The Dangers of Hormone Therapies

Hormone replacement is sold as a fountain of youth for men and women, but researchers keep finding risks

Hormone replacement therapy is supposed to offer us the keys to health and longevity, but researchers warn that all too often, the opposite is true. Image Point Fr/Shutterstock

Women approaching menopause today probably have no idea how stigmatized their natural aging used to be.

In 1966, a bestselling book called “Feminine Forever,“ written by Robert A. Wilson, a Wyeth-funded gynecologist, called post-menopausal women ”flabby,“ ”shrunken,“ ”dull-minded,“ and ”desexed.” Ads for hormone replacement therapy (HRT) in medical journals accused women of “outliving their ovaries” and other health crimes. The solution was HRT.

By 1966, HRT was already well established. Since 1941, women had been routinely prescribed “conjugated equine estrogens”—pregnant mare urine—for menopause in drugs such as Premarin, made by Wyeth, a pharmaceutical company that was purchased by Pfizer in 2009.

But in 1975, The New England Journal of Medicine (NEJM) published disturbing research titled “Association of exogenous estrogen and endometrial carcinoma.” Of the studied women, those on menopausal estrogen had 4.5 times the risk of endometrial cancer of those not on the hormone.

In 1979, NEJM put another nail in HRT’s coffin.

“There was a sharp downward trend in the incidence of endometrial cancer that paralleled a substantial reduction in prescriptions for replacement estrogens,” it reported.

Not wanting to lose a dependable franchise, hormone drug makers added progestin to the estrogen-only HRT, which reduced the risk of endometrial cancer. Drugs such as Prempro then debuted, which combined the two hormones. In 2001, more than 126 million prescriptions for HRT were written in the United States, according to The New York Times. In 2002, 13 percent of Canadian women aged 50 to 69 were on HRT.

A Drug Empire Unravels

How were drugmakers able to convince so many doctors and women that HRT was necessary? HRT was presented as a fountain of youth—an anti-aging therapy—and pushed by beautiful people such as top model Lauren Hutton. In addition to the youthful skin and hair benefits implied in HRT ads, scientific papers claimed that HRT therapy “may decrease the risk for or delay the onset of AD [Alzheimer’s Disease] in postmenopausal women” and “may even reduce the risk of atherosclerosis.” Look pretty and not get “old person” diseases? What’s not to like?

But, like the 1970s debacle, the newer HRT soon began to be linked to cancer and defensive, scientific papers such as, “Is there an association between hormone replacement therapy and breast cancer?” and “Sex Hormone-Binding Globulin and Breast Cancer Risk,” emerged. At least 26 scientific papers defending or promoting the therapy were commissioned by Wyeth—not written by doctors, but by a marketing company.

And it soon became apparent that HRT needed defending. The results from the federal Women’s Health Initiative (WHI) in 2002, which investigated HRT, made it look less like a “fountain of youth” and more like a “fountain of age.”

The study found that women on HRT had a 26 percent higher risk of breast cancer, a 29 percent higher risk of heart attacks, a 41 percent higher risk of stroke, and a doubled risk of blood clots. Newly released data published in the Journal of the American Medical Association also found an increased risk of dementia.

“These findings, coupled with previously reported WHI data, support the conclusion that the risks of estrogen plus progestin outweigh the benefits,” the researchers wrote.

Other studies have found that women on HRT were found to be more likely to lose their hearing; develop gallbladder disease, asthma, or melanoma; experience urinary incontinence; need joint replacement; develop ovarian and/or lung cancer; and develop non-Hodgkin’s lymphoma.

HRT not only increased the risk of breast cancer; it made detection more difficult. A 1995 article in the journal Radiology states that “an increase in mammographic density” was demonstrated in most subjects undergoing continuous combined HRT. In 2008, researchers said that “this adverse effect on breast cancer detection should be incorporated into risk-benefit discussions with women considering even short-term combined hormone therapy.”

