Experts Warn Against Recommending Compounded Bioidentical Hormones in Menopause

Two internationally recognized women's health experts raise concerns from use of hormone therapy from a compounding pharmacy to manage menopausal symptoms.

Interviews with JoAnn E. Manson, MD, DrPH, and Cynthia A. Stuenkel, MD

Compounded bioidentical hormones (cBHT) are risky at best and most likely hazardous, and should be regulated by the Food and Drug Administration just as other menopausal hormone therapy products are,1 according to JoAnn E. Manson, MD, DrPH, professor of medicine at Harvard Medical School and chief of preventive medicine at Brigham and Women's Hospital, and Cynthia A. Stuenkel, MD, clinical professor of medicine, at the University of California San Diego School of Medicine.

These two internationally recognized experts in women’s health, both of whom are past presidents of the North American Menopause Society, raised a warning about the hazards that should be heeded by clinicians, including endocrinologists, before writing another prescription for compounded bioidentical hormone replacement therapy, in a commentary published in JAMA Internal Medicine.1

Dr. Manson and Dr. Stuenkel have been attempting to draw heightened attention to consequences of using these compounded hormone products for quite a while, and to express the urgency in making endocrinologists, primary care physicians, and women aware of the concerns to arrest further prescribing of cBHT. 

To be very clear, "we don't have any concerns about bioidentical hormone therapy products that have received FDA approval," Dr. Manson told EndocrineWeb, "Our point is to assure that for women who want to take bioidentical hormones, they receive a prescription for an FDA-approved hormone formulation (either transdermal or oral) and not a compounded product."

Bioidentical hormones are preceived as natural but pose greater harm than HRT.

The Dangers of Compounded Bioidentical Hormones

This urgency stems from an assessment that cBHT, while popular with women who view these products as more “natural,” present more harm than benefit to patients looking for symptom relief arising from the menopausal transition.

"A compounded bioidentical hormone is dispensed from a compounding pharmacy, or possibly a retail pharmacy," yet, these products have not been approved by the FDA, whereas bioidentical hormone preparations that have FDA-approval will be accompanied by a package insert outlining risks and benefits.

As long ago as 2012, a similar alarm was raised about dietary supplements by Pieter A. Cohen, MD, an associate professor of medicine at the Harvard Clinical and Translational Science Center, in a commentary published in the New England Journal of Medicine.2  

The parameters of the Dietary Supplement Health and Education Act of 1994 shields manufacturers from meeting the same stringent regulations for safety and efficacy before marketing these popular over the counter, nutrient and herbal products.2

Drs. Stuenkel and Manson identified six issues with custom. compounded bioidentical hormones in making their case for advising patients to avoid these pharmacy-designed products over traditional hormone replacement therapy.

Their concerns — similar to cautions raised with dietary supplements — are as follows:

  • Lack of evidence about effectiveness and safety
  • A lack of uniform product dosing
  • Inconsistent standards for manufacturing
  • Insufficient federal and state regulatory oversight
  • Lack of a package insert detailing potential risks with use
  • Potential for product contamination or impurities or both

Compounded bioidentical hormones fall under this regulation, and has become a growing focus of concern from many professional medical organizations, with virtually every medical society providing guidance to clinicians recommending against prescribing cBHT,3,4 according to the authors.

While Use of cBHT Grows So Do Concerns

Drs. Manson and Stuenkel found new data about cBHT, showing their use is prevalent, in some age groups equaling the use of traditional, FDA-regulated hormone therapy, and that women are not aware of the risks.1

"This is a call to action to tell women the truth," Dr. Manson tells Endocrine Web. "Women are not given information about risk," she says. "At present, there is not a requirement to provide information about risk so women are led to believe compounded hormones are as safe or safer and more natural than standard bioidentical hormone replacement therapy.''

When women take FDA-regulated hormone therapy, she said, they receive a package insert with a black box warning, detailing the risks of heart disease, heart attacks, strokes and breast cancer. Not so with compounded products.

