The Safety and Effectiveness of Compounded Bioidentical Hormone Therapy

National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Committee on the Clinical Utility of Treating Patients with Compounded Bioidentical Hormone Replacement Therapy; Leigh Miles Jackson; Ruth M. Parker; Donald R. Mattison

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National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Committee on the Clinical Utility of Treating Patients with Compounded Bioidentical Hormone Replacement Therapy; Jackson LM, Parker RM, Mattison DR, editors. The Clinical Utility of Compounded Bioidentical Hormone Therapy: A Review of Safety, Effectiveness, and Use. Washington (DC): National Academies Press (US); 2020 Jul 1.

7The Safety and Effectiveness of Compounded Bioidentical Hormone Therapy

The primary charge to the committee is to assess the clinical utility of treating patients with compounded bioidentical hormone therapy (cBHT) preparations, which, as outlined in Chapter 1, requires an evidence-based examination of safety and effectiveness. In this chapter, the committee provides a narrative review of the relevant peer-reviewed evidence on the safety and effectiveness of cBHT and outlines the current framework for adverse event reporting, a critical component in assessing the safety of medications.

This chapter has a prioritized focus on bioidentical hormone therapy (BHT) preparations containing estrogens, progesterone, testosterone, dehydroepiandrosterone (DHEA), and pregnenolone. The committee recognizes that this prioritized list of bioidentical hormones may not be a comprehensive list of all ingredients used in cBHT preparations. In fact, there are other hormones (e.g., gonadotropin-releasing hormone), that are compounded to treat different hormone-related health conditions, but they are outside the scope of the committee's study. However, the omission of a specific hormone or unique cBHT preparation from this chapter's review does not imply any level of safety, effectiveness, or potential usefulness.

A large proportion of patients using cBHT appear to be women seeking treatment for menopausal symptoms and conditions, and indeed, of the limited number of studies that examine the safety and effectiveness of compounded preparations, the majority had research aims that focused on this patient population. As a result, the committee's conclusions focus on the use of cBHT to treat menopausal symptoms; however, evidence related to the safety and effectiveness of compounded testosterone in males is discussed where relevant. See Box 7-1 below for the medical indications for hormone therapy products approved by the U.S. Food and Drug Administration (FDA).

The chapter begins with a summary of the research strategy used to identify relevant data on safety and effectiveness. The summarized research strategy is followed by a narrative review of the committee's findings on the safety and effectiveness of various cBHT preparations, organized according to the bioidentical hormones reviewed. Next the committee outlines its conclusions related to the quality of evidence reviewed and the overall safety and effectiveness of cBHT preparations. The chapter closes with a short discussion on the role of adverse events reporting as a critical component of safety assessment.

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 7-1Overview of 13 Studies Reviewed by the Committee with Relevance to the Safety and Effectiveness of cBHT

