Compounded Bioidentical Hormones: What the NASEM 2020 Review Found

By Benn Bluestein-Veyra, M.Sc. Organic Chemistry · Updated 8 November 2026

The National Academies of Sciences, Engineering, and Medicine reviewed compounded bioidentical hormone therapy at FDA's request and reported on 1 July 2020 that it "could not draw definitive overall conclusions on the safety or effectiveness of cBHT preparations" because of "a substantial dearth of safety and efficacy data, including little or no high-quality pharmacokinetic data".^[1] The committee recommended that prescribers restrict compounded hormone preparations to two documented circumstances, an allergy to an ingredient of an FDA-approved product or a requirement for a dosage form no approved product offers, and that the Pharmacy Compounding Advisory Committee review ten hormones and every pellet preparation as candidates for FDA's difficult to compound list.^[1] FDA states that it "does not have evidence that compounded “bioidentical hormones” are safe and effective, or safer or more effective than FDA-approved hormone therapy."^[2]

This page reports what the NASEM record, FDA's own pages, section 503A and the professional societies state about compounded hormone preparations, and how those sources frame the choice between an FDA-approved product and a compounded one.^[3][4]

Bioidentical describes a molecule, and the marketing term describes a product class

In chemistry, a bioidentical hormone is a molecule with the same structure as the hormone the human body produces: estradiol, progesterone and testosterone are bioidentical whether the finished product is an approved drug or a compounded preparation. Stanczyk and colleagues noted that "the chemical structures of many of the hormones used in bioidentical HT (BHT) are the same as those used in conventional HT", and that many patients nonetheless consider compounded hormones natural and conventional products synthetic.^[5] Bhavnani and Stanczyk described the same misconception in 2012.^[6]

The NASEM committee used the term with a caveat: "the term bioidentical is often misinterpreted by the general public" as "a consequence of cBHT marketing strategies", and its use "should not be interpreted as an endorsement."^[1] The ACOG Clinical Consensus of 2023 stated that "Many compounding pharmacies use the phrase “bioidentical hormone” as a marketing term to imply that these preparations are natural and, thus, safer and more effective than" FDA-approved menopausal medications.^[7] FDA's consumer page makes the same distinction from the regulator's side: "Many marketed products that are called “bioidentical hormones” are compounded drugs, which are not FDA-approved", while "FDA has approved drugs containing hormones that are identical to the hormones made naturally by women in their reproductive years."^[2]

FDA charged NASEM with assessing clinical utility, and the committee defined the term before answering

FDA's compounding program page records that in September 2018 the agency asked NASEM "to provide an independent assessment and evaluate scientific evidence relating to the safety and effectiveness of these products and discuss whether the available evidence supports use of cBHT products to treat patients."^[4] The committee's own account states that FDA asked for "a prioritized focus on preparations containing estradiol, estrone, estradiol cypionate, estriol, dehydroepiandrosterone (DHEA), pregnenolone, progesterone, testosterone, testosterone cypionate, and/or testosterone propionate"; thyroid preparations and growth hormone were outside the charge.^[1]

Because no standard definition existed, the committee defined clinical utility "as a multidimensional construct that reflects evidence about safety, effectiveness, and therapeutic need", with patient preference as a fourth component.^[1] It held nine meetings, five of them public, reviewed the peer-reviewed and gray literature, took submissions from FDA, boards of pharmacy, compounders, professional societies and "thousands of patients who use cBHT", and delivered its report on 1 July 2020.^[1][4]

NASEM found the evidence base insufficient to support marketing claims of safety or effectiveness

The committee reported that "the vast majority of the relevant studies reviewed had severe methodological limitations", found "few well-designed, double-blind, randomized, placebo-controlled trials" and concluded that "the data do not support the claims of superior safety or efficacy of cBHT preparations compared to FDA-approved BHT products", while noting "some evidence to suggest that estriol may be effective in treating certain menopausal-related symptoms".^[1] The report added that "the lack of data should never be interpreted as a marker of safety and/or effectiveness", and that "the contraindications for cBHT are expected to be similar to those of FDA-approved hormone products of the same class."^[1]

FDA summarized the finding on its own page: NASEM "determined there was a lack of rigorous evidence of safety and effectiveness from well-designed or properly controlled clinical studies", found that information "came mostly from low quality data, such as anecdotal claims, patient reports, and prescriber testimonies", and "concluded that their wide-spread use poses a public health concern."^[4] A 2022 systematic review and meta-analysis of 29 randomized trials in 1,808 perimenopausal and postmenopausal women, authored in part by employees of a compounding supplier, reported no association between compounded preparations and adverse lipid or glucose changes in primarily short-term trials, and stated that "There are insufficient RCTs of cBHT to assess clinical risk of breast cancer, endometrial cancer, or cardiovascular disease."^[8]

