A committee of the National Academies of Sciences, Engineering and Medicine (National Academies) recently concluded that there is insufficient evidence to support the clinical utility* of compounded bioidentical hormone therapy (cBHT) to treat symptoms of menopause and male hypogonadism (testosterone deficiency), as well as a number of other conditions for which these products are marketed. (Free download of prepublication report available here; Highlights here [PDF].)
While the FDA has approved dozens of hormone therapy products for men and women, such as estrogen, progesterone, and testosterone, many health care providers and patients have turned to compounded hormone preparations as an alternative. These products, often marketed as “bioidentical” or “natural”, account for an estimated 26 to 33 million prescriptions and cost upwards of $2 billion annually. While FDA-approved hormone therapies must undergo extensive safety and efficacy testing before they can legally be marketed, cBHT products are exempt from these requirements.
The report finds that there are likely tens of thousands of different cBHT products available to patients, including a wide array of different dosage forms, single active ingredient and multiple active ingredient preparations, and “an extensive range of different active ingredient doses and dose combinations.”
Because the popularity of cBHT products presents a “substantial public health concern”, the FDA asked the National Academies to examine the clinical utility of treating patients with these preparations. In response, an ad hoc committee of experts appointed by the National Academies undertook a review to understand why providers and patients are using cBHT preparations in lieu of FDA-approved therapies and whether there is evidence to support marketers’ claims of their safety and efficacy. Their report, some 350 pages long, details the committee’s findings and makes recommendations, including restricting the use of cBHT preparations.
The committee defines “bioidentical hormones” as
hormones that are chemically and structurally identical to those produced by the human body, with the implication that an identical structure translates to an identical physiologic response as endogenous hormones. Bioidentical hormones may be synthesized from plant or animal sources or completely synthesized chemically, and they are offered both as products approved by the U.S. Food and Drug Administration (FDA) and as preparations that have not undergone FDA approval. [Emphasis added.]
The vast majority of FDA-approved BHT products are indicated for treating symptoms of menopause and male hypogonadism, and the report focuses on cBHT use for these indications as well. However, as the committee notes, marketed claims for cBHT also include the treatment of conditions related to “antiaging” (longer, fuller hair; smoother skin), sexual health, joint pain, general chronic pain, insomnia, cardiovascular disease, and mental health disorders.
As the report points out, current evidence-based clinical practice guidelines recommend the use of FDA-approved products for treatment of menopausal symptoms and male hypogonadism. Why, then, are cBHT preparations so popular with health care providers and patients? Unfortunately, there is a paucity of evidence addressing this question. Based on the available research, the report concludes that drivers of patient interest in, and use of, cBHT, may include unsubstantiated marketing claims of superior safety and effectiveness from compounding pharmacies, medical clinics, and “wellness clinics”, amplified by social media and celebrity endorsements; “boutique patient experience”; mistrust in the healthcare and pharmaceutical industries; and the appeal of “natural” hormones and/or dosage forms.
Interestingly, the committee found that, despite healthcare provider claims of “customized” and “personalized” cBHT formulations,
compounders often offer preprinted prescription pads for cBHT with a checklist of popular ingredient combinations, concentrations, and dosage forms. These are often used as a marketing tool to increase the requests for and sale of cBHT, and they may appeal to certain clinicians by making the compounding prescription process “quick and easy.” However, there is no available evidence to suggest the sample menus of formulations, and associated doses and dosage forms, are supported by empirical data related to their safety and efficacy. [Citations omitted.]
The committee also accepted public testimony and written comments. Disturbingly, the report concluded,
It is clear from these communications that many clinicians, compounding pharmacists, and patients using cBHT hold minimum, if any, concerns regarding the medications’ safety and effectiveness.
Compounding the problem
As the report discusses extensively, the compounding process itself introduces its own issues due to “inadequate regulation and oversight”.
Compounding – defined as “the process of combining, mixing or altering ingredients to create a medication tailored to the needs of a patient” – can take place in community pharmacies, physicians’ offices, hospitals, or in large outsourcing facilities. (We’ve discussed problems with compounded drugs several times here on SBM.) Issues identified by the report include:
- Pharmacists’ lack of adequate training in compounding.
- Lack of standardization in drug formulae and production methods, as well as formulation difficulties (e.g., the poor water solubility of steroid hormones).
- Significant variations in pharmacy oversight from state to state and lack of coordination between state and federal regulators.