Author	Objective	Study Design	Population	Treatment	Other Notes	Measure	Main Outcomes Relevant to the Committee's Charge	Serious Adverse Events	Limitations
Dahir and Travers-Gustafson, 2014	Determine effect of DHEA on sexual health	Quasi-experimental pilot (4 weeks)	Women with breast cancer taking AI therapy n = 12 Race/ethnicity not reported Age (mean): 59.7 years	DHEA vaginal cream; 300 μg/daily	Exclusion criteria described	Female Sexual Function Index (FSFI) survey	Compared to baseline, improvements in individual domain scores of desire (P = 0.000), arousal (P = 0.002), lubrication (P = 0.018), orgasm (P = 0.005), satisfaction (P = 0.001), and pain (P = 0.000) No recurrence or progression of breast cancer over 3 years	Authors reported that no serious adverse events occurred	Narrow time frame for enrollment and follow-up Small sample size Excluded surgical menopause under the age of 50 and women with recurrent G. vaginalis infection Sexual functioning may have been affected by history or events such as relationship conﬂict, stress, or vacation Absence of a randomized control group
Davis et al., 2018	Determine effect of testosterone on sexual satisfaction, vaginal symptoms	Randomized double-blind, placebo-controlled (26 weeks)	Postmenopausal women taking an AI with VVA symptoms n = 44 Race/ethnicity not reported Age (mean): 57.7 years (treatment) 55.1 years (placebo)	Testosterone intravaginal cream; 300 μg/dose	Exclusion criteria described Treatment schedule: Daily for 2 weeks and then 3x/week for 24 weeks	FSFI survey Female Sexual Distress Scale–Revised (FSDS-R), Profile of Female Sexual Function Questionnaire for UI Diagnosis; serum levels of sex steroids	Greater improvements seen in treatment group in FSFI satisfaction scores (P= 0.043); FSDS-R scores (P = 0.02); sexual concerns (P < 0.001); sexual responsiveness (P < 0.001); vaginal dryness (P = 0.009); dyspareunia (P = 0.014) No between-group differences in serum levels of sex steroids at baseline or posttreatment No between-group differences in reported UI symptoms at 26 weeks, adjusted for baseline status	Authors did not report on adverse events for this study	Higher dropout rate in control group Low power to assess additional domains of sexual function Recruitment was limited by patient concerns about the safety of hormone therapy after a diagnosis of breast cancer
Glaser et al., 2011	Determine effect of testosterone on somatic, psychological and urogenital symptoms	Cohort (12 weeks)	Pre- and postmenopausal women n = 300 Race/ethnicity not reported Age (mean): 42.7 years (premenopausal) 53.0 years (postmenopausal)	Testosterone pellet (3.1 mm) Initial dose varied across patient based on their weight (ranged from 75 mg to 160 mg) Subsequent dose adjustments based on weight, avoidance of adverse events, and adequacy of clinical response	Exclusion criteria described	Menopause Rating Scale (MRS) Total scores and psychological, somatic, and urogenital subscale scores Health-Related Quality of Life (HRQOL)	Premenopausal women: Higher testosterone doses correlated with greater improvement in MRS total score (P < 0.05) and urogenital subscore (P < 0.01) Higher testosterone doses did not correlate with greater improvement in either the psychological or somatic subscores (P > 0.05) Postmenopausal women: Higher testosterone doses correlated with greater improvement in MRS total score and three subscores: somatic, psychological, and urogenital (P < .001)	Authors reported that no serious adverse events occurred	Short-term study Absence of a randomized control group or comparison group
Jankowski et al., 2006	Determine effect of DHEA on BMD and body composition	Randomized, double-blind, placebo-controlled (12 months)	Older men and women Participants were primarily White Women n = 70 (36 DHEA; 34 placebo) Age (mean): 68 years Men n = 70 (35 DHEA; 35 placebo) Age (mean): 69 years	Oral DHEA; 50 mg/daily	Exclusion criteria described	BMD measured at baseline and 12 months	Men and women: Greater increase in BMD in DHEA group: Total hip (1.0%, P = 0.05), trochanter (1.2%, P = 0.06), and shaft (1.2%, P = 0.05) Women only: DHEA increased lumbar spine BMD (2.2%, P = 0.04; sex-by-treatment interaction, P = 0.05)	Placebo: One death (unrelated to study); one hospitalization for coronary artery stenting DHEA: One hospitalization for transient ischemic attack and one hospitalization for urinary tract infection	Small sample size Patient use of other reproductive steroids Short duration of the therapy
