The new science of hormone therapy
Here's how the therapy containing estrogen and progesterone initially got a bad rap—and what the research says about its potential benefits.
If you asked your doctor about taking hormone replacement therapy (HRT) for menopausal symptoms even a few years ago, you may have been met with hesitation, dismissed, or handed a pamphlet touting the benefits of antidepressants instead.
HRT—medications that replenish ovarian hormones that decline during menopause to alleviate symptoms like hot flashes and night sweats—have been the subject of significant controversy among physicians and patients alike ever since a 2002 study linked the medications to breast cancer and heart attacks. As a result, many have avoided the treatment due to concerns about its safety.
But attitudes about HRT may soon change. On November 10, the Food and Drug Administration (FDA) announced HRT, including creams, gels, patches, and pills, will no longer require a black box warning—the agency’s strongest warning that indicates a drug may trigger severe harm or death.
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Here’s how misinformation about HRT snowballed over the years—and what the science actually says.
The flawed 2002 study
In the 1980s and ‘90s, a handful of observational studies suggested that HRT offered numerous health benefits, including menopausal symptom improvement, a lower risk of chronic diseases such as osteoporosis, and improved cardiovascular health, says Kathryn Marko, an ob-gyn and assistant professor of Obstetrics & Gynecology at the George Washington School of Medicine and Health Sciences.
To better understand how HRT impacted women’s heart health, the Women’s Health Initiative (WHI) launched an eight-and-a-half year study that recruited thousands of women who were given either HRT—specifically, conjugated equine estrogen combined with a progestin called medroxyprogesterone acetate—or a placebo.
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But the study stopped prematurely after five years because there initially appeared to be a heightened risk of breast cancer and cardiovascular disease among the women who took HRT. In 2002, the findings were released and, in the days that followed, there was an onslaught of media headlines exaggerating and reinforcing the idea that HRT causes breast cancer. “As soon as it came out, we were steamrolled out of using HRT,” says Steven J. Fleischman, president of the American College of Obstetricians and Gynecologists (ACOG).
A year later, the FDA slapped a black box warning on the therapy, stating it potentially contributes to breast cancer, stroke, blood clots, heart attacks, and dementia. In response, attitudes surrounding HRT plummeted. The number of prescriptions for HRT decreased by 80 percent, as did the number of women inquiring about them. HRT education nearly disappeared from residency programs, leaving a new generation of doctors in the dark about menopause care. “There was a timeframe where a lot of women were not getting treated for their menopausal symptoms because of fear for hormone therapy by themselves and their providers,” says Marko.
The consequences have lingered: Over 80 percent of women experience menopausal symptoms, including mood swings, night sweats, hot flashes, and weight gain that last for years. But, as of 2020, only 5 percent receive treatment—a fall from nearly 27 percent in 1999. And of those who are prescribed, many don’t end up taking the medications over fear of that black box warning.
Newer research linking HRT to health benefits
Many physicians, including Fleischman, were immediately skeptical of the WIH’s conclusions and tried to speak out against them—but the misconceptions had already taken root.
A couple years later, the wider medical community started to recognize that the WIH study contained multiple design flaws. It predominately examined older women with an average age of 63 who have very different risk profiles and health statuses than the 50-somethings who typically go through menopause and start HRT, says Marko. The older women may have already had cardiovascular issues, like years of plaque build-up, that worsened when exposed to HRT, explains Fleischman, and yet the findings were generalized to younger women. The study also evaluated HRT formulations (medroxyprogesterone acetate) and oral delivery methods that are rarely used anymore.
Further analyses revealed the participants who took estrogen alone (without progestin) actually had a reduced risk of breast cancer, Marko adds, though today we know this isn't quite the case for those who take estrogen and progestin. Younger women also didn’t have an increased risk of heart disease, stroke, or breast cancer.
"As our knowledge from the WIH has evolved, we’ve realized that those risks, overall, were overstated,” Marko says. The original investigators eventually acknowledged that the results were distorted for publicity and widely misunderstood.
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More recent studies, by and large, have found that HRT provides a wide range of health benefits, including a decreased risk of bone fractures. That’s significant considering one in three women over 50 experiences osteoporosis fractures—serious injuries that can lead to loss of independence and a higher risk of blood clots, pneumonia, and death.
The cognitive effects are less clear, but growing evidence suggests HRT may protect cognitive function, with one report finding it cuts the risk of dementia by roughly 23 to 32 percent. It can also help ward off depression and anxiety in some women, especially when used alongside antidepressants, and, by alleviating symptoms, enables people to function better at work and be more present with their families, Fleischman says. “There is no doubt that HRT is good for mental health and mental well-being in postmenopausal women,” he says.
HRT has also been linked to a lower risk of colon cancer, and multiple studies show it significantly reduces all-cause and cardiovascular mortality when initiated in women under 60. In younger women, estrogen helps diminish the deposition of plaque in the arteries and causes the blood vessels to dilate, according to Mary Jane Minkin, a gynecologist and codirector of the Sexuality, Intimacy & Menopause Program at Yale Medicine. “You get better blood flow and less gunk,” she says.
Vaginal hormone therapy—a type of HRT that’s not absorbed systemically but administered directly to the vagina—can ease genital and urinary symptoms like vaginal dryness, irritation, pain during sex, and urinary tract infections that, in rare cases, can trigger sepsis, says Marko. “It’s too bad a black box warning was ever on vaginal estrogen because it truly does not have any of those risks,” she says.
HRT risks that are still present
As is the case when considering any treatment, it’s best to have a conversation with your doctor. They can evaluate your health history, medical issues, family history, and attitudes to determine what drug, if any, may alleviate your symptoms. HRT is safest and most effective when started within 10 years of your last menstrual period. “That’s the golden window of opportunity,” says Minkin.
HRT is not for everyone—those with a history of heart disease and hormone-sensitive cancers should avoid the therapy as it may increase the risk of a cardiac event, like stroke, or cancer recurrence. In some cases, HRT may still be an option, but a careful conversation about the risks and benefits, plus ongoing monitoring, is crucial, says Marko.
As for HRT and breast cancer? “There may be a slightly increased risk, but is it high? No, it’s not,” says Marko. It boils down to approximately one additional case of breast cancer per 1,000 women per year. That’s less risky than two glasses of wine a day, notes Fleischman. But experts also say if you already have a history of breast cancer, taking certain types of HRT could increase your risk of the cancer returning.
For those who are still concerned about side effects, there are plenty of ways to mitigate the risk of breast cancer. Applying treatment to the skin via a patch or gel rather than taking a pill can be beneficial, as well as exercising regularly, getting regular mammograms, eating a healthy diet, and cutting back on alcohol, says Marko. Adding progestin to the regimen can lower the risk of endometrial cancers.
Looking ahead, Fleischman hopes this news encourages people to keep an open mind about HRT and recognize that some of that early data may have been misinterpreted. “I do think it’s going to make patients healthier,” he says.
