Hormones for Hot Flashes - Is "Natural" Better?

by Adriane Fugh-Berman, M.D.

A French study has found that some types of menopausal hormone therapy may be safer than others, in terms of breast cancer risk. A large, long-term, observational study called E3N, which is part of the European Prospective Investigation into Cancer and Nutrition, has collected data at 7 time-points for 98,995 metropolitan French-women (primarily teachers) ages 40—65. The 12-year study ended in 2002. A recent analysis of 80,377 post-menopausal women followed for an average of 8.1 years examined breast cancer rates among women using different hormone regimens.¹

In France, the most commonly used estrogen for menopausal hormone therapy is estradiol, either taken orally or topically. Topical estrogen is applied to the skin through a patch, cream, or gel, and is much more popular in France than the oral version. Women with a uterus must add a progestagen hormone to topical and oral estrogen, because estrogen alone increases their risk of endometrial (uterine) cancer. There’s a wider variety of progestagens used in French menopausal hormone therapies than in U.S. therapies but, in both countries, progestagens are usually used orally.

In the E3N study, 2,354 women were diagnosed with invasive breast cancer. Compared to women who never took any menopausal hormones, taking estrogen alone increased the breast cancer risk. The majority of progestagens further increased risk, but there were two notable exceptions. Compared to women who never took menopausal hormones, women who used estrogen combined with the progestagen progesterone or dydrogesterone (the latter is unavailable in the U.S.) had no statistically significant increase in breast cancer risk. E3N can’t rule out the possibility that there are differences among women who choose to use different kinds of progestagens. But, the study’s important because it is very large and includes information on hormone combinations that are not widely used in the U.S.

In the U.S., conjugated equine estrogens (CEE, brand name Premarin®) are the most commonly used estrogen; medroxyprogesterone acetate (MPA, brand name Provera®, and also available generically) is the most commonly used progestagen. The combination of the two drugs is called Prempro®. The Women’s Health Initiative (a very large, NIH-funded, randomized controlled trial) found the combination of CEE and MPA increased breast cancer risk, but the use of CEE alone did not. CEE (with or without MPA) increased women’s risk of stroke, blood clots, and dementia, and had no protective effect on cardiovas-cular disease. Although combined hormones reduced women’s risk of fractures, the risks of the therapy outweighed benefits and the findings confirmed that menopausal hormones should not be used to prevent disease.

Many of the women in E3N used a combination of estradiol and progesterone, both of which (along with estriol and estrone), have been touted by some compounding pharmacies and alternative medicine proponents as “natural”, “bioidentical”, and safe, just because they match human hormones (the hormones themselves are synthesized). For this reason, some alternative medicine proponents use these results to bolster claims that “natural” or “bioidentical” hormones are superior to synthesized hormones. So-called Bioidentical Hormone Replacement Therapy” (BHRT) uses estriol, estradiol, estrone, and progesterone in combinations mixed by compounding pharmacies. The Food and Drug Administration (FDA) recently sent letters to seven compounding pharmacies warning them that claims of such compounded hormone products’ efficacy and safety were unproven and requiring the pharmacies to stop making hormone preparations containing estriol, which is not an approved drug in the U.S.

In response, full-page ads sponsored by the HOME (Hands Off My Estrogens!) Coalition appeared in The New York Times, USA Today, and The Wall Street Journal, defending compounded hormones, particularly estriol. BHRT proponents argue that human hormones, albeit synthesized, are harmless and/or health-promoting, but this claim is just wrong. Women whose bodies have naturally higher levels of estradiol and estrone are at higher risk of breast cancer than women with lower levels of these estrogens. In clinical trials, estradiol has not protected women against stroke or cardiovascular disease; in E3N, estradiol alone was associated with an increased risk of breast cancer.

The E3N study does raise the possibility that progesterone (and dydrogesterone) could be more benign, in terms of breast cancer risk, than MPA and other progestagens.Women who decide to use progesterone should use the oral form; topical progesterone may not be absorbed reliably enough to protect the uterus.

Topical estrogen options have proliferated recently. While we shouldn’t assume that these preparations are safer in terms of breast cancer risk, they may be safer in terms of estrogen-associated blood clots and gallbladder disease, because effective doses are much lower than oral doses and don’t pass through the digestive tract. Estradiol patches and several estradiol gels have been approved recently, including metered-dose pumps (Estrogel, 1.25 mg estradiol/actuation, and Elestrin, 0.52 mg estradiol/actuation); single-use packets (Divigel 0.25, 0.5, and 1.0 mg estradiol/dose); and a spray (Evamist 1.53 mg estradiol/ spray). Other topical forms include estradiol patches (Climara®, Alora®, Estraderm®, Vivelle®, and generics), vaginal creams (Estrace® and generics), vaginal ring (Estring®), and vaginal suppository (Vagifem®).

Estrogen is an effective therapy for hot flashes, night sweats and vaginal dryness and relief from bothersome menopausal symptoms may be worth some risk for some women. Women with a uterus should always take a progestin with estrogen, because estrogen alone increases the risk of endometrial (uterine) cancer. In any case, menopausal hormones should be taken in the lowest effective dose for the shortest amount of time possible.

Adriane Fugh-Berman, M.D., is an associate professor in the Georgetown University School of Medicine, Department of Physiology, and a former chair of the NWHN.

REFERENCES

1. Fournier A, Berrino F, Clavel-Chapelon F. “Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study,” Breast Cancer Res Treat 2008; 107(1):103-11.