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Due to the results of the 2002 WHI, many women decided to follow the advice of their doctors and switch from using synthetic hormones to using compounded bioidentical hormone therapy (cBHT). This led to an increase in the prescription of these compounds in the last decade to up to around 33 million annual prescriptions and with a progressive increasing trend. This prompted the FDA to ask NASEM (National Academy of Science, Engineering, and Medicine) to evaluate the available evidence on cBHT, concluding that there was a lack of high-quality research establishing the safety and efficacy of cBHT, and that studies with a higher level of evidence were needed, as well as a systematic review and a meta-analysis. Bearing this in mind, Liu and collaborators [1], carried out a systematic review and meta-analysis based on protocols registered in PROSPERO and carried out in accordance with the Cochrane Manual for Systematic Reviews of Interventions and the checklist of 27 items Preferred Reporting Items for Systematic Review and Meta-Analysis Statement (PRISMA) [2,3], in order to evaluate the existing evidence related to the safety and efficacy of cBHT that are prescribed to peri- and postmenopausal women. The authors searched across systems, choosing for analysis randomized controlled trials (RCTs) that compared outcomes in peri- and postmenopausal women using cBHT against placebo or FDA-approved hormonal products. They analyzed bias, according to the Cochrane risk of bias tool and took primary outcomes of safety (changes in lipid profile and glucose metabolism) and efficacy (changes in symptoms of vaginal atrophy). Secondary outcomes included changes in the endometrium, risk of adverse events, vasomotor symptoms, change in hormone levels, and change in bone mineral density.

A total of 29 RCTs were chosen from a total of 40 articles, where 1,808 peri- and postmenopausal women were analyzed, evaluating two risk factors for cardiovascular disease, lipid profile and glucose metabolism in women using cBHT. Endometrial thickness, adverse events, and changes in serum hormone levels were also evaluated. The results showed that compounded androgen was not related to changes of lipid profile or the metabolism. There was no change in endometrial thickness or serious adverse events. There were more androgenic side effects with the use of compounded dehydroepinandrosterone (DHEA) compared to placebo as expected. Other safety measures, including clinical cardiovascular events, endometrial biopsy, and breast cancer risk, were not evaluated in these studies. cBHT in the form of compounded vaginal androgen was found to significantly improve vaginal atrophy symptoms. This finding was supported by the association between compounded vaginal androgen and improved female sexual function scores. The changes of serum hormone levels were also evaluated. Despite the variations in absorption from different types of compounded hormones, routes, and strengths, the trends were consistent with published data from FDA-approved products. The authors conclude that, acknowledging the limitations of the available evidence, partly because they were short-term studies that did not exceed a year for the most part, cBHT was found to be beneficial regarding vaginal androgens, without altering the lipid profile, glucose metabolism, endometrial thickness, or presenting serious adverse events. There was a consistent trend regarding changes in serum hormone levels, however, there were not enough clinical trials to assess the effects of these formulations on hot flashes and no benefits on bone mineral density could be determined in them. Authors suggest and encourage further long-term studies to conclude on clinical cardiovascular events, risk of breast cancer, endometrial cancer, and prevention of bone loss.


As women age, changes in hormone production have a negative impact on symptoms and quality of life. Many women are turning to hormone replacement treatment options to improve symptoms and quality of life. The selection of the type of treatment is not only the choice of the professional, but also that of women. In this sense, many of them consider cBHT to be safe and effective, and choose these [4,5]. With cBHT, the hormones that are administered are handcrafted, bioengineered to be chemically identical, at the molecular level, to hormones created by the human body. Whether it is estrogen, progesterone, DHEA, testosterone, or adrenal hormones, these chemically identical recreated hormones mimic the hormones that women would naturally produce.

The present research being commented on took the NASEM report and applied the objective and search strategy such as that chosen by NASEM, expanded it, and incorporated some analysis that had not originally been used, such as data on cardiovascular disease, lipid profile and glucose metabolism. It is a review in the form of an exhaustive meta-analysis, which included more than 3,000 full-text articles related to the proposed objective, managing data analysis that had not been carried out previously. Only RCTs were analyzed, which allows us to assume the high quality and reliability of the evidence. The risks of bias were low to moderate and having compared studies with a high risk of potential bias the results showed that it did not affect the general trend of the results.

