Bio-identical hormones safe and effective in randomized placebo controlled trial

Using naturally occurring hormones in the form that your body produces them to treat hormone imbalances, such as hot flashes, has always made a lot of sense to me. Such hormones are sometimes referred to as “bioidentical hormones” or “human identical hormones” or “naturally occurring hormones”.  Many of the synthetic combinations of female hormones available on the market, although FDA approved, are mismatches for our cellular receptors for estrogens and progesterones, and several studies have established clear risks with their use.   This has led to many patients and their physicians looking to bioidentical hormones, as a potential alternative, based on the physiology of these hormones and promising observational studies.

“Compounded bioidentical hormone therapy is estimated to have become the most prevalent hormone therapy by U.S. prescription volume” according to Dr. Rogerio Lobo, professor of obstetrics and gynecology at Columbia University.  “Up to 39 million prescriptions may be written for up to 2.5 million women in the United States”.  Despite the immense popularity of bioidentical hormones among patients and physicians, none of the currently available combinations of beta estradiol and progesterone are FDA approved in the USA.  Physicians may still prescribe compounded hormones and other compounded medications if they feel they are in the best interests of an individual patient, but in the absence of placebo controlled randomized clinical trials demonstrating safety and efficacy, many clinicians either don’t feel comfortable prescribing them or proceed only with very careful monitoring of the patient.  In addition to monitoring clinical signs and symptoms, many obstetrician/gynecologists who prescribe bioidentical hormones monitor hormone levels regularly in an effort to achieve the safest and most physiologic balance.  This may be particularly important for women who have risk factors for breast and endometrial cancer.  Although many clinicians who prescribe bioidentical hormones become comfortable with general trends, ratios, and outliers when doing such monitoring, there are unfortunately no formal evidence based guidelines for obstetrician/gynecologists to turn to.  

 Like most obstetrician/gynecologists, I have wished many times that we had more formal and well funded research on this topic than what is currently available in the medical literature.  So I was excited to hear that Dr. Lobo and his team at Columbia University had presented the results of a randomized placebo controlled double blind trial to establishing the safety and efficacy of 4 combinations of natural progesterone and beta-estrodiol, comparing them to each other and to placebo.

This study (the REPLENISH trial) demonstrated clear benefits in reducing hot flashes and improving measures of menopausal quality of life, while not increasing endometrial cancer or precancer.

 This is an important trial on the road to FDA approval and formal guidelines for the use of bioidentical hormones, and very much welcomed.   Kudos to Dr. Lobo and associates at Columbia for tackling this topic and to TherapeuticsMD for developing the formulations evaluated in this Phase 3 trial.

 One important note if you read the details of this study.  Women with a BMI higher than 35 were excluded, and the average BMI for women in this study was 27.  There are good reasons for excluding women with a BMI over 35.  The amount of estrogen and progesterone, and one’s sensitivity to these hormones is dramatically altered in obesity.  Obesity is a disease of hyperestrogenism (high estrogen levels) because the fat is a hormonally active tissue.  Fat can produce a great deal of estrogen when insulin resistance and obesity are present.  In addition, the insulin resistance that causes obesity also causes ovarian dysfunction (often called “polycystic ovarian syndrome”) in which the ovaries don’t cycle and don’t produce much progesterone, while still producing high levels of estrogen and testosterone.  Obesity is associated with a marked increased risk in breast and endometrial cancer.  In women with obesity, it is not clear that any study of the risks and benefits of synthetic hormones or bioidentical hormones can be relied on.  Most studies have been done on non-obese women, as has this study, and safety cannot be extrapolated to women with obesity, as they are hormonally very different from non-obese women, and may need additional monitoring.

Women with obesity often present to their doctor’s office with atypical menopausal and perimenopausal symptoms.  They usually don’t have vasomotor symptoms to nearly the extent that non-obese women do.  That’s because their endogenous estrogen levels are higher than non-obese women.  Their symptoms tend to be those of hyperestrogenism, ie, emotional sensitivity, difficulty sustaining sleep, irritability, headaches and fogginess.  They are often diagnosed with depression, and treated with antidepressants, most of which are “weight positive”, thus a vicious cycle begins.  Progesterone supplementation makes physiologic sense in this group of women, both to buffer the high estrogen doses, and to reduce the risks of hyperestrogenism, such as endometrial cancer, and also to help directly to relieve some of their symptoms.  Synthetic progestins are not as good of a choice, as they induce further insulin resistance, reduce bone density and can exacerbate depression.  Individualizing treatment makes sense in many women, but particularly in those with obesity.  Ultimately, of course, controlling the disease of obesity gets to the root of these obesity induced female hormone problems, but this can be a lifelong struggle.

Debra Ravasia, MD, FACOG, April 29, 2017

Contact Dr. Debra Ravasia


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