For the last 30 years, experts have warned women that hormone replacement therapy (HRT) posed a risk for both breast cancer and cardiovascular disease. That’s because investigators published the first really large, randomized controlled trial of HRT in 2002, and it contained bad news (JAMA, July 17, 2002). The Women’s Health Initiative (WHI) was a landmark study. It included 160,000 postmenopausal women for 15 years. Physicians have been arguing about the results ever since. A new overview of the medical literature published in the Canadian Medical Association Journal (May 15, 2023) attempts to answer the question: is hormone therapy safe? Read on for our analysis of the latest research.
The Premarin Predicament:
The Food and Drug Administration approved Premarin (conjugated estrogens) in the early 1940s. Few drugs in medical history have stimulated more controversy.
Let’s start with the name.
According to the International Journal of Pharmaceutical Compounding (July-August, 2007):
“Premarin, a complex of conjugated equine estrogens manufactured by Wyeth for use as hormone replacement therapy in women, was originally developed by the Canadian pharmaceutical firm Ayerst, McKenna and Harrison. The name Premarin was coined from pregnant mare urine, from which the estrogen complex was isolated. Although the complete composition of Premarin and its active components remains undisclosed or unknown, Wyeth reports that it contains a mixture of 10 estrogens. The history of Premarin is entangled in a fascinating story of human intrigue involving ingenuity, influence, controversy, animal rights, competition, money, protection of stockholders, government regulatory power, patient rights, emotions, greed, power, personal and professional freedom, state rights, and perhaps even, ultimately, constitutional issues.”
A Short History of Premarin:
Prior to the publication of the Women’s Health Initiative study, Premarin was one of the most prescribed drugs in America. In 1966 Dr. Robert Wilson published his book “Feminine Forever.” He promoted estrogen for a wide range of “female problems.” Although this Manhattan gynecologist received financial support from the maker of Premarin, most doctors and patients probably did not know about that relationship.
Dr. Wilson promoted estrogen for its ability to keep “a woman sexually attractive and potent.” He also claimed it protected the heart, brain, and kidneys and preserved “the strength of her bones, the glow of her skin, the gloss of her hair.” He also maintained that fears of cancer were misguided and claimed that estrogen actually prevented cancer.
However, by the late 1970s doctors had discovered that women on estrogen were far more likely to develop cancer of the uterine lining. Sales of Premarin took a nose dive until a decade later, when physicians found that adding progesterone to the regimen seemed to protect the uterus.
Sales doubled between 1990 and 1993 and continued to climb throughout that decade. Doctors reassured women that fears about breast cancer were overblown and that products like Prempro (estrogen plus progestin) would protect the heart.
As an added bonus, they suggested that hormone replacement therapy might prevent mental decline or even Alzheimer’s disease. Not surprisingly, Premarin became the most prescribed drug in America.
New Research on Dual Hormone Replacement Therapy and Dementia:
Of all the purported benefits of HRT, reducing the risk of Alzheimer’s disease might have been the most attractive for many women. That’s because many women witnessed an older relative losing the battle against dementia. It was something they desperately wanted to avoid.
A study in Danish women (BMJ, June 28, 2023) shows that, instead, women who use HRT have a greater risk of developing dementia. The researchers examined 18 years of health records for more than 60,000 women who were between 50 and 60 years old in 2000.
Women who took combined estrogen and progestogen hormones longer ran a higher risk. Those with just one year or less of HRT had a 21 percent higher risk than those who never took it. In comparison, those taking hormones for more than 12 years were 74 percent more likely to develop dementia.
These findings also applied to women who started HRT before they were 55 years old. The investigators admit that women who need HRT may simply be at higher risk of dementia, and suggest further research to untangle this question. Once again we are reminded that early enthusiasm does not always pan out.
Is Estrogen Alone Safer?
Ever since the Women’s Health Initiative was published, some gynecologists have expressed skepticism about the findings. One criticism involved the age of the women when starting HRT. Another suggested that progestogen might be the bad actor, and that estrogen alone could be safer. The Danish scientists have now published a further analysis of their data, focusing on women who had had hysterectomies (JAMA, Dec. 18, 2023). As a result, these women took only estrogen for their menopausal treatment.
The researchers followed the outcomes of women who had hysterectomies and were between 50 and 60 years old in 2000. For this analysis, they found 29,000 women who qualified; 540 of them received a dementia diagnosis during follow-up. When those with dementia were compared to matched controls without dementia, the scientists found that women using estrogen were about 50% more likely to develop dementia. Needless to say, this has bearing on the question Is hormone therapy safe? The researchers recommend further studies to confirm whether estrogen-only hormone replacement therapy really increases the risk for dementia.