- Minimal labelling requirements for compounded drugs. For example, an FDA-approved drug may have a black-box warning, but a compounded drug with the same active ingredient is not required to carry the same warning.
- Inadequate safety inspections, particularly of community pharmacies.
- Undisclosed financial conflicts of interest between health care providers and compounding pharmacies as well as the inherent conflict arising when the health care provider and the compounder are the same person. (The disclosure requirements for physicians and pharmaceutical companies do not apply.)
In sum, under the current regulatory scheme, there is no assurance that
the compounded preparation contains the purported amount of active ingredient or can deliver the active ingredient to the patient and the site of action. Because of these limitations, different compounders may use different processes to compound an identical prescription, and as a result, cBHT preparations ordered with identical prescriptions and labeled with the same name will likely vary between compounders. Indeed, FDA has received adverse event reports that reveal harmful variations in compounding.
Marketing versus evidence
In addition to problems associated with compounding itself, the report finds the evidence does not support the cBHT marketing hype. For starters:
Many patients believe that bioidentical means that plants are the source of the hormones, however, it is the chemical structure and not the source that determines whether a hormone is bioidentical. Furthermore, bioidentical hormone medications that have plant sources and are called “natural” are, in fact, chemically modified in the laboratory before they are provided to a patient.
In fact, the source isn’t the important thing anyway:
Regardless of whether the bioidentical steroid hormone is produced endogenously or exogenously, it is the structure of the hormone and the way in which it is metabolized that determines its biological action. This point is critical to understanding the effects of steroid hormones.
[Not just that, it is critical to the understanding of any drug, dietary supplement, homeopathic remedy, or TCM herb. Scott Gavura crafted an excellent tutorial on why this is so.]
As for the widely touted “personalization” of cBHT, while the committee says, diplomatically, that it “appreciates the potential of personalized medicine and what it can offer patients”, personalization must be balanced against safety and effectiveness. When “personalization” means an
immense number of potential combinations of different hormones, excipients, dosage forms and strengths, as well as the lack of uniformity of . . . cBHT preparations . . . determining definitive bioavailability of those preparations [is] difficult. Without reliable bioavailability data, an accurate characterization of the safety and effectiveness of cBHT preparations is not possible.
And if this personalization is based on blood, serum, or saliva tests, “there is insufficient evidence to support claims that these tests can be used to individualize hormone therapy”.
Nor do marketing claims about the superior safety and effectiveness of cBHT products hold up to an exhaustive evidence review:
The majority of marketing claims about the safety and effectiveness of compounded bioidentical hormone therapy preparations, whether in absolute terms or in comparison to FDA-approved bioidentical hormone therapy, are not supported by evidence from well-designed, properly controlled studies.
As well, adverse event reporting for compounded preparations in general is “voluntary and incomplete” and “limits assessment of the frequency, type, and severity of adverse events” related to cBHT use.
Based on its review, the committee makes several recommendations, the first of which is to “restrict the use of cBHT preparations”. The committee also says that prescribers and compounders should “clearly explain the limited evidenced-based information” and that cBHT preparations are not FDA-approved. Unfortunately, the recommendation is addressed to providers, not regulators, and will likely be ignored by physicians, naturopaths, and other healthcare providers who prescribe cBHT, except for perhaps the few who were genuinely unaware of the lack of evidence and care about such things. The same observation goes for recommendations to “improve education for prescribers and pharmacists who market, prescribe, compound, and dispense cBHT preparations” and disclosure of financial conflicts of interest, although the latter does come with the suggestion that states collect this information and make it publicly available.
Improvements in the compounding process are also recommended, among them the inclusion of a standardized insert for dispensed cBHT preparations, analogous to the inserts required for FDA-approved drugs, as well as boxed warnings for prescriptions including estrogens and androgens. The committee also wants the FDA to review some BHT therapies as candidates for the FDA Difficult to Compound List, which prohibits listed substances from being used in compounding.
Unfortunately, but perhaps understandably in light of the pandemic, I cannot find that the National Academies report has been picked up by the mainstream media, despite its importance to the thousands of patients who are prescribed cBHT, unaware of the lack of evidence and health risks. Absent action by the FDA and state regulators, none of them will be the wiser.
* “Clinical utility” is defined as “A multidimensional construct that reflects evidence about safety, effectiveness, and therapeutic need. Patient preference is also a component of clinical utility, reflecting patients’ variable acceptance of benefits and risks.”