As doctors and patients absorbed the extreme hyping of HRT benefits and the hiding of its risks, prescriptions dropped precipitously. So did breast cancer. Between 2001 and 2004, U.S. cases of breast cancer in postmenopausal women dropped by 8.6 percent and estrogen-fed cases of breast cancers fell by 14.7 percent.

Aftermath and Dawn of Low T

After the second HRT meltdown, the lowest hormone dose possible for the shortest duration was the medical recommendation for menopausal symptoms; long-term use was discouraged, despite positive estrogenic effects on bones. But drugmakers didn’t concede the anti-aging territory, especially because drugs taken long-term (think statins and blood pressure pills) are their best products versus short-term drugs such as antibiotics that make no real money. Some studies have since tried to support HRT but a 2019 WHI  follow-up found women still had a 29 percent greater incidence of breast cancer 19 years after using the drugs.

The only exception to that risk were women over 50 who took estrogen alone. Because taking estrogen alone raises the risk of uterine cancer,  this therapy is only recommended for women over 50 who no longer have a uterus. For these women, taking estrogen alone may actually decrease breast cancer risk, though other risks remain.

Critics of the WHI study, particularly drug makers, say the women in the study were “too old” and “too menopausal.”  Some doctors and researchers suggested HRT drugs should be used earlier. Enter the concept of “perimenopause,” which, it was said, could occur as early as a woman’s mid-30s.

“Just when you get used to PMS, they say you have perimenopause,” a related cartoon said.

The apparently bad WHI results also stemmed from the wrong hormones being used, HRT promoters said as they rolled out new HRT candidates and “bio-identical” hormones.

Most of these bio-identical hormone producers already had skin in the HRT game. Thanks to promoters like Suzanne Somers, bio-identical hormones became a lucrative second wave of HRT but the FDA, Mayo Clinic, Cleveland Clinic and the American Cancer Society all say there are no large-scale, well designed studies to support those claims. In other words, there is no reason to believe they are safer.

Meanwhile, the emergence of “Low T” or “low testosterone” in men was déjà vu all over again. Although ads didn’t accuse men of “outliving their testicles,” the rest of the sales pitch was the same. If men were losing their sex drive, energy, muscles, and looks, it wasn’t aging—it was testosterone deficiency. A 40-fold increase in testosterone prescriptions occurred between 2005 and 2015, according to research in the Journal of the American Geriatrics Society.

Many testosterone replacement products, including pills, injections, patches, gels, solutions, and even underarm deodorant have been approved by the Food and Drug Administration, but they aren’t without risks, according to researchers in Therapeutics and Clinical Risk Management. Risks can include a worsening of benign prostate problems, heart failure, sleep apnea, and liver toxicity.

“Low T” is likely overdiagnosed and overtreated, according to the Journal of the American Geriatrics Society researchers.

“We join others who characterize the mass marketing of testosterone coupled with the permissive prescribing of testosterone for common, nonspecific, aging-related symptoms as disease mongering,” the researchers wrote.

In an interview, Dr. Thomas T. Perls, a professor of medicine at the Boston University School of Medicine and one of the paper’s authors, told me that what’s called Low T may actually be signs of a suboptimal lifestyle and diet.

“Men who are in excellent general health tend to have no decline in their testosterone, but men with common underlying problems such as obesity and poor fitness may. The irony is that the poor fitness level puts these male patients at risk for heart attack and stroke, and they are being given a drug that puts them at further risk,” Perls said.

In a 2020 video, Drs. Mark Hyman and George Papanicolaou agreed that lifestyle factors should always be considered before testosterone replacement.

After the many dramas around HRT for women, I asked Perls if nothing had been learned about the reckless promotion of “fountain of youth” products.

“Actually, marketers did learn from watching a hormone marketed to prevent the ills of aging,” he said. “They invented the term ‘andropause’ for a condition that numerous endocrinology experts state does not exist and began selling testosterone.”