Since the late ’60s, menopausal hormone therapy has been touted as not just a tool for alleviating menopausal discomfort but as a way to preemptively protect women against cardiovascular disease, cancer and stroke.

After New York gynecologist Robert A. Wilson, MD, advocated for the treatment in 1968, the U.S. saw an influx of Premarin prescriptions, Nanette K. Wenger, MD, wrote in an JAMA Cardiology editorial. Women believed Wilson’s words that “hormone replacement therapy” would rejuvenate them, keep them sexually attractive and preserve bone strength.

Still, Wenger wrote, “the greatest experiment ever performed on women” had its shortcomings. Meta-analyses of more than 30 observational estrogen studies have identified a coronary risk reduction—anywhere between 35 and 50 percent—but those trials often fall victim to selection and compliance biases. As the research continues to roll in, Wenger said, it’s becoming clearer this quick fix could do more harm than good—and people are noticing.

“Has the last chapter been written on menopausal hormone therapy for chronic disease prevention?” she wrote in her editorial. She said many avenues, like the “timing hypothesis” that concerns the interval between menopause onset and initiation of hormone therapy, are still unexplored, but for now, this is why hormone therapy is looking weak as a cardioprotector.

1. The HERS study.

The Heart and Estrogen/Progestin Replacement Study (HERS) was one of the initial randomized clinical trials for hormone treatments in women with coronary heart disease, Wenger wrote, and it produced mixed results. In 2,763 women who took daily conjugated equine estrogen and medroxyprogesterone acetate for four years, researchers saw no overall coronary risk reduction. There was, however, an increased coronary risk during early treatment, which later subsided.

Those lower rates of risk didn’t persist in HERS patients, though. Researchers found the women’s coronary risks had resurfaced in a follow-up study. The original HERS trial also unveiled a threefold increase in risk for venous thromboembolism and a 40 percent increased risk for gallbladder disease requiring surgery.

2. The Women’s Health Initiative clinical trials.

An estrogen-plus-progestin study randomized 16,608 healthy women enrolled in the Women’s Health Initiative (WHI) database to 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate daily or a placebo and was terminated early when the Data and Safety Monitoring Board recommended shutting it down for health and safety concerns.

The trial’s leaders found an unfavorable preestablished global risk score in the study population, as well as an increased risk for invasive breast cancer and increased risks for coronary disease and stroke. According to Wenger’s research, women enrolled in this study saw an 81 percent increased risk of myocardial infarction, and a sister study examining estrogen alone was also terminated early for safety concerns.

3. The WHIMS study.

The WHIMS—or WHI Memory Study—trial explored dementia and mild cognitive impairment among 4,532 WHI enrollees older than 65. All patients were dementia-free at baseline, but with hormone therapy the risk of probable dementia doubled when compared to a placebo group.

Hormone therapy also didn’t prevent mild cognitive impairment in the study population, the researchers reported.

4. The FDA’s re-labeling move.

Citing this evidence and more, the U.S. Food and Drug Administration made labeling changes to menopausal hormone therapy drug containers, identifying an increased risk of heart disease, heart attack, stroke and breast cancer. This labeling, implemented in January of 2003, also emphasized that estrogen wasn’t approved for heart disease prevention.

“The FDA 2003 labeling identified that research was needed for unanswered questions, including whether lower-dose estrogen plus progestin decreased risk, whether other types of estrogen and progestin or other methods of administration decreased risk and whether risk-benefit associations of complementary medicine preparations for menopausal symptoms were evident,” Wenger wrote.

In 2004, the FDA added that hormone therapy increased the risk of probable dementia in women 65 and older.

5. The U.S. Preventive Services Task Force recommendations.

More recent data prompted the U.S. Preventive Services Task Force to issue a series of recommendations in 2013 for women considering hormone therapy as a way to prevent chronic disease. The task force recommended against the use of estrogen plus progestin or estrogen alone in women with hysterectomy, since previous trials had proven no net benefit for women taking the drugs.

“The harms are likely to exceed the benefits to prevent disease,” Wenger wrote. The task force still recommends against the therapy in 2017, excluding women who are considering hormone therapy for relief of menopausal symptoms.