Kenny et al., 2010	Determine effect of DHEA and exercise on bone mass, strength, and physical function	Randomized, double-blind, placebo-controlled (6 months)	Women over 65 with DHEA levels < 550 ng/dL n = 99 (assigned) Participants were primarily White Age (mean): 76.6 years	Treatment arm 1: Oral DHEA 50 mg/d supplemented with yoga Treatment arm 2: Oral DHEA 50 mg/d supplemented with aerobics Control arm 1: Placebo supplemented with yoga Control arm 2: Placebo supplemented with aerobics	Exclusion criteria described All received calcium and Vitamin D supplements	BMD measured at baseline and 6 months	There were no signiﬁcant changes in BMD or bone turnover markers between groups	Author did not report on adverse events for this study	Small sample size Short duration of therapy
Leonetti et al., 1999	Determine effect of progesterone on vasomotor symptoms, BMD	Randomized, double-blind, placebo-controlled (12 months)	Healthy women within 5 years of menopause n = 90 (assigned) All participants were White Age (mean): 52 years	20 mg transdermal progesterone cream; applied daily	Exclusion criteria described All received daily multivitamins and 1,200 mg of calcium	Weekly symptom diaries (self-report) BMD measured in the lumbar spine, femoral neck, and hip	Symptoms: Greater self-reported improvement in vasomotor symptoms found in treatment group compared to placebo (83% versus 19%); (P < 0.001) BMD: No significant difference between group comparisons	Author did not report on adverse events for this study	Limited consumer access to the custom-compounded preparation Limited generalizability of research results
Mahmud, 2010	Determine effect of Bi-est, progesterone, testosterone and/or DHEA on menopausal symptoms	Observational (average 30 month follow-up)	Postmenopausal women n = 189 (assigned) Race/ethnicity not reported Age (mean): 53.7 years	Treatment arm 1: transdermal Bi-est cream (estradiol 1 mg plus estriol 4 mg per gram) and sublingual progesterone (50–100 mg) and testosterone perivaginal cream Participants began with a 0.5 gm twice daily dose of Bi-est cream, which was increased or decreased as needed to control hot flashes and breast tenderness Total testosterone was maintained around 25 ng/dl with dose adjustments as needed based on blood levels Adjustments to progesterone doses were made to achieve blood levels close to 4 ng/ml Treatment arm 2: Transdermal Bi-est cream (estradiol 1 mg plus estriol 4 mg per gram) and sublingual progesterone (50–100 mg) and DHEA Participants began with a 0.5 gm twice daily dose of Bi-est cream, which was increased or decreased as needed to control hot flashes and breast tenderness Adjustments to progesterone doses were made to achieve blood levels close to 4 ng/ml Participants received DHEA if levels were determined to be low. Average dose began at 25 mg/day and was typically reduced to 25 mg every other day to maintain the desired level (approx. 120 μg/dl)	No exclusion criteria provided	Patient outcomes assessed over an average follow-up of 30 months Common symptoms assessed: hot flashes, night sweats, insomnia, lack of energy, low libido, and minor stiffness or achy joints	122 patients reported improvement in all common symptoms, 49 patients reported relief of most symptoms; 13 patients reported some improvements; 5 patients reported little to no improvement in symptoms	One patient was found to have an ER+ and PR+ breast cancer after 6 months of treatment Prior to joining this study the patient had been taking Premarin for 10 years, which the researchers believe may have caused the development of breast cancer in this patient	Absence of a randomized control group Lack of predetermined dosage formulation, participant outcomes, and statistical analysis of results Multiple dosage forms of treatments (subset of patients switched from Bi-est cream to sublingual route)
Morales, 1998	Determine effect of DHEA on steroid levels, body composition and muscle strength	Randomized double-blind, placebo-controlled crossover (12 months)	Older men and women Women n = 10 (assigned) Race/ethnicity not reported Age (mean): 54.5 years Men n = 9 (assigned) Race/ethnicity not reported Age (mean): 55.6 years	Oral DHEA; 100 mg/daily	Exclusion criteria described 2-week washout period between crossover	BMD measured at baseline and 6 months	There were no signiﬁcant changes from baseline in the BMD of the hip and spine in men or women	Author reported that no serious adverse events occurred	Small sample size
Narkwichean et al., 2017	Determine effect of DHEA on In-Vitro Fertilization (IVF) outcomes	Randomized, double-blind, placebo-controlled pilot trial (2 years)	Women receiving IVF with diminished ovarian reserves Treatment group: n = 27 All White British women Age (mean) = 36.8 years Placebo group: n = 25 84% White British women Age (mean) = 35.2 years	Oral DHEA; 75 mg/day; 12 to 20 weeks before starting ovarian stimulation	Exclusion criteria described Long protocol using hMG 300 IU/day	Number of oocytes retrieved; live birth rates; mRNA expression of developmental biomarkers in granulosa and cumulus cells	Treatment did not improve the response to controlled ovarian hyperstimulation or oocyte quality or live birth rate during IVF Treatment with long protocol in women predicted to have poor ovarian reserve	Author reported that no serious adverse reactions occurred	No power calculation to determine sample size
