Concerns About Safety and Efficacy of Compounded Bioidentical Hormone Therapy

JoAnn V. Pinkerton, MD, FACOG, NCMP

Disclosures

Menopause. 2021;28(8):847-849. 

In This Article

Abstract and Introduction

Introduction

Following the release of the Women's Health Initiative (WHI) results in 2002,[1] many women began to use compounded bioidentical hormone therapy (cBHT) in the mistaken belief that it was safer, more effective, and without the risks described in the WHI trial. Further analysis of the WHI results and newer clinical studies have shown that hormone therapy is safe and effective for the treatment of menopausal symptoms for women who initiate hormone therapy before age 60 or within 10 years of menopause.[2–4] For women requesting bioidentical hormone therapy, ie, hormones similar to what their bodies made before menopause, there are many FDA-approved preparations available, including estradiol (oral, patch, transdermal, and vaginal), oral and vaginal progesterone, intravaginal dehydroepiandrosterone, and transdermal testosterone (although approved and dosed only for men in the US). For FDA-approved hormone therapies, the pharmacokinetics are extensively studied and are provided with extensive package inserts delineating efficacy, safety, and potential risks.

Concerns about safety, efficacy, and overuse of cBHT remain a significant issue for many menopause specialists. The North American Menopause Society (NAMS) and other major societies, including ACOG, ASRM, Endocrine Society,[5,6] as well as a 2020 scientific review and analysis published by the National Academies of Sciences, Engineering, and Medicine (NASEM)[7] recommends that prescribers avoid prescribing compounded hormone medications to treat menopausal symptoms, female sexual dysfunction, and other hormonal conditions. Similar to the other major medical societies, NASEM concluded that there was a "paucity of data on the safety and effectiveness of cBHT' leading to "insufficient evidence to support the overall clinical utility of cBHT as a treatment for menopause."

Safety issues that have been raised include lack of FDA approval and monitoring, the potential for dose variability (of overdosing, underdosing, or contamination), risks due to the compounding process, with potential for increased endometrial cancer risk, lack of collection of adverse events, and inconsistent package labeling and warnings about side effects and risks. Compounding pharmacies are expected to comply with USP Standards related to the preparation of compounded prescriptions. Although the 2013 Drug Quality and Security Act[8,9] increased FDA oversight for the compounding facilities which outsource (ship across state lines), local regulation is by state pharmacy board and voluntary participation as accredited pharmacies, listed on the website of the Pharmaceutical Compounding Accreditation Board (PCAB).[10]

To date, there are no randomized, controlled trials comparing cBHT with placebo or with FDA-approved therapies. There is no scientific evidence to support the notion that cBHT has fewer risks than FDA-approved hormone therapies that demonstrate a high degree of safety and efficacy in clinical trials.[7] In their report, NASEM[7] recommended that patient preference alone should not be the reason cBHT is prescribed. Thus there is no rationale for the routine prescribing of cBHT, therapies that are not approved, regulated, or monitored by the FDA. Despite these safety concerns and wide availability of FDA-approved bioidentical HT, there continues to be a large market of prescription cBHT,[11,12] often based on unsubstantiated marketing claims of increased safety.

There is currently a lack of consistent labeling and adverse event reporting for compounded therapies. In their report, NASEM[7] recommended against the use of non-FDA-approved cBHT except for specific medical circumstances, such as allergies to components in FDA-approved HT or dosages not available in FDA-approved drug products. NASEM recommended compounding pharmacy industry provide consistent labeling when cBHT is prescribed, including a statement that cBHT is not FDA approved, regulated, or monitored and including a boxed warning of risks and adverse events. This recommendation is to ensure that women understand they are receiving non-FDA-approved therapies and receive up-to-date, accurate, and consistent information about cBHT therapies.

Recommendations from NASEM[5–7] include:

  • Limiting the use of cBHT preparations to those with a documented allergy or medical need for a different dose or product than those approved by the FDA.

  • Adding bioidentical hormones and doses to the FDA Difficult to Compound List including estradiol, estriol, estrone, dehydroepiandrosterone, pregnenolone, progesterone, testosterone, and ALL pellet therapies.

  • Increasing education for both prescribers and pharmacists, including those who prescribe, compound, market, or dispense cBHT.

  • Increasing state regulation and certification of prescribers using evidence-based guidelines.

  • Advocate for improved federal and state oversight of cBHT for safety and efficacy.

  • Use of standardized package labeling for cBHT, including boxed warnings currently required on all FDA-approved therapies and the information that these products are not FDA approved or monitored.

  • Transparency of financial relationships and conflicts of interest.

  • Increase research on the safety and efficacy of cBHT.

One of the areas of most concern to menopause specialists and those who take care of menopausal women is the use of cBHT for postmenopausal women in the form of supraphysiologic dosing, particularly pellet therapies. Pellet therapy and other compounded hormone products are regulated by the rules governing vitamins and nutritional supplements and do not need to meet the rigor of data for FDA-approved hormone therapies. NASEM,[7] in their review, discussed the lack of well-designed, randomized controlled trials of safety and efficacy and concerns about the lack of pharmacokinetic and bioavailability data and potential for harm from supraphysiologic dosing. Similarly, a global consensus recognized the potential benefit of physiologic dosing of testosterone for hypoactive sexual desire, but warned against supraphysiologic dosing.[13]

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