NASEM asked FDA to review ten hormones and every pellet preparation for the difficult to compound list

Section 503A(b)(3)(A) withholds the compounding exemption from drug products that FDA identifies by regulation as presenting demonstrable difficulties for compounding.^[3] NASEM's Recommendation 2 reads: "The Pharmacy Compounding Advisory Committee should review the following bioidentical hormone therapies as candidates for FDA's Difficult to Compound List: estradiol, estrone, estradiol cypionate, estriol, dehydroepiandrosterone, pregnenolone, progesterone, testosterone, testosterone cypionate, and testosterone propionate", citing "the lack of bioavailability data and product-to-product variability", and adds that the committee "should consider all compounded bioidentical hormone therapy preparations formulated in pellet dosage form as candidates".^[1]

On pellets specifically, the report concluded that "cBHT pellet formulations may be difficult to compound given the complexity of drug delivery mechanism, lack of required bioavailability testing, insufficient guidance for compounders, and the need for specialized equipment."^[1] A 2021 medical-record study of 539 postmenopausal women reported that those on pellet therapy had a higher incidence of side effects than those on FDA-approved therapy (57.6 percent against 14.8 percent), more abnormal uterine bleeding among women with a uterus, more hysterectomies, and peak serum estradiol and testosterone concentrations the authors described as supraphysiological.^[9]

As of 8 November 2026, FDA has proposed but not finalized the demonstrably difficult lists. The 20 March 2024 proposed rule (89 FR 19776) names three initial categories: "(1) oral solid modified-release drug products that employ coated systems (MRCs), (2) liposome drug products (LDPs), and (3) drug products produced using hot melt extrusion (HMEs)."^[10] No hormone and no pellet dosage form appears in it, and a Federal Register search on 8 November 2026 returned no final rule.^[10]

NASEM reported that salivary and serum testing used in marketing lacks support in clinical guidance

The bioavailability chapter opens with the finding that "Current clinical guidance suggests there is insufficient evidence to support claims that multiple blood, serum, or saliva tests can be used to precisely individualize hormone therapy", citing ACOG, the Endocrine Society, the North American Menopause Society and the Santoro statement.^[1] On saliva, the committee recorded that "several professional medical societies have issued public statements that saliva testing is unnecessary and has not been proven to be accurate nor reliable", because day-to-day variation in an individual's hormone concentrations is "large enough to make any one measurement uninformative", and that mail-in test kits "often use bioanalytical methodology that lacks the rigors of the validated bioanalytical methods" used in FDA-approved clinical studies.^[1]

The Endocrine Society's 2016 scientific statement reached the same conclusion: there is "no evidence that monitoring compounded HT with serial salivary or blood testing is effective", with thyroid hormone the stated exception.^[11] Stanczyk and colleagues described the underlying error as "a misconception that salivary hormone levels are equivalent to non-protein-bound (free) hormones in blood."^[5]

The professional societies recommend FDA-approved products and restrict compounded use to specific circumstances

The Endocrine Society's 2016 scientific statement "finds that there is no rationale for routine prescribing of unregulated, untested, and potentially harmful custom compounded bioidentical hormone therapies", citing "a general lack of standardization and quality control" and the risk of "overdosing, underdosing, or contamination".^[11] The Society's 2015 menopause guideline carries recommendation 3.1i, an ungraded best practice statement, which recommends "against the use of custom-compounded hormones".^[12]

The 2022 Menopause Society position statement states that "The risks of hormone therapy differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used", and NASEM records the Society among the bodies whose guidance finds no support for individualizing therapy by hormone testing.^[1][13] The 2023 ACOG consensus stated that compounded bioidentical menopausal hormone therapy "should not be prescribed routinely when FDA-approved formulations exist", and that clinicians receiving a request for it "should educate them on the lack of FDA approval of these preparations and their potential risks and benefits, including the risks specific to compounding."^[7]

NASEM summarized this guidance: "Evidence-based clinical guidance recommends use of FDA-approved drug products for treatment of menopause and male hypogonadism. Some, but not all, guidelines reviewed acknowledge the potential for limited use of cBHT in specific medical circumstances".^[1] It also reported that "the current volume and scope of cBHT use contrasts with evidence-based clinical guidance": surveys estimated 1 million to 2.5 million US women use compounded hormone therapy, 86 percent of surveyed women were unaware the products are not FDA approved, and compounded products were 35 percent of current hormone therapy use among 3,725 women surveyed by the Menopause Society.^[1][14][15]

FDA-approved bioidentical products exist for estradiol, progesterone and testosterone

