7The Safety and Effectiveness of Compounded Bioidentical Hormone Therapy

RESEARCH STRATEGY

The committee conducted a literature search to identify a comprehensive body of evidence to inform its work. In coordination with one of the National Academies' senior research librarians, the committee constructed a literature search strategy that produced a broad range of research publications. A preliminary search queried six databases (Medline, Embase, PubMed, Scopus, ClinicalTrials.gov, and Toxnet) for content related to the safety, effectiveness, and clinical utility of cBHT. Results from the search were limited to peer-reviewed articles published in the English language, including human, animal, and in vitro studies. The search was not limited by date of publication, but editorials, commentaries, letters, and notes were excluded. This search resulted in more than 16,000 articles. The committee decided to expand and restrict certain search terms in order to produce a more relevant literature base. With all other search parameters remaining the same, this second search provided more than 11,000 articles with potential relevance to the committee's charge. Of these articles, those that included the terms compounding, compounded, bioidentical, or bioidentical, and any of the committee's prioritized hormones in the title, keywords, or abstract were considered. Applying these criteria provided the committee with less than 50 articles relevant to the committee's charge.¹ For a more detailed description of the literature review and other data-gathering efforts performed by the committee, see Appendix B.

In addition to the formal literature searches, study stakeholders, including FDA, Professional Compounding Centers of America, representatives of select 503B outsourcing facilities, nonprofit professional organizations, and practicing medical prescribers of cBHT also submitted suggested articles and other references for the committee's review.² Furthermore, during the National Academies' external review process, additional articles were suggested by reviewers of the report. Based on the criteria described above, all relevant articles were added to the total body of collected peer-reviewed evidence.

The primary data collected in these searches had a specific focus on safety, effectiveness, and efficacy studies in humans. While the terms effectiveness and efficacy are similar, they are not the same. The effectiveness of a drug refers to its therapeutic effect in real-world settings. The efficacy refers to the therapeutic effect in controlled clinical settings—such as phase 2 or phase 3 randomized clinical trials. This difference is critically important.³ Given the limited data on efficacy for cBHT preparations, the committee also considered clinical studies of effectiveness in its examination of clinical utility of cBHT preparations. Owing to its broader application to the body of research reviewed, the term effectiveness is used more generally across the chapter.

To inform its research conclusions, from the mixed body of evidence produced by the literature review results, the committee prioritized the findings of systematic reviews and randomized controlled trials (RCTs), followed by relevant observational studies with large study populations. RCTs in particular are essential for studies of treatments intended to produce a therapeutic effect, given that measures of change over time can be influenced by many factors other than the actual treatment. Without the ability to compare to a treatment control group, observational studies rarely produce reliable estimates of treatment effects (CEBM, 2020). In addition to study type, the committee also considered the importance of methodological rigor. As such, small, low-quality cohort studies, case reports, and submitted anecdotal testimonies were reviewed to inform the committee's overall findings but are not formally summarized within the current chapter.

In its review of the literature, the committee recognized that the cBHT preparations used in many of the research studies were formulated and dispensed by various types of pharmaceutical and health care facilities, details of which are not often clearly specified within the methods sections of the reviewed studies. To ensure that the committee's review of the literature met the Statement of Task's requirements, the committee focused its review on studies that examine the safety and effectiveness of cBHT preparations compounded in a 503A compounding pharmacy or 503B outsourcing facility. However, owing to the lack of such relevant studies, the committee's review also includes studies that used preparations compounded in governmental health care facilities, those compounded for use in academic research,⁴ or in certain instances, those produced for studies that examined FDA-approved drug products with outcomes of interest that differ from the regulatory indication. In addition, because certain bioidentical hormones (i.e., estriol) are only manufactured and only approved for use outside of the United States, the committee reviewed select international studies to collect general findings related to the hormone's safety and effectiveness.

The committee identified a total of 13 studies related to cBHT that were of adequate methodologic rigor for inclusion in its review of safety and effectiveness of these preparations.⁵ Table 7-1 provides an overview of these 13 studies, including a summary of their research objectives, findings, and reported adverse effects.

ESTROGENS AND PROGESTERONE COMPOUNDED PREPARATIONS

Effectiveness

The section below provides a summary of the studies that describe evidence related to the effectiveness of cBHT based on the known indications of FDA-approved drug products.⁶ Estradiol has been shown to be one of the most effective hormone therapies for reducing vasomotor symptoms. However, based on the committee's review of the literature, including several systematic literature reviews, it appears that most of the evidence supporting this statement are based on the findings of safety and efficacy derived from clinical trials conducted by pharmaceutical companies during the FDA drug product approval process (L'Hermite, 2017; Marjoribanks et al., 2017; Stuenkel et al., 2015). Given that the effectiveness of estrogens is commonly assessed while in combination with progesterone, this section summarizes the committee's findings for both hormones.

