New WHI Analysis: This Time Estrogen Saves Lives
A subgroup analysis in 2004 showed a reduction in mortality risk among Women's Health Initiative study participants who had undergone hysterectomy and were treated with estrogen alone.
By Charles Bankhead, MedPage Today
Medically Reviewed by Robert Jasmer, MD
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THURSDAY, July 18, 2013 (MedPage Today) —Thousands of postmenopausal women may have died prematurely over the past decade because they avoided estrogen therapy after hysterectomy, a new analysis and math model of a landmark study projected.
The most conservative estimates placed the total number of projected deaths at 18,601, and the toll could be as high 91,610 according to the new model.
The estimates came from an updated analysis of the Women's Health Initiative (WHI) Estrogen Plus Progestin Trial, which ended prematurely in 2002 after an interim review showed an increased risk of adverse events associated with combined hormonal therapy.
The updated analysis was limited to younger women (50 to 59) who had undergone hysterectomy. In that subgroup of patients, unopposed estrogen significantly reduced the mortality risk, Philip Sarrel, MD, of Yale University, and co-authors reported online in theAmerican Journal of Public Health.
"The finding is so dramatic — reporting thousands of women dying every year — if this gets the attention that it deserves, we hope it will change clinical practice," co-author David Katz, MD, the Yale-Griffin Research Center, said in an interview. "We hope that clinicians will start routinely talking to their patients who have had a hysterectomy and bringing up the issue that taking estrogen may save your life. We have data to show that it can save your life.
"Frankly, our paper should do that. It's not every paper that has the potential to change clinical practice. This one should. It occurs in the context of a growing awareness of the damage we have done by talking women out of all forms of hormone replacement."
In the 1990s, as many as 90 percent of women in their 50s took estrogen after hysterectomy, and treatment continued for an average of 4 to 5 years. Multiple studies had indicated that estrogen reduced the risk of bone and heart disease after hysterectomy.
Publication of the WHI results in July 2002 led to a rapid decline in the use of estrogen by postmenopausal women, even though the findings included women who were taking combined estrogen and progestin rather than estrogen alone. Within 18 months, half of the women using hormonal therapy had stopped, the authors noted.
However, a subgroup analysis in 2004 showed a reduction in mortality risk among WHI participants who had undergone hysterectomy and were treated with estrogen alone. A follow-up analysis in 2011 confirmed a decreased mortality risk of 13 per 10,000 per year among hysterectomized women 50 to 59 treated with estrogen.
Despite the positive follow-up results from WHI, prescriptions for all types of hormonal therapy have continued to decline, the authors said. Fewer than one-third of hysterectomized women are using estrogen.
"The decline in estrogen therapy prescription and usage seems to reflect a generalized avoidance of any forms of hormone therapy not supported by the WHI data," the authors wrote. "This raises the possibility that there has been and continues to be a considerable resultant mortality toll."
To examine the issue, Sarrel and colleagues undertook a study to calculate the number of premature deaths that might have occurred due to estrogen avoidance by hysterectomized women 50 to 59 since the WHI ended. For a point estimate, they used the 2011 WHI publication, showing a 13/10,000/yr increased mortality in that subgroup of women assigned to placebo.
Overall mortality estimates were calculated from population estimates based on census data, age variability in hysterectomy rates, and different rates of estrogen usage prior to 2002.
Investigators used census data to determine the population of women 50 to 59 from 2002 to 2011, and they used national hospital discharge data to determine hysterectomy rates from 1997 to 2005, with and without oophorectomy. For women 50 to 59, the hysterectomy rate ranged between 33 percent and 40 percent.
An estimated 54 percent of women undergo oophorectomy at the same time as hysterectomy. Before 2002 post-hysterectomy estrogen usage among women without ovaries was 90 percent and 53 percent among those with ovaries. Investigators performed separate analyses of mortality associated with declining estrogen use for women with and without ovaries.
Applying the lower estimated hysterectomy rate resulted in a best point estimate over 10 years of 49,128 projected excess deaths and an extreme low estimate of 22,677 projected excess deaths. Use of the higher hysterectomy estimate resulted in a best point estimate of 59,549 estimated excess deaths over 10 years, increasing to 91,610 for the extreme high estimate.
Finally, the authors factored in a lower mortality associated with estrogen avoidance for women with and without ovaries. Application of the lower estimated hysterectomy rate resulted in a best point estimate of 40,292 excess deaths over 10 years and a low-end estimate of 18,601 excess deaths according to the new model's projection.
Use of the higher estimated hysterectomy rate resulted in a point estimate of 48,835 excess deaths due to estrogen avoidance, and a high-end point estimate of potentially up to 75,125.
"Thus, across a reasonable range of all assumptions, the excess mortality was between 18,601 and 91,610," the authors concluded. "Using the best available point-estimate values with year-by-year adjustment and adjustment for differential rates of estrogen use among women with and without retained ovaries at hysterectomy, the range was 40,292 to 48,835."
The results indicate that clinicians should not be as reluctant to prescribe estrogen for women who have undergone hysterectomy and are estrogen deficient, said Holly Thacker, MD, of the Cleveland Clinic.
"It's not only going to improve the quality of their life but likely the longevity of their life," Thacker toldMedPage Today. "It's really kind of a game changer, in that we're not just talking the use of estrogen for the lowest dose for the shortest amount of time for treatment of symptoms. We're also thinking in terms of prevention and lifespan and quality of life and work productivity.
"Women and their doctors need to stop being fearful of treating estrogen deficiency."
A founder of the North American Menopause Society said these math modeling results are part of an ongoing effort to repair damage caused by early reports from the WHI.
"This is not the first paper to demonstrate that the way the WHI interpreted their results and presented them to the media has resulted in far more death and disability than it prevented," Wulf Utian, MB BCh, of Case Western Reserve University in Cleveland, said by email.
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