When Women Began Asking: Is Hormone Therapy Safe?
Even before the Women’s Health Initiative (WHI) study was first published in 2002 some women were asking: is hormone therapy safe? There were rumors about blood clots and breast cancer.
Once the first data from the WHI study was published, however, concerns mounted.
Here were the original conclusions from the 2002 JAMA article:
“Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women.”
The authors went on to comment:
“It is noteworthy that the increased risks for cardiovascular disease and invasive breast cancer were present across racial/ethnic and age strata and were not influenced by the antecedent risk status or prior disease. Hence, the results are likely to be generally applicable to healthy women in this age range. At the time the trial was stopped, the increases in numbers of invasive breast cancers, CHD [coronary heart disease], stroke, and PE [pulmonary embolism] made approximately equal contributions to harm in the estrogen plus progestin group compared with placebo, which were not counterbalanced by the smaller reductions in numbers of hip fractures and colorectal cancers.”
That is pretty technical. The bottom line was that there were more cases of heart disease, breast cancer and stroke among women taking HRT than those on placebo.
Researchers Are Still Arguing Over the Question: Is Hormone Therapy Safe?
On March 7, 2012, an online article in The Lancet Oncology suggested that estrogen by itself (without progestin or medroxyprogesterone) does not increase the risk for breast cancer and might even lower it.
The key author (Garnet Anderson) was quoted as saying:
“Women who have had a hysterectomy may be reassured that taking estrogen by itself, short term, to relieve menopausal symptoms will not increase their risk of breast cancer.”
But 25 days later on April 1, 2012, a much larger study was presented at a cancer conference in Chicago with just the opposite results. The research involved roughly 60,000 nurses who participated in The Nurses Health Study. Data was analyzed from 1980 through 2008.
Women who took both estrogen and progesterone (Prempro for example) had an 88 percent higher risk of breast cancer after 10 years on the treatment. Those who took estrogen alone for at least a decade had a 22 percent increased risk of developing breast cancer. Those women who were exposed to just estrogen for more than 15 years had a 43 percent greater chance (relative risk) of being diagnosed with breast cancer.
The lead author, Dr. Wendy Chen, was quoted as saying:
“There’s a continued increase in risk with longer durations of use and there does not appear to be a plateau.”
With such conflicting research and dueling headlines (one month you read that “Estrogen Pills Reduce Breast Cancer Risk” and the next you see that “Long-Term Estrogen Therapy Does Up Breast Cancer Risk“), it is hardly any wonder women remained totally confused.
Confusion Remains: Is Hormone Therapy Safe?
The article in the Canadian Medical Association Journal (May 15, 2023) encourages doctors to weigh the benefits of hormone replacement therapy along with the drawbacks. They point out that menopausal hormone therapy can cut hot flashes and night sweats by as much as 90%. In addition, women taking HRT sleep better and have fewer mood disturbances.
The authors emphasize the benefits of HRT and even suggest that hormone therapy might reduce coronary artery disease “among younger menopausal patients, specifically those who start menopausal hormone therapy before age 60 years or within 10 years of menopause.”
They downplay the risks of breast cancer:
“In the WHI 20-year follow-up study, patients on conjugated estrogen alone showed a lower risk of breast cancer than those on placebo. Other studies also showed a lower risk of breast cancer among those on estrogen alone, compared with those on combined menopausal hormone therapy, with synthetic progestins conferring a higher risk of breast cancer than micronized progesterone.”
So…Is Hormone Therapy Safe?
There is no simple yes or no answer to this question. It is clear that even after two decades researchers are still arguing about the pros and cons of HRT. This has left millions of women confused and frustrated.
You can read their stories at this link:
The People’s Pharmacy Analysis:
Many physicians felt betrayed by the results from the Women’s Health Initiative. Others resisted the WHI findings and criticized the study, despite its large size and long-term follow-up.
In recent years, some researchers described HRT concerns as “mass fear” and “hysteria.” They continue to insist that the benefits of hormones far outweigh the risks of breast cancer or heart attacks.
We caution you to be wary of misleading headlines and quick analyses of complicated topics like hormone replacement therapy. When women are in dire distress because of menopausal symptoms, HRT can be a life line. The shorter the duration of the treatment, the lower the risks.
Any woman who is considered a candidate for hormone therapy should be carefully assessed for her risks of developing breast cancer, a blood clot or stroke. Side effects of HRT should be presented objectively.
You may also want to learn more about topical estrogen creams. Are they as safe as some physicians believe? Here is a link to more information.
Please share your own experience with hormone replacement therapy below and how you have dealt with hot flashes and night sweats.