People’s Pharmacy | The confusing history of hormone replacement therapy

Women contemplating hormone replacement therapy to ease hot flashes, night sweats and other miseries of menopause might be feeling confused. Controversy has followed Premarin, one of the dominant brands of replacement estrogen, throughout its history of more than 80 years. Few drugs have lasted as long or seen such extreme swings in popularity.

The conjugated estrogens in Premarin are made from pregnant mares’ urine. We suspect that is the origin of the brand name.

Premarin grew in popularity from the post-war years through the 1960s (when Feminine Forever was a best-selling book) and the 1970s. By the 1990s, when the baby boomers began to hit menopause, doctors prescribed Premarin more often than any other drug in America. Women took it expecting not only to alleviate menopausal symptoms but also to improve their cardiovascular health and ward off osteoporosis.

But problems with the estrogen story started appearing early. In 1946 doctors published a case in which a woman on prolonged estrogen therapy developed endometrial cancer (JAMA, July 6, 1946). The authors argued that estrogen was responsible for this cancer of the uterine lining.

It took decades for doctors to fully grasp the seriousness of this problem. In the mid 1970s Premarin was peaking in popularity. But major studies convinced many doctors that uterine cancer was too big a risk to ignore. Prescriptions plummeted.

Then physicians discovered that adding progesterone could protect the uterus from cancer. Sales soared. The makers of Premarin added progestin (medroxyprogesterone acetate) to the pill to create the brand Prempro.

In 2002 the largest study to date, the Women’s Health Initiative, was stopped early, however. Investigators detected more strokes, cardiovascular events and cases of breast cancer among women on Prempro than among those on placebo (JAMA, July 17, 2002). The FDA required a boxed warning on all hormone replacement therapies. Many gynecologists responded with fewer prescriptions. Others decided to prescribe bioidentical hormones, arguing that the problem might have been the mismatch between horses or synthetics and humans.

Recently the FDA removed the boxed warning from all hormone replacement therapies. As a result of increased demand in the wake of this decision, estrogen patches became hard to find. No wonder women might be experiencing whiplash.

Here’s what we know about hormone replacement therapy for menopausal symptoms. First, it does help most women who are suffering feel better. In addition, women on HRT may ward off osteoporosis.

Women should also be aware of some other considerations, though. Estrogen alone, whether in a pill or a patch, natural or synthetic, can increase the risk for endometrial cancer. Consequently, women who have not had their uterus removed via a hysterectomy should not take unopposed estrogen. An estrogen prescription should always include some form of progesterone to protect the uterus.

What about breast cancer? There the evidence is murkier. According to a follow-up of the volunteers in the Women’s Health Initiative, estrogen alone may not increase the risk (Lancet Oncology, May 2012). Use of estrogen plus progestin, however, is associated with an elevated risk of breast cancer (JAMA, July 28, 2020).

Another consideration is the risk of ovarian cancer. Twenty years after the Women’s Health Initiative, data show that unopposed conjugated estrogens doubled the risk for this rare but deadly cancer (Journal of Clinical Oncology, Oct. 20, 2024). Combination therapy did not.

We are disappointed that the granddaughters of the first women who took hormone replacement therapy are still confronted with so many unanswered questions about this treatment.

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Joe Graedon is a pharmacologist. Teresa Graedon holds a doctorate in medical anthropology and is a nutrition expert. Their syndicated radio show can be heard on public radio. In their column, Joe and Teresa Graedon answer letters from readers. Write to them in care of this newspaper or e-mail them via their Web site: www.PeoplesPharmacy.com.