rates in the combination group compared with placebo. Overall, eight deaths occurred in the combination group and five in the placebo group for a hazard ratio of 1.60. The risk of any event in the combination group was 390.9 per 10,000 person-years of observation compared with 410.9 in the placebo group, for a hazard ratio of 0.95.

Outcomes in direct comparison of the combination group (815 women) and the estrogen-only group (826 women) showed no significant differences in a relatively low number of events (35 and 23, respectively). Most events occurred in women older than 64 years who had cardiovascular risk factors.

Conclusion: The authors conclude that women starting or restarting hormone therapy many years after menopause are at increased risk of cardiovascular disease and venous thromboembolism. They stress that the trial was unable to address the original intent (studying the impact of hormone therapy started soon after menopause) and that the “critical window” hypothesis (benefit if hormone therapy begins before age 60 or within 10 years of menopause) has not been extensively studied.

editor's note: This study does little to resolve the challenges of advising patients about hormone therapy during the perimenopause and early menopause years, and illustrates the chilling effect that the publication of the WHI study had on those attempting large randomized controlled trials (RCTs) in this area. The WISDOM study was terminated before a sufficient number of younger women had been recruited to answer the core questions concerning “early start” hormone therapy. The definitive RCT on this topic may never be possible because of legitimate concerns about patient safety.

Evidence continues to accumulate that starting hormone therapy in the critical window soon after menopause could offer benefit for some women. A meta-analysis of 23 RCTs reported reductions in cardiovascular disease if hormone therapy was started before age 60 or within 10 years of menopause.¹ At a more basic level, a study of women 50 to 59 years of age showed a reduction in coronary artery recalcification with estrogen therapy.² Amid this evolving and often confusing mixture of science and opinion, the importance of individualizing advice for each woman remains the core principle. Our duty is to ascertain and address the risks to the health and quality of life for each patient and advise accordingly. For hormone therapy, this goes beyond cardiovascular conditions to include cancer (especially of the breast or colon), osteoporosis, and perhaps other conditions for which evidence is less well developed.—a.d.w.