Panjari et al., 2009	Determine safety of DHEA used to improve sexual function	Randomized, double-blind, placebo-controlled parallel group trial (52 weeks)	Postmenopausal women with low libido Race/ethnicity not reported Treatment group: n = 47 (assigned; age (mean) = 55.1 years Placebo group: n = 46 (assigned); age (mean) = 53.9 years	Oral DHEA; 50 mg/day	Exclusion criteria described	DHEA versus placebo on androgenic side effects, lipid profile, insulin–glucose homeostasis, and the endometrium were assessed over 52 weeks	DHEA did not significantly alter lipid profile or insulin sensitivity in postmenopausal women The pattern of breakthrough bleeding did not substantially differ between the DHEA and placebo groups, and no significant adverse endometrial effects were apparent	Author reported that no serious adverse events occurred	Length of study is insufficient to have confidence in the reported endometrial safety outcomes Endpoint for endometrial effects was not sufficiently powered
Virkki et al., 2010	Effect of DHEA on Sjorgren's syndrome-related fatigue	Multicentered, randomized, double-blind, placebo-controlled crossover trial (9 months)	Men and women with primary Sjorgren's Syndrome (reported as one group) n = 107 (including 7 men) Race/ethnicity not reported Age (range): 18–80 years	Oral DHEA; 50 mg/day	Exclusion criteria described 1 month washout period between crossover (2 treatment groups lasting 4 months each)	General fatigue using the 20-item Multiple Fatigue Inventory (MFI-20); Health-Related Quality of Life (HRQOL)	All of the MFI-20 subscales and the fatigue Visual Analog Scale showed improvements from baseline levels as a result of treatment (P < 0.001) No significant differences between placebo and DHEA treatment	Placebo Treatment: One case of pneumonia and pneumococcal sepsis Other serious events resulting in patient dropout: (1) unilateral numbness, (2) suspected transient ischemic attack, and (3) exanthema DHEA treatment: Serious events resulting in patient dropout: muscle cramps in the calves and maculae on the back and cheek, (suspected as being discoid lupus erythematosus lesions)	Owing to increased number of statistical analyses of the MFI-20s six subscale variables, there is an increased risk of analyses resulting in statistical significance by chance
Wiser et al., 2010	Effect of DHEA on IVF outcomes	Prospective, randomized, open-labeled, controlled trial (19 months)	Women with poor ovarian response to previous IVF cycles Race / ethnicity not reported Treatment group: n = 17; age (mean) = 36.9 years Control group: n = 16; age (mean) = 37.8 years	Oral DHEA; 75 mg/day, at least 6 weeks before starting first cycle of IVF ovulation Women who did not conceive took DHEA for at least 16–18 weeks	Exclusion criteria described All patients received long-protocol IVF	Estradiol levels, number of retrieved oocytes, quality and number of embryos, pregnancy and birth rate	Live birth rate for women in the DHEA group for both IVF treatment cycles = 23.1%; Live birth rate from women in the control group = 4.0%. (p = 0.05)	Author reported that no serious adverse events occurred	Small sample size Outcomes may have been affected by variations in IVF protocol
Witherby et al., 2011	Effect of vaginal testosterone on estradiol and testosterone levels, and vaginal atrophy in breast cancer patients on AIs	Observational (28 days)	Women undergoing treatment with an AI in early stage breast cancer with reported vaginal itching, dryness, or dyspareunia Ethnicity not reported n = 20 (divided into two treatment groups) Age (range): 45–69 years	Group 1 (n = 10): 300 μg intravaginal testosterone cream compounded with 13.5 mg of testosterone propionate Group 2 (n =10): 150 μg intravaginal testosterone cream compounded with 6.75 mg of testosterone propionate	Exclusion criteria described	Assessment of hormone levels to confirm estradiol suppression Clinical effect based on analyses of serial questionnaire results Pathologic improvement of vaginal atrophy was analyzed based on a comparison of baseline and posttreatment maturation index, pH, and clinical examination	No significant difference in median serum estradiol levels before and after treatment (P = 0.91) No difference in posttreatment estradiol levels between dosing levels (P >0.99) Significant improvement in mean total symptom score for vaginal atrophy (P < 0.001) and remained low at 1 month post-therapy (P = 0.003) No significant difference between dosing levels Posttreatment maturation values were significantly higher for 300 μg group (P = 0.005)	Author reported that no serious adverse events occurred	Lack of a randomized control group Recruitment of subjects was not systematic Small sample size