Treatment of Vasomotor Symptoms

Based on its review, the committee could not identify any studies that could inform conclusions on the safety or effectiveness of compounded estrone or estradiol for the treatment of vasomotor symptoms. While there are RCT and observational studies to suggest that estriol (as manufactured and approved drug products outside of the United States) is effective in treating vasomotor symptoms (e.g., Ali, 2017; Foidart et al., 1991; Head, 1998), the study designs and small participant numbers of many of the studies do not provide enough evidence to suggest it is safer or more effective than FDA-approved hormone therapy products. Furthermore, as with the estradiol studies in the United States, the bulk of the evidence for estriol was collected by pharmaceutical companies seeking product approval in other countries.

For progesterone, a review by Whelan and colleagues (2012) identified three randomized, double-blind, placebo-controlled trials that evaluated the effectiveness of progesterone cream for the treatment of menopause-related vasomotor symptoms (Benster et al., 2009; Leonetti et al., 1999; Wren et al., 2003). Of the three studies, one used a compounded preparation (Leonetti et al., 1999), while the others used manufactured progesterone creams (see Table 7-1). The results from the 12-month study by Leonetti et al. (1999) had a low risk of bias and demonstrated a significant improvement in vasomotor symptoms in the treatment group compared to placebo. However, Whelan et al. (2012) noted that owing to limited consumer access to the custom-compounded preparation and a reliance on self-reporting, there are limitations to the generalizability of the research results (see Table 7-1). The other two studies (manufactured progesterone product) were found to be no more effective than placebo in treating vasomotor symptoms (Benster et al., 2009; Wren et al., 2003).

TABLE 7-1

Overview of 13 Studies Reviewed by the Committee with Relevance to the Safety and Effectiveness of cBHT.

Protection Against Bone Loss

Osteoporosis is a long and continuous process associated with aging and reduced gonadal function. The utility of estradiol in preventing osteoporosis by sustaining bone density has been well documented in multiple studies, and thus, bone loss prevention is an FDA label-indicated use for estradiol products (NLM, 2020). Based on its review, the committee was unable to identify any studies that could inform conclusions on the effectiveness of various formulations of compounded estrone or estradiol in preventing bone loss.

In a 1-year randomized double-blind, placebo-controlled trial, Leonetti et al. (1999) examined the effect of compounded transdermal progesterone on bone density and found no significant difference in the percentage increase in bone mineral density of the spine, femoral neck, and total hip between treatment and placebo groups (see Table 7-1).

Estriol is a less potent estrogen than estradiol and considered to be a relatively weak estrogen. Given the claims by certain advocates that estriol is a lower risk estrogen, the efficacy of estriol in combating bone mineral density loss, either alone or combined with a progestogen, has been the subject of multiple clinical investigations. Importantly, in the studies identified by the committee, the clinical investigations use treatments that are not compounded preparations, but are instead prescription products manufactured and approved for use outside of the United States. The overall results of these studies have been mixed, and none demonstrated that estriol is more effective than estradiol (example reviews: Ali, 2017; Cirigliano et al., 2007; Conaway, 2011; additional studies to consider: Devogelaer et al., 1998; Kika et al., 2009).

Treatment of Vaginal Atrophy (Genitourinary Syndrome)

Vaginal atrophy is associated with symptoms of vaginal dryness, itching, or pain, and is a common condition found in approximately 50 percent of postmenopausal women (Wysocki et al., 2014). This condition worsens with age and is one of the most common reasons for the use of hormone therapy in menopausal women. Based on its review, the committee was unable to identify any studies that could inform conclusions related to the effectiveness of various formulations of compounded estrone, estradiol, estriol, or progesterone in the treatment of vaginal atrophy.

Research suggests that various estriol manufactured products are effective for the treatment of vaginal atrophy (Ali et al., 2017) and are approved for this indicated use in several countries outside of the United States (e.g., Synapause, Estriel). However, of the studies identified by the committee, only two compared the effectiveness of estriol with estradiol. One of these studies, a 12-week, open-label, parallel-group RCT with active control compared the efficacy of a 2 mg micronized estradiol-releasing silicone rubber vaginal ring (product manufactured outside of the United States; releasing 6.5 to 9.5 µg per 24 hours; n = 112) to a 0.5 mg estriol-releasing vaginal pessary (product manufactured and approved outside of United States; n = 53)⁷ in treating symptoms of vaginal atrophy in postmenopausal women (Henriksson et al., 1994). The estradiol product appeared more effective than the estriol product at preventing vaginal atrophy, and patients who previously used vaginal pessaries reported a strong preference for the estradiol-releasing vaginal ring.