Also important and not well understood is that there are a variety of systemic menopausal hormone formulations available, but not all are approved by the FDA (unless otherwise indicated), including: 1

Estrogen products:

  • Estradiol (oral tablets)*
  • Estriol (estradiol transdermal patches)*
  • Bi-estrogen (20% estradiol, 80% estriol as estradiol transdermal gels, emulsions, and spray), tri-estrogen (10% estrone, 10% estradiol, 80% estriol as estradiol vaginal ring)

Progesterone preparation:

  •  Micronized progesterone oral capsules*

Combination products:

  • Estradiol and progesterone
  • Estriol and progesterone
  • Bi-estrogen and progesterone
  • Tri-estrogen and progesterone


*Only these have received FDA-approval

Popularity Has Superseded Safety

The trend in hormone replacement therapy (HRT) has been a steady rise in the popularity of compounded bioidentical hormones since the publication of the Women's Health Initiative findings that after five years of daily oral conjugated equine estrogen combined with medroxyprogesterone in women ages 50 to 79, the harms surpassed the anticipated benefits in chronic disease prevention.5

Celebrity endorsements from high profile actors including Angelina Jolie, Susan Sarandon, Samatha Jones, Whoopi Goldberg, Rose O’Donnell, have fueled a desire for and acceptance of bioidentical hormone therapy to manage common complaints of menopause.

A New Climate and Finally, A Receptive Ear

In related news, Dr. Manson, a Women's Health Initiative principal investigator who co-authored the recent JAMA analysis following a long-term follow-up of over 18 years, reported that the use of HRT for five to seven years was not linked with risk of all-cause, cardiovascular, or cancer mortality.6

Drs. Stuenkel and Manson efforts to publish this ''call to action'' began more than five years ago.

The authors told EndocrineWeb, “even some of the leading journals were not familiar with the field; they would say, 'Where is the research?'" Until now.

To bolster what they knew already, and to gain further evidence for their concerns, Dr. Stuenkel said, she and Dr. Manson collected several surveys. Among their findings:1

  • Among 9% of 3,725 women surveyed used hormone therapy, with one-third using a compounded bioidentical hormone formulation.
  • In other words, about 1 to 2.5 million women in the US who are 40 years or older have used cBHT.
  • Half of the women taking cBHT mistakenly thought the formulation was FDA approved.

“While the surveys did not include other valuable information, “Dr. Stuenkel said, “such as how long women were using the bioidentical therapies, this information may help inform clinicians.”

Time for a Change in Direction Before Prescribing

Requiring package labeling would be a good starting point, they said.

"We think any dispensation of hormone therapy should be accompanied by package labeling,'' said Dr. Stuenkel. In the JAMA Internal Medicine paper, they referred to that as ''the easiest shortcoming to remedy."

Additionally, the authors indicated that in 2003, the FDA stipulated that ''in the absence of evidence to the contrary, all approved menopausal hormone therapy products should be considered to have the same risks as those evaluated in the WHI and include the same boxes warnings (class labeling)."3

That means, of course, that even low-dose vaginal estrogen therapies, with little if any systemic absorption, ought to include the same warnings about heart attack, stroke, blood clots, breast cancer, endometrial cancer, and dementia.

The physicians are proposing that cBHT products should be labeled as not having FDA approval and that the risks of using these products are unknown (or may have the same as those of FDA-approved therapies).

Action Steps for Women’s Health Prescribers and Legislators

What should endocrinologists and PCP's do going forward?

According to Drs. Stuenkel and Manson:

  • Be cautious about prescribing cBHT. Fully inform patients if the products are prescribed.
  • Participate in the call to action by contacting their state pharmacy boards, which primarily regulate compounding pharmacies, with FDA oversight. Ask them to insist the pharmacies provide a patient package insert.
  • Ask for state legislatures to pass laws mandating this information be given to patients.

Congress could also provide the FDA with full legal authority over the compounded hormone therapy industry.

The authors reported no conflicts of interest.

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