: NOTE: AI = aromatase inhibitor; BMD = bone mineral density; DHEA = dehydroepiandrosterone; ER = estrogen receptor; FSDS-R = Female Sexual Distress Scale– Revised; FSFI = Female Sexual Function Index; IVF = in vitro fertilization; MFI = Multiple Fatigue Inventory; MRS = Menopause Rating Scale; PR = progesterone receptor: UI = urinary incontinence; VVA = vulvovaginal atrophy.

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 ring^⁸ (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.

Safety

The section below provides a summary of the studies that describe evidence related to the safety of cBHT based on the known indications of FDA-approved drug products.^¹⁰ Estradiol is a common active ingredient in hormone therapy. However, based on the committee's review of the literature, many of its findings on the potential risks related to estradiol treatment are derived from clinical trials designed to explore estradiol safety in studies 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 safety of estrogens is commonly assessed while in combination with progesterone, this section summarizes the committee's findings for both hormones.

Risk of Breast Cancer

The committee was unable to identify research studies that could inform conclusions on the safety of various formulations of compounded estrone, estradiol, estriol, or progesterone related to risk of developing breast cancer. Given that a lack of evidence does not imply safety, below, the committee provides a brief overview of findings based on the examination of potential risks attributed to FDA-approved drug products or drug products manufactured and approved for use outside of the United States.

Results from primarily large observational studies suggest there may be an increased risk of developing breast cancer associated with unopposed use of estradiol, but by combining estradiol therapy with micronized progesterone this risk may be lessened (Asi et al., 2016; L'Hermite 2017; Stute, 2018). Furthermore, in comparison to synthetic progestins and estradiol therapy, combined micronized progesterone and estradiol therapy has been shown to lessen the risk of breast cancer (Asi et al., 2016; Stute, 2018). In addition, estrogen therapy is contraindicated in breast cancer survivors because of the potential to increase the odds of cancer reoccurring (L'Hermite, 2017; Moegele et al., 2013; Ortmann et al., 2011). Although it has been suggested that vaginal delivery of low-dose estradiol or estriol is a safe option for hormone receptor-positive breast cancer patients treated with aromatase inhibitor therapy, the data are limited to a few small observational studies (Dew et al., 2003; Pfeifer et al., 2011).

Risk of Endometrial Cancer

Safety studies have identified endometrial cancer as a clearly associated risk with use of unopposed estrogen therapy in women with an intact uterus, and that this risk is effectively decreased when the estrogen is taken in combination with adequate doses of a progestogen (Smith, 1975; Stuenkel, 2015). The committee was unable to identify research studies that could inform conclusions on the safety of various formulations of compounded estrone, estradiol, estriol, or progesterone related to risk of developing endometrial cancer. However, as mentioned in Chapters 5 and 6, it can be assumed that if a compounded medication is erroneously formulated or dosed, certain intended effects, such as protective factors, may not be achieved.