A similar 12-week, open-label, parallel-group RCT with active control study compared the efficacy of an 2 mg estradiol-releasing vaginal ring⁸ (FDA-approved drug product; releasing 7.5 µg per 24 hours; n = 72) to an 1 mg estriol vaginal cream (product manufactured and approved outside of United States; 0.5 administered daily for 2 weeks followed by 0.5 administered three times weekly; n = 66)⁹ in alleviating vaginal dryness (Barentsen et al., 1997). Both treatments produced similar improvements in vaginal health, but in the crossover phase of this study, found that women preferred the estradiol-releasing vaginal ring over the estriol cream.

Risk of Venus Thromboembolism

Venus thromboembolism is also associated with the use of oral estrogen therapy. Although studies have shown a clear association between the use of unopposed estradiol and the risk of stroke, multiple reviews suggest that combining progesterone with estradiol therapy can help to prevent a stroke from occurring (Bath, 2005; Cobin et al., 2017; L'Hermite, 2017; Oliver-Williams, 2019; Renoux, 2010). In addition, the risk for venous thromboembolism may be decreased when using transdermal estrogen therapy as opposed to oral estrogen (Canonico, 2008; Mohammed, 2015).

The committee was unable to identify research studies that could inform conclusions on the effect of various formulations of compounded estrone, estradiol, estriol, or progesterone on the risk of developing venus thromboembolism. However, as mentioned above and throughout this report, if a compounded medication is erroneously formulated or dosed, certain intended effects, such as protective factors, may not be achieved.

Box

Conclusion 7-1.

TESTOSTERONE THERAPY IN MEN

Testosterone is widely used by middle-aged and older men. However, it is only FDA approved for men who suffer from male hypogonadism resulting from an associated medical condition, such as a failure of the testicles to produce testosterone because of genetic factors or chemotherapy treatment. As an FDA-approved drug product, the efficacy of testosterone products in men is supported by numerous high-quality randomized and placebo-controlled studies, including studies examining its effectiveness for off-label use (Mohler et al., 2018; Roy et al., 2017; Santoro et al., 2016; Snyder et al., 1999, 2016, 2017; Storer et al., 2017).¹¹ The committee was unable to identify relevant studies that could inform conclusions regarding the safety and effectiveness of various formulations, doses, and dosage forms of compounded testosterone for FDA-approved indications in men.

TESTOSTERONE THERAPY IN WOMEN

As discussed in earlier chapters of the report, there is interest in the use of testosterone treatment for women; however, currently there are no FDA-approved drug products with indications to treat health conditions in women. As a result, high-quality evidence on the effects of testosterone in women is more limited than the evidence for men.

DHEA THERAPY

DHEA is a precursor to testosterone and estrogen that is known to decrease as people age. Although sometimes compounded into hormone therapy preparations, DHEA is also sold as commercially available supplements. Often the methodical sections of studies fail to adequately describe the origins of DHEA used in studies, which presents a challenge for accurately assessing the safety and effectiveness of the hormone in cBHT preparations. Therefore, unless specifically identified as a compounded preparation, the committee considered the hormone to be a commercially available supplement.

CBHT RESEARCH CHALLENGES

Although bioidentical hormones are used in both FDA-approved and compounded preparations, the dose and combination of ingredients used in compounded preparations depend on the formulation chosen by the prescriber and/or compounding pharmacist (see Chapter 5 for an additional discussion on this topic). As a result of the countless permutations of cBHT formulations, evidence supporting the safety and effectiveness of compounded hormone preparations is limited to the specific combinations of hormones, inactive ingredients, and formulation chosen by the research team conducting the study.

Often, compounding pharmacies combine multiple hormones into a single formulation; however, the evidence to support the effectiveness or safety of these formulations is scant.¹² One prospective cohort study examined the effects of transdermal cBHT formulations containing estriol, progesterone, DHEA, and testosterone on 75 postmenopausal women (Stephenson et al., 2013). Improvements were noted in climacteric symptoms, measures of quality of life, and selected cardiovascular biomarkers. Study limitations included the absence of randomization and the small, community-based participant sampling, which limits the power and generalizability of the study results.

In another observational study, researchers examined the effect of transdermal Bi-est cream and sublingual progesterone and either testosterone or DHEA on the relief of common menopausal symptoms (hot flashes, night sweats, insomnia, lack of energy, low libido, and minor stiffness or achy joints) (Mahmud, 2010). Authors reported improvements in all symptoms in 122 out of 189 participants. Study limitations included an absence of randomization and appropriate control groups, and the use of multiple cBHT dosage forms (18 patients switched from transdermal to sublingual dosage forms) throughout the course of the study (see Table 7-1).

