WASHINGTON — The use of compounded bioidentical hormone therapies (cBHTs) — an increasingly popular approach to relieve symptoms of menopause and male hypogonadism — should be limited to the small number of patients who cannot benefit from an FDA-approved hormone therapy product, says a new report from the National Academies of Sciences, Engineering, and Medicine. It recommends that prescribers restrict the use of cBHTs to two circumstances: when a patient is allergic to an ingredient in an FDA-approved hormone product, and when a patient requires a specific dosage form not available for an FDA-approved product.

“Bioidentical” hormone therapies (BHTs) contain hormones that are chemically and structurally identical to those produced by the human body. They are available as FDA-approved products or non-FDA-approved compounded preparations. Unlike FDA-approved BHT products, compounded preparations have not been subjected to regulatory oversight or rigorous safety, efficacy, and quality control testing. Further, because cBHTs are custom-blended in different doses and forms — such as pills, creams, or pellets — the lack of standardization can increase the possibility of overdosing, underdosing, or contamination, says The Clinical Utility of Compounded Bioidentical Hormone Therapy: A Review of Safety, Effectiveness, and Use.

Millions of men and women use cBHTs to alleviate symptoms associated with age-related hormone changes, such as hot flashes in menopause, or low muscle mass due to decreased testosterone. Marketing campaigns and celebrity influencers have touted claims of superior safety, effectiveness, and the “natural” and anti-aging properties of cBHTs, but these claims of clinical utility are not substantiated by evidence from well-designed studies, says the report.

The report concludes there is currently insufficient evidence to support the clinical utility of cBHT — a multidimensional construct that reflects evidence about safety, effectiveness, therapeutic need, and patient preference.

“Consumers may be lured by the prospect of personalized medicine and avoiding perceived ‘one-size-fits-all’ treatments,” said Donald Mattison, chief medical officer of Risk Sciences International and chair of the committee that wrote the report. “However, cBHT preparations, across doses and dosage forms, are not supported by a sufficient body of evidence to inform providers and patients of potential benefits and harms. Providers have an obligation to educate patients about the potential risks of using cBHTs, and present a clear rationale if they do need to prescribe them.”

The committee also examined the potential therapeutic need for cBHT among patients with documented female sexual dysfunction (FSD) and gender dysphoria (a mismatch between biological sex and gender identity), two indications for which there are no FDA-approved medications. Often, both indications are treated with off-label use of FDA-approved hormone products. However, the committee was unable to identify any clinical guidelines that recommend the use of compounded preparations to treat either condition instead of off-label use of FDA-approved medications.

Identifying Candidates for FDA’s Difficult to Compound List

The report recommends that the FDA’s Pharmacy Compounding Advisory Committee review 10 BHTs as candidates for the agency’s Difficult to Compound list, which prohibits pharmacies from compounding certain products that are complex in terms of formulation, delivery mechanism, and bioavailability (the extent to which the drug is absorbed by the body and has an active effect). These 10 candidates are: estradiol, estrone, estradiol cypionate, estriol, dehydroepiandrosterone, pregnenolone, progesterone, testosterone, testosterone cypionate, and testosterone propionate.

cBHTs in pellet form (a tiny cylinder that is implanted under the skin) should also be considered for FDA’s Difficult to Compound List, given specific safety concerns related to the complexity of the drug delivery mechanism, insufficient guidance for compounders, and a lack of required bioavailability testing.  

The report also raises caution regarding the use of multihormone cBHTs. While it may be convenient for patients to have multiple hormones combined into a single pill or other delivery mode, the more hormones in a formulation, the greater the potential for adverse effects due to drug-drug interactions or other issues.

Future Research Priorities

To address the public health concerns related to the unsubstantiated claims of clinical utility of cBHT, the committee recommended additional education for prescribers and compounding pharmacists, increased federal and state-level oversight, and an expanded research agenda. Specifically, to clarify the potential health benefits and risks specific to cBHT preparations, funders of research should prioritize well-controlled trials for commonly prescribed cBHT preparations that include estrone, estradiol, estriol, progesterone, or testosterone. FDA, state medical and pharmacy boards, and other stakeholders should also support efforts to improve data collection and surveillance of cBHT use to estimate the volume, scope, and financial costs of the medications, as well as associated adverse events.

The study — undertaken by the Committee on the Clinical Utility of Treating Patients with Compounded “Bioidentical Hormone Replacement Therapy” — was sponsored by the U.S. Food and Drug Administration. The National Academies are private, nonprofit institutions that provide independent, objective analysis and advice to the nation to solve complex problems and inform public policy decisions related to science, technology, and medicine. They operate under an 1863 congressional charter to the National Academy of Sciences, signed by President Lincoln. 

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