Hormone-Replacement Therapy: Could Estrogen Have Saved 50,000 Lives?

For more than a decade, doctors have cautioned women about the risks  associated with hormone-replacement therapy. But those warnings may have put one  group of women at increased risk of dying early, according to the latest  study.

Researchers at Yale University say nearly 50,000 women may have died  prematurely after they stopped taking hormone-replacement therapy (HRT) to treat  menopause symptoms, following a much publicized 2002 study that revealed the  treatment increased risk of heart disease and breast  cancer.

The 2002 Women’s Health  Initiative (WHI) study, a 15-year investigation into the factors that  contribute to the health of postmenopausal women, was stopped three years early when a preliminary review of the  data showed that women taking the combination of estrogen and progestin had a higher rate of breast cancer, heart disease and stroke than women taking a placebo. The  results stunned both the public and the medical community, since doctors had  been prescribing the hormones not just to treat menopausal symptoms like hot  flashes, but for extended periods of time to protect women against heart  disease.

Almost immediately, doctors and public-health officials began shifting women  away from such long-term use of hormones, recommending that postmenopausal women  restrict hormone use to the few months surrounding menopause to address the most  intense symptoms. In 2012, the U.S. Preventive Services Task Force confirmed the WHI trial’s findings, concluding after a  review of 51 studies published since 2002 that the risks of HRT outweighed the  benefits, which were limited to a reduced risk of fractures.

But the WHI scientists had always cautioned that their findings might not be  broadly applicable to all women past menopause. They noted that the trial  included women who were at least a decade beyond menopause, and that the  participants used one specific formulation of HRT called Prempro, which is  a combination of conjugated estrogens and a synthetic form of progesterone known  as medroxyprogesterone acetate.

(MORE: The  Truth About Hormones)

The WHI also continued to evaluate women who had had a hysterectomy, and  therefore could take estrogen alone; women with an intact uterus are not advised  to take estrogen without the protective effect of progesterone since estrogen is  linked to a higher risk of uterine cancer. In 2007, the WHI reported that women  with a hysterectomy who took estrogen alone had fewer calcium-based plaques in  their arteries, and therefore may have enjoyed some protection against heart  disease. This finding was supported by a 2011 study published in the Journal of the American Medical  Association (JAMA) that found a slightly lower risk of breast  cancer and no significantly increased risk of heart disease, blood clots, stroke  or early death among women taking estrogen only compared with women with  hysterectomies who took a placebo.

Based on those results, the Yale scientists decided to study this group of  women further, to determine whether widespread coverage about the risks of HRT —  the combination of estrogen and progestin — had persuaded these women to stop  taking their estrogen-only therapy, and whether that decision impacted their  mortality. Could women without a uterus benefit in some way from estrogen-only  therapy, and were they putting their health at risk if they avoided the hormone  therapy?

Their analysis, published in the American Journal of Public Health, confirmed their suspicions.  Before the WHI study, about 90% of women who had a hysterectomy would have  relied on estrogen therapy to replace what their reproductive system no longer  produced. Following WHI, however, 10% of these women used the hormone, and based  on a formula the researchers created to estimate their survival rates, they  determined that 50,000 women died during the study period, between 2002 and  2011, prematurely. Dr. Philip Sarrel, professor emeritus of obstetrics,  gynecology and reproductive sciences at Yale University School of Medicine and  lead author of the study, said in a video discussing the study that none of these women, who  were aged 50 to 59 at the start of the study, lived to reach their 70s. Most  died of heart disease, bolstering the connection that earlier studies had found  between estrogen-only therapy and a lower risk of heart problems among women who  had a hysterectomy.


The analysis highlights the challenges in crafting and distributing  public-health messages so that they are interpreted correctly and applied to the  right people. Following the surprisingly negative effects of HRT that WHI  revealed, most in the medical community focused on warning women away from  hormone therapy en masse, and the more nuanced message that some women might be  able to continue taking estrogen alone became lost in that effort. “All we  really knew [in 2002] was that this one kind of HRT used late in menopause  resulted in a modest degree of harm,” says Dr. David Katz, the director of  the Yale University Prevention Research Center and one of the authors of  the new paper. “We developed a cultural aversion to HRT and unfortunately it was  shared by doctors and patients alike, and it extended to all women and all forms  [of the hormones].”

Katz says it’s not just the media that is responsible for such  overgeneralizing — research journals do it too. And he suspects that many  patients probably never discussed the results of the 2002 study in depth with  their doctors, to determine if the findings applied to them, heightening the  perception that hormone therapy of any kind was not a good idea for any  postmenopausal woman.

“We would like to think that physicians are a case apart, that we  are always guided by high professional standards and meticulously reading the  literature,” says Katz. “If that were the case, every doctor would’ve read the  WHI study, every doctor would’ve read the 2011 study and we wouldn’t have this  problem. But actually the practice of medicine is consumed in the prevailing  current in our culture.”


And as is the case with any scientific finding, not everyone in the medical  community is convinced that the 50,000 women would have lived had they taken  estrogen therapy. But most experts agree that the results should start a serious  discussion about how to communicate public-health messages so they are applied  to the right populations in the correct way.

“What makes it a challenge is that there is not a simple set of evidence.  There is not one truth about estrogen,” says Andrea LaCroix, the co–project  director of the Clinical Coordinating Center for the Women’s Health Initiative  and author of the 2011 study. “Anytime something is less straightforward and  more complicated, it’s difficult in a quick media sound bite to get the message  across. We tried very hard when we published that data to show that the findings  were different for different age groups of women. In terms of the challenge, I  actually agree with these authors that there was a lot of media attention when  the 2011 paper came out, but there was not a lot of discussion about translation  for women afterwards.”

In that spirit, LaCroix says the Yale results should not necessarily drive  all women who have had a hysterectomy to take estrogen pills. More research will  need to tease apart how estrogen may or may not be contributing to premature  death in these women. “I find it incredibly brash in a way and almost arrogant  to recommend the use of a pill to prevent death in women when it is totally  unproven to do that in women of any age group. If the results of this paper were  true and has public-health significance, we would’ve seen deaths in U.S. women  age 50 to 59 increase concomitant with the decline in estrogen use,” she says.  “The death data exists, and it would be important to do a study relating the  decline in estrogen use to changes in mortality directly in our  country.”


In the meantime, women should be asking their doctors about hormone therapy,  and whether any version of the treatment is right for them. These discussions  that could clear up confusion over what the latest data shows about the risks  and benefits of hormones. “The primary messenger for all messages ought to be  the doctors to the patients,” says Dr. Georges Benjamin, executive director  of the American Public Health Association. “The public hears a lot from  trusted messengers that may not be knowledgeable.”