Certain studies have suggested that estriol may pose a lower risk for promoting endometrial cancer by acting as an antagonist to block the endometrial neoplastic effects of estradiol and estrone; however, these research conclusions are debated in the field (see reviews: Ali et al., 2018; Cirigliano, 2007). Furthermore, studies suggest that providing the correct route of administration, dose, and length of treatment are critical factors in the hormones' endometrial stimulatory effects. For example, one meta-analysis of 12 studies (Vooijs and Geurts, 1995) determined that intravaginal estriol treatment at recommended doses did not produce endometrial proliferation, even after treatment lasting a maximum of 2 years.

Data from a population-based, case–control study of endometrial cancer in postmenopausal women suggest that oral estriol increases the relative risk of endometrial cancer and atypical hyperplasia, while only weak associations were observed between vaginal formulations of low potency estrogens and relative risk of developing endometrial cancer (Weiderpass et al., 1993). Given the wide range of marketed dosage forms for compounded estriol preparations, these are important details for prescribers to consider.

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.

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.

Effectiveness

Testosterone treatments of men with hypogonadism caused by a medical condition have been approved on the basis of their effects on testosterone levels, without any studies of clinical efficacy in this population. Beneficial effects observed in other men taking FDA-approved testosterone products include increased muscle mass and grip strength, heightened libido and increased sexual activity, resolution of mild anemia, and increased bone density (Roy et al., 2017; Snyder et al., 1999, 2016, 2017; Storer et al., 2017).

A number of other effects, not in the list of FDA-approved indications, have been observed. Small decreases in total, high-density lipoprotein, and low-density lipoprotein cholesterol, and fasting insulin have been found in an RCT (Mohler et al., 2018). Other reported effects, including weight loss, delayed development of type 2 diabetes, enhanced recovery from stroke, and reduced risk of venous thrombosis, prostate cancer, major cardiovascular events, and overall mortality have been claimed on the basis of observational studies but have not been confirmed in RCTs.

Safety

Prostate Cancer Risk

Testosterone increases levels of prostate-specific antigen (PSA) in men, but long-term studies required to assess increased risk of prostate cancer have not been conducted. Men considered at elevated risk of prostate cancer associated with family history or elevated PSA levels are generally advised to avoid taking supplemental testosterone treatment (Santoro et al., 2016).

Cardiovascular Risks

Data on the risk of cardiovascular events are mixed. A number of observational studies have suggested that there are benefits of testosterone therapy, but a few clinical trials have indicated potential harm (Basaria et al., 2010; Budoff et al., 2017). Because of these contradictory findings, FDA has asked manufacturers of testosterone gels to conduct a large, long-term study to address this issue of cardiovascular safety. This study is currently under way (ClinicalTrials.gov NCT03518034).

Other Potential Risks

Other warnings and precautions noted on FDA-approved drug product labels include urinary symptoms, azoospermia, sleep apnea, gynecomastia (an enlargement or swelling of breast tissue in males), and erythrocytosis (excessive red blood cell production) (FDA, 2020a). Virilization can occur in women and children with secondary exposure to testosterone (FDA, 2020a).

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.

Effectiveness

Sexual Health

Several randomized studies have shown that compounded testosterone treatment improved libido and increased sexual activity in menopausal women who had previously reported diminished sexual desire or satisfaction (Dahir and Travers-Gustafson, 2014; Davis, 2018; Glaser et al., 2011; Islam et al., 2019; see Table 7-1). Similar findings were found in studies that used manufactured testosterone (Shifren et al., 2006; Simon et al., 2005).

A consensus statement on the use of testosterone therapy for women, developed and endorsed by major professional societies focusing on endocrinology, women's health, and menopause, supports the findings that testosterone therapy can improve sexual function in postmenopausal women, but cautions that the dose administered should approximate physiological testosterone concentrations in premenopausal women (Davis et al., 2019).