As a final example, in one observational study, which included 200 women 18 years of age or older, participants received a cBHT prescription including multiple hormones following consultation services. The researchers reported reductions in vasomotor, anxiety, sleep disturbances, and other quality-of-life symptoms in women who received sublingual formulations, while topical formulations were associated with more modest reductions in symptoms. However, the absence of randomization and use of participant-specific dosing regimens with no control group for comparison limits the types of conclusions that can be drawn about the effectiveness of these formulations (Ruiz and Daniels, 2014).¹³

SUMMARY OF RESEARCH FINDINGS

In its review of the evidence, the committee determined there is a dearth of high-quality research with a primary or secondary endpoint focused on the safety, effectiveness, and performance of cBHT preparations. Many of the studies had severe methodological limitations, the most common being the lack of standardized measures (e.g., assessments of hormone level, randomizations, participant exclusion and inclusion criteria, reporting measures) and minimal details on participant-specific dosing regimens, formulations, and dosage forms of the treatment, and where relevant, control arms of the study. The variability of cBHT formulations and research methodologies not only affects the quality of the evidence used to support research conclusions, but it also minimizes the ability to compare results among studies or apply meta-analytic methods to draw conclusions from a larger number of patients (Boothby et al., 2004). The committee recognizes that for the large patient population using cBHT, it is difficult, if not impossible, for clinicians to provide evidence-based guidance on the safety and effectiveness of each unique formulation. That being said, safety and effectiveness data are still required for understanding the risks-to-benefit ratio for all medications, which is fundamental to the practice of medicine in this country.

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Conclusion 7-3.

ADVERSE EVENT REPORTING FOR CBHT

In addition to the data acquired through high-quality, well-controlled research studies, adverse event data are also critical for characterizing the safety of a medication. Adverse drug events are defined by FDA as “any unanticipated experience or side effect associated with the use of a drug or therapeutic biologic in humans, whether or not it is considered related to the product” (FDA, 2020b). Adverse events range from minor symptoms to permanent disability and death. The Centers for Disease Control and Prevention (CDC) regularly tracks the number of emergency department visits attributed to adverse events and has reported that they are responsible for approximately 1.3 million emergency department visits annually by adults (CDC, 2017a) and 200,000 visits by children and adolescents (CDC, 2017b).

Underreporting of Adverse Events

Underreporting of adverse drug events related to prescribed drugs is common. Underreporting may be attributable to confusion as to the actual cause of the adverse event. Many physicians and patients may not know that an adverse outcome is caused by a drug, and when they do, often do not think to report that outcome to FDA or the manufacturer (Kesselheim et al., 2019). Underreporting may also occur because individual patients and physicians are not required to make such reports.

Nonetheless, adverse event reporting is important to advance knowledge about drug safety. According to QuarterWatch, an independent analysis of the quarterly release of FDA MedWatch data, essentially all safety signals identified by FDA come from analysis of the FAERS Quarterly Data Extract Files rather than direct reporting from 503A and 503B facilities. In the wake of recommendations by the Institute of Medicine in 2000 to expand adverse event reporting systems, some states created their own systems to work in parallel with the FDA reporting requirements. However, a 2015 report revealed that only 28 states had systems for reporting adverse events (Hanlon et al., 2015).

Underreporting of adverse events related to compounded drugs may be more extensive than for FDA-approved drugs. First, while manufacturers of FDA-approved drugs are required to report adverse events that they learn about, 503A compounding pharmacies are not required to report adverse events. Second, parallel state systems do not fill this gap. A survey in 2015 found that only 30 percent of states (13 out of the 43 that responded) require sterile compounding facilities to report serious adverse events (The Pew Charitable Trusts, 2016). Third, underreporting is driven by manufacturers' disincentives to reveal their own products as potentially unsafe. For example, 503B outsourcing pharmacies—unlike 503A compounding pharmacies—are required to report adverse events to FDA. But in 2018, FDA inspectors visiting a 503B outsourcing facility discovered a company-owned data file containing more than 4,000 unreported adverse events that occurred between 2013 to 2018 (FDA, 2019a). While the bulk of these reports were considered minor adverse drug events, more than 300 were serious adverse drug events (see Table 7-2). These events should have been reported no more than 15 days after they were identified. In addition to being a violation of FDA regulations, the failure to report these events hinders the ability for researchers to identify data patterns that could signal specific safety issues (FDA, 2019b).

TABLE 7-2

Adverse Events Discovered During an FDA Inspection.

Importance of Drug Safety Surveillance

Although the industries required to comply with adverse event reporting regulations often consider them to be burdensome, the data they provide are part of the system that can help inform patients about drug safety. In recent decades, advances in technology have opened new pathways to search for such safety signals through other data sources through claims databases, clinical trial data databases (e.g., ClinicalTrials.gov), and social media. Data collected from the FAERS database have been a valuable component of this network to help understand the root causes of adverse events. It is therefore critical that all known and suspected adverse drug events are reported.

Box

Conclusion 7-6.

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