Lengthened WHI Follow-Up: Postmenopausal Estrogen Therapy

Summary and Comment |
April 5, 2011

Lengthened WHI Follow-Up: Postmenopausal Estrogen Therapy

  1. Andrew M. Kaunitz, MD

Women's Health Initiative follow-up of postintervention phase showed estrogen had no substantial adverse effects on most health outcomes; reduction in relative risk for breast cancer persisted.

  1. Andrew M. Kaunitz, MD

In the Women's Health Initiative (WHI) Estrogen-Alone Trial, 11,000 postmenopausal women with hysterectomies (age range at baseline, 50–79) received conjugated equine estrogen or placebo for a median of 5.9 years; the trial was stopped at mean follow-up of 7.1 years when initial findings showed excess risk for stroke in the estrogen group. Subsequent analysis showed that, in younger WHI participants (age range at baseline, 50–59), estrogen use was associated with lower risk for coronary heart disease (CHD) and overall mortality during the intervention period. Now, investigators have assessed postintervention health outcomes in 7645 WHI participants.

Overall, at a mean 10.7 years after baseline, estrogen use was not associated with excess risk for stroke or other adverse outcomes (CHD, deep venous thrombosis, hip fracture, colorectal cancer, and mortality during follow-up). As had been noted in previous WHI analyses of the intervention phase, risk for invasive breast cancer was lower in the estrogen group than in the placebo group (hazard ratio, 0.77; 95% confidence interval, 0.62–0.95); moreover, among younger women, estrogen use was associated with lower risk for CHD (HR, 0.59; 95% CI, 0.38–0.90) and marginally lower risk for mortality during follow-up (HR, 0.73; 95% CI, 0.53–1.00).


Although these new findings from the WHI are intriguing, they do not imply that estrogen-only therapy should be recommended at this time for cardioprotection or breast cancer chemoprophylaxis. What these results do provide is reassurance to young menopausal women who are posthysterectomy and who present with bothersome vasomotor symptoms that use of estrogen therapy for as long as 6 years is safe.


Reader Comments (2)


I have always been skpetical of subgroup analyses in clinical trials, especially when they clash with the overall findings. The HRT "timing hypothesis" is a popular excuse for estrogen's failure to reduce cardiovascular disease. The validity of this theory, however, is very suspect because you have one age group (70+) where CHD, colon cancer, and total mortality are ELEVATED, but then you have another (the 50-59 group) where these risks are reduced. I ask - what drug out there prevent the very diseases it exacerbates? Frankly, the most reliable and responsible interpretation of this study is - cessation of estrogen alone therapy attenuates both the risks and benefits seen while taking the drug, except for the clear and continued 23% reduction in breast cancer.

What I find troubling though is that there is too much evidence already showing that estrogen does not prevent heart disease in anyone, especially since oral contraceptives, pregnancy, and even high dose Premarin in men with prostate cancer all markedly raise the risk of vascular events - CHD, stroke, and venous thromboembolism. And the WHI estrogen-alone trial also did an analysis for medication COMPLIANCE, and those results were very different - during the trial, according to the 2004 initial results, women who took >80% of their study pills for the entire 7.1 years had an even higher risk of stroke, embolism, and total mortality, with no reduction in heart disease (but a greater reduction in breast cancer). The follow-up results, presented in April, also showed different results based on compliance - an even larger reduction in breast cancer (32%) but also a continued elevation in stroke risk (50%). Additionally, and most importantly, NO AGE DIFFERENCES were seen for any outcome.

I wish I knew why this need to make estrogen therapy be something it is not persists. It's harmful to women and it's an affront to good science.

Competing interests: None declared

Levonne K Kelly

I question the validity of the above followup study since my abrupt termination of the WHI study pills was followed by months of menopausal- like symtoms and I never received a request for further information from WHI re any of the above reported conditions.

Competing interests: None declared

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