Menopause-Related Symptoms

Other studies suggest compounded testosterone may be effective in treating vaginal atrophy and other menopausal symptoms (Glaser et al., 2011; Witherby et al., 2011; see Table 7-1). As noted earlier in the chapter, however, these are largely uncontrolled studies, and outcomes related to the treatment of symptoms are difficult to interpret as improvement in symptoms can be influenced by many factors other than treatment administered. No well-controlled studies have demonstrated benefit of treatment with compounded testosterone preparations for menopausal symptoms.

Safety

Breast Health

The role of testosterone in breast growth and breast cancer risk are highly debated within the field and, at present, there are insufficient long-term data from controlled studies to support conclusions regarding potential benefits and risks (Davis, 2019; Glaser et al., 2019; Kotsopoulos and Narod, 2012).

Other Potential Risks

Studies of short-term use of testosterone in women have not uncovered any major safety concerns, but they have noted hair growth and acne as adverse effects (Achilli et al., 2017; Islam et al., 2019). Long-term safety data are lacking.

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.

Effectiveness

Sexual Health

The only FDA-approved DHEA product (Intrarosa) is a vaginal insert used to treat moderate to severe pain in women during sexual intercourse (NLM, 2020). However, systematic reviews, and a 2019 consensus position statement published by professional societies with a focus on women's health, concluded that systemic DHEA is not associated with improvements in sexual desire or function among postmenopausal women whose adrenal function is normal (Davis et al., 2011, 2019; Elraiya et al., 2014).

Cognitive Function and Mental Health

A 2006 review of six studies addressed the use of DHEA supplementation for cognitive function in healthy men and women over age 50 (Evans et al., 2006). This review concluded that data from controlled trials do not support the claims of a beneficial effect of DHEA supplementation on cognitive function in this population. Another systematic review of randomized, placebo-controlled trials evaluating the effect of DHEA on depression found a significant positive effect of DHEA supplementation (Peixoto et al., 2018).

Bone Loss

Reported outcomes on DHEA's effectiveness on bone density have been mixed. Although a few studies have reported marginally significant effects on bone density (Jankowski et al., 2006), other studies have not (Kenny et al., 2010; Morales et al., 1998; see Table 7-1).

Other Potential Effects

Additional health outcomes of DHEA use include effects on physical performance and fatigue, insulin resistance, and fertility problems. Other small RCTs found no fatigue-related effects of compounded DHEA therapy in Sjögren's syndrome patients with a DHEA deficiency (Virkki et al., 2010; see Table 7-1) and a decrease in insulin resistance in older men and women (Weiss et al., 2011). One small RCT, conducted over a period of 2 years, found no significant benefits to physical performance, insulin sensitivity, or quality of life in elderly women or men treated with DHEA (Nair, 2006).

A small RCT on women with diminished ovarian reserves who were not responding well to in vitro fertilization and who were given compounded DHEA were found to have improved embryo quality and higher live birth rates compared to untreated controls (Wiser et al., 2010; see Table 7-1). A somewhat larger study using compounded DHEA found no significant improvement in live birth rates in women undergoing in vitro fertilization (Narkwichean, 2017; see Table 7-1), and a review published in 2015 found a possible increase in the chance of live birth in women receiving DHEA but noted that when studies that appeared to be at high risk of bias were excluded from the analysis, no such effect was found (Nagels et al., 2015).

Safety

In contrast to the extensive literature investigating the effectiveness of DHEA therapy, there is scant literature to support the safety of DHEA use in men or women. Most of the current data on DHEA safety have been derived from adverse events reported in trials such as those discussed above. However, in a placebo-controlled, double-blinded RCT examining the safety of daily DHEA, Panjari and colleagues (2009) reported findings of no adverse endometrial effects (see Table 7-1). More randomized data is needed to determine if DHEA use is associated with other conditions such as breast cancer and cardiovascular disease (Davis et al., 2011; Elraiyah et al., 2014).

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.

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).