NASEM wrote that "many patients may believe that bioidentical hormone medications are only available through custom preparations at compounding pharmacies. However, FDA has approved several bioidentical hormone therapy (BHT) medications at different doses and with various routes of administration."^[1] FDA's menopause medicines list names estradiol products in several dosage forms and lists micronized progesterone (Prometrium) among progestin-only medicines.^[16] FDA's 2025 testosterone statement lists the approved formulations as "oral, topical gel, transdermal patch, buccal system (applied to upper gum or inner cheek), and injection".^[17]

Estriol is a common ingredient in compounded "Bi-est" and "Tri-est" preparations. FDA states: "FDA does not have evidence that drugs containing estriol are safe and effective, or are “safer forms of estrogen.” There are no FDA-approved drugs containing estriol. Marketed drugs that contain estriol are compounded drugs, which are not FDA-approved."^[2]

The FDA label record for approved hormone products changed in 2025 and 2026

On 10 November 2025 FDA asked application holders of menopausal hormone therapies to remove from the Boxed Warning "the language related to cardiovascular diseases, breast cancer, and probable dementia", while retaining the endometrial cancer Boxed Warning on systemic estrogen-alone products and the cardiovascular and breast cancer information elsewhere in the labeling; on 12 February 2026 FDA announced approved changes for a first batch of six products.^[18][19] For testosterone, FDA announced class-wide changes on 28 February 2025 that add the TRAVERSE results to all labels, retain the "Limitation of Use" language for age-related hypogonadism, remove the Boxed Warning language on adverse cardiovascular outcomes and add a blood pressure warning; its Testosterone Information page, current as of 23 June 2026, records a June 2026 request to remove that limitation of use and to revise prostate safety information.^[17][20] NASEM's Recommendation 4 asked that compounded estrogen and testosterone preparations carry boxed warnings "like those used in FDA-approved drug products".^[1]

Section 503A bars regular compounding of essentially copies, and FDA defines the exception

The statute conditions the 503A exemption on a compounder who "does not compound regularly or in inordinate amounts (as defined by the Secretary) any drug products that are essentially copies of a commercially available drug product."^[3] Section 503A(b)(2) then defines the exception: the term "does not include a drug product in which there is a change, made for an identified individual patient, which produces for that patient a significant difference, as determined by the prescribing practitioner, between the compounded drug and the comparable commercially available drug product."^[3]

FDA's January 2018 guidance (docket FDA-2016-D-1309) treats a compounded drug as essentially a copy if it "has the same active pharmaceutical ingredient(s) (API) as the commercially available drug product", in "the same, similar, or an easily substitutable dosage strength", and the commercial product "can be used by the same route of administration as prescribed for the compounded drug".^[21] The prescriber's determination must be documented: "the compounder should ensure that the determination is documented on the prescription", a prescription that "identifies only a patient name and drug product formulation" is not sufficient, and "Other factors, such as a lower price, are not sufficient".^[21] As an enforcement matter, FDA "does not intend to take action against a compounder" that "fills four or fewer prescriptions for the relevant compounded drug product in a calendar month", and prescriptions carrying a documented significant difference are not counted toward that number.^[21]

What the sources frame as the choice between an approved product and a compounded preparation

Where an FDA-approved product with the same hormone, a comparable strength and a usable route exists, section 503A and FDA's guidance treat a compounded version as essentially a copy unless the prescriber documents a significant difference for that patient.^[3][21] NASEM named the allergy and dosage form cases as those circumstances and stated that "Patient preference alone should not determine the use of cBHT preparations."^[1] The documents a practice would hold follow from those statements.^[1][21]

• A record that no FDA-approved product with the same hormone, a comparable strength and a usable route met the patient's need, or the prescriber's documented significant difference on the prescription in the form FDA's guidance describes.
• NASEM's stated expectation that compounded potency "should not exceed those of FDA-approved hormone therapy products because of potential safety concerns".
• Patient counseling that the preparation is not FDA approved, which NASEM, the Endocrine Society and ACOG each describe.
• The pharmacy's certificate of analysis for each lot of bulk hormone, given NASEM's findings on product-to-product variability.

ExaVeyra's compounded hormone preparations reach a practice through a licensed 503A pharmacy partner on a patient-specific prescription. The partner dispenses testosterone and any other controlled substance under its own DEA registration and supplies a certificate of analysis for each lot on request. Diagnosis, the choice between an approved product and a compounded preparation, and the monitoring plan are decisions for the prescribing practitioner.^[3][21]

This article summarizes publicly available federal regulation for licensed practitioner education. It is not legal advice, medical advice, or regulatory guidance, and it does not establish that any particular product or practice is compliant. Confirm current federal and state obligations with qualified counsel.