I Think I Need Hormones, But Aren’t They Dangerous?

There is so much information available about hormone replacement these days that it is difficult even for doctors to keep it straight. In 2002, now 22 years ago, the largest study ever done on hormone replacement called the “Women’s Health Initiative” (WHI) changed the way we think about hormones. That study was widely and poorly reported, and many broad and out-of-context statements such as “estrogen causes cancer” or “hormones cause heart disease” were perpetuated in the media. As a result, many doctors and patients alike decided to avoid hormone replacement therapy altogether, which caused many perimenopausal (close to menopause) and postmenopausal patients to suffer unnecessarily. 

The WHI was a huge study looking at different aspects of women’s health. The hormone replacement arm of the study included almost 30,000 women. Patients in the study took an oral product called Premarin (an estrogen that was popular at the time, made from pregnant mares’ urine, hence the name) or PremPro (a combination of Premarin and Provera, the latter being a progesterone-like drug added to prevent uterine cancer). The study was stopped earlier than planned when the investigators reported that patients taking Prempro had a higher risk of breast cancer, blood clotting, heart disease, and stroke than the group taking placebo. The actual number of adverse events was very small, but it was surprising since earlier data from other large studies suggested that estrogen actually lowered the risk of heart disease. In fact, even in the WHI, patients taking estrogen-only did not have an increased risk of breast cancer and other diseases; it was the Provera compound that was the bad actor. Even in the Prempro group, the increase in breast cancer amounted to one additional case per 1000 women.  Later analysis found that neither group showed an increase in dying from breast cancer, and that breast cancer deaths were actually reduced. Also not reported initially was a significant decrease in colon cancer and osteoporosis. Heart disease and dying from all causes was also significantly reduced in patients who started on hormones in the first 10 years after menopause, and the small increased risk in heart attack in the older women only happened in the first year. 

One of the most important facts that were not reported in the media was that the average age of patients in the study was 63, and study participants included patients who smoked, were obese, and had a history of heart disease, among other things. When we are considering prescribing hormones to a younger (45-60 year old), healthy patient, one cannot assume that her risks will be the same as a 63 year old obese smoker. Similarly, patients who need hormones due to surgical removal of the ovaries before age 50 were not involved in the study, and without hormone replacement the quality of life and risk of heart disease and osteoporosis for these patients can be seriously affected. 

Importantly the products that we use now are different than those used in the study. The trend is now to use estrogen transdermally (across the skin) rather than in pill form, and to use estradiol rather than Permarin. Transdermal estrogen in the form of a patch, cream, sublingual or pellet form, has been shown in many studies to have no increased risk of blood clot, heart disease and stroke, compared to that seen with oral estrogen. (Transdermal estrogen avoids the liver and is directly absorbed into the bloodstream, which may be why we see those risks decrease). It’s also now clear after many studies that Premarin is more inflammatory than estradiol, which is the estrogen we make in our own bodies. The term “bio-identical” can be applied to any form of estradiol, including several FDA approved products such as patches, gel and vaginal applications, as well as compounded options like pellets and  creams.

Many studies have looked at the association of estrogen replacement to breast cancer and some studies suggest a small increased risk after prolonged use of estrogen. How long? There is no clear answer, but it does seem clear that short term use (a few years or less) has no adverse effect on the breast. After many studies looking at estradiol and breast cancer, there appears to be no increased risk of breast cancer and a decrease in death from breast cancer, although hormones will cause an existing cancer to grow faster. One problem is that many women have breast cancer, 1:8 is the current lifetime risk in this country, and the vast majority of those patients did not take hormones. There are so many factors that affect the development of breast cancer, deciding cause and effect is very difficult. For patients taking estrogen of course we recommend an annual mammogram, as we do for all of our patients over 40. The great news is that both progesterone and testosterone seem to decrease breast cancer risk, so for patients who take both combined MHT, overall breast cancer risk is likely lowered.

Clearly the issues surrounding hormone replacement are complex and individual. But for most patients, correctly administered hormone replacement can improve quality of life dramatically, as well as helping with bone density, reducing heart disease, colon cancer and possibly Alzheimer’s risk, especially if started early. The key is timing, since MHT prevents damage in blood vessels that later put as at risk of dementia or heart attack, so starting within the first few years of menopause is recommended.