The general position is clear that each woman must be evaluated in the context of her unique presentation of concerns and physical findings, for the indication of appropriate menopausal hormone therapy (MHT) [6]. The authors of the current meta-analysis [1], in addition to others [7] agree that the black box warning that the FDA placed for all MHT regimens in 2002, has remained essentially unchanged, even with the appearance of data in many publications indicating the contrary. That decision, coupled with sustained and unprecedented attention to the initial results of the WHI in the popular press, caused a dramatic exodus not only from the use of MHT, but also from clinical training education [7].

Is there less risk with the use of cBHT than synthetic hormones? So far there is no scientific proof that bioidentical hormones are safer than synthetic ones. Having too much estrogen in the blood, whether synthetic or natural, can potentially increase women’s risk of breast and uterine cancer. The possible advantage of bioidentical hormones compared to synthetic ones, according to different organizations, is that hormone levels can be measured in the blood, before starting therapy, in order to evaluate if they are low and to evaluate improvements with therapy. They claim this is important because it individualizes therapy for each woman and avoids the “one size fits all” approach used by synthetic hormones [8].

It has been shown that serum hormone levels do not necessarily predict the efficacy or safety of a formulation. In this sense, NAMS and NASEM express the need for more information to show that cBHT is being absorbed. The FDA also recommends a pharmacokinetic study in this regard. A survey at the 2021 NAMS Annual Meeting involving more than 400 US cBHT professionals showed that nearly all physicians regularly test hormone levels in their practice. Therefore, it is necessary to examine the absorption of cBHT, as proposed by the FDA.

As a result, in this systematic review and meta-analysis of RCTs, cBHT in the form of vaginal androgens was found to be beneficial over vaginal atrophy symptoms without showing major safety concerns for lipid profile, glucose metabolism, vaginal thickness endometrium or serious adverse events. Consistent trends in changes in serum hormone levels were observed in the included studies. There are not enough published clinical trials to assess the effects of cBHT on hot flashes, and no benefits on bone mineral density have been found in the revised short-term studies. More long-term studies are needed to draw conclusions about clinical cardiovascular events, risk of breast cancer, endometrial cancer, and prevention of bone loss [1].

Hence, beyond the results found in this valued meta-analysis, more high-quality RCTs would now be needed to inform conclusions regarding other important outcomes, such as blood pressure and coagulation factors, breast cancer risk, cognitive function, and mental health.

Prof. Alejandra Elizalde-Cremonte, MD, PhD
Full Professor, Chair, Department of Women and Children, Faculty of Medicine, National University of the Northeast (UNNE), Corrientes, Argentina
President of the Latin American Association of Gynecological Endocrinology (ALEG)
President of the Argentine Association of Perinatology (ASAPER)
Associate Member of the International Menopause Society (IMS)


  1. Liu Y, Yuan Y, Day AJ, et al. Safety and efficacy of compounded bioidentical hormone therapy (cBHT) in perimenopausal and postmenopausal women: a systematic review and meta-analysis of randomized controlled trials. Menopause. 2022;29(4):465-482.
  2. Cumpston M, Li T, Page MJ, Chandler J, Welch VA, Higgins JP, Thomas J. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev. 2019;10:ED000142.
  3. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264-9, W64.
  4. Pinkerton JV, Santoro N. Compounded bioidentical hormone therapy: identifying use trends and knowledge gaps among US women. Menopause. 2015;22(9):926-36.
  5. Crawford SL, Crandall CJ, Derby CA, et al. Menopausal hormone therapy trends before versus after 2002: impact of the Women’s Health Initiative Study Results. Menopause. 2018;26(6):588-597.
  6. Langer RD, Hodis HN, Lobo RA, Allison MA. Hormone replacement therapy – where are we now? Climacteric. 2021;24(1):3-10.
  7. Langer RD. The evidence base for HRT: what can we believe? Climacteric. 2017;20(2):91-96.
  8. Jaffe RB, Salomone L, Santen RJ. Bioidentical (Natural) Hormones and Menopause. J Clin Endocrinol Metabol 2005;90(11):E1



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