Adverse Event Identification

Clinical trials assessing drug efficacy are a required component of FDA's drug approval process and provide insight into the drug's safety as well. Following FDA's Physician Labeling Rule, adverse events identified during preapproval clinical trials must be described in product labeling. The critical information listed in a drug's labeling is intended to inform practitioners' benefit–risk analysis when making prescribing decisions in concert with their patients (FDA, 2013).

Although 503B outsourcing facilities are not required to comply with FDA's labeling regulations applicable to approved drugs, they must prepare a modified label that includes some of the labeling requirements such as a list of active and inactive ingredients and the drug dosage form and strength. However, 503A compounding pharmacies are not subject to any specific labeling requirements (FDA, 2018). In the absence of evidence to the contrary, boxed warnings for compounded hormones are similar to those in FDA-approved drug products.

Reporting Systems

Because the clinical trials conducted to support drug approval—which are often conducted for short periods of time in highly selected populations of patients—cannot fully characterize a drug's safety profile, FDA requires that all “[c]ompanies with approved applications for drugs and therapeutic biologics as well as manufacturers, packers and distributors listed on product labels … submit postmarketing safety information to FDA” (FDA, 2020b). FDA also extends the requirements for postmarketing safety reporting to “companies marketing unapproved prescription drugs or over-the-counter drugs as well as retailers whose name appears on the product label as a distributor” (FDA, 2020b). These adverse events are collected in the FDA Adverse Event Reporting System (FAERS), which can be publicly searched and subject to analysis.^¹⁴

Under Section 503B(b)(5) of the Federal Food, Drug, and Cosmetic Act, an outsourcing facility must submit adverse event reports to FDA “in accordance with the content and format requirements established through guidance or regulation under Section 310.305 of Title 21, Code of Federal Regulations (or any successor regulations).” Section 310.305 requires, among other things, that manufacturers, packers, and distributors of marketed prescription drug products that are not the subject of an approved new drug application or an abbreviated new drug application, to establish and maintain records of all serious, unexpected adverse drug experiences associated with the use of their prescription drug products, and to make these reports available to FDA. In addition, those subject to mandatory reporting regulations must maintain records of all adverse events for 10 years, including “raw data and any correspondence relating to the adverse event” (FDA, 2015). However, these requirements do not apply to 503A compounding pharmacies, which therefore are not required to submit reports for any known or suspected adverse events.

MedWatch is another component of adverse event reporting. MedWatch permits submission of reports of adverse events or other problems with products by anyone—patients as well as health professionals—using Form 3500. Patients can contact an FDA consumer complaint coordinator to assist them in submitting a report (FDA, 2016).

In addition to the reporting systems, data are collected through the peer-reviewed literature or pilot research and case studies presented at professional meetings. For example, FAERS data collected from peer-reviewed articles describe adverse events that resulted from excessive dosages of estrogen, progesterone, and testosterone caused by the unpredictable delivery of hormones from compounded pellets (Foreman et al., 2010). In addition, preliminary data presented by Dr. Daniel Jiang at recent North American Menopause Society annual meetings describes increased incidences of abnormal uterine bleeding and hysterectomies in postmenopausal women treated with compounded pellet hormonal therapy, as compared to those treated with FDA-approved pellets (Jiang, 2017, 2018).

Adverse Event Data for cBHT

At the request of the committee, FDA shared FAERS cases on cBHT.^¹⁵ Reported events included incidences of overdosing (often related to the treatment of gender dysphoria), hormone withdrawal symptoms experienced by children after second-hand exposure to bioidentical estrogens and androgens, and compounding errors. One example of an adverse drug effect caused by medical error relates to an allergic reaction to propylene glycol in a product, which had erroneously been labeled as propylene glycol free. The quality of sterile drugs used in injected or implanted formulations were also identified as the source of localized infections occurring in patients. Pellet extrusions were also identified as a source of localized infections. One side effect reported by many women included nausea and vomiting, which is a common side effect of exposure to high dose estrogens (FDA, 2019b). Because cBHT preparations contain the same active ingredients as FDA-approved BHT products, there are similar risks of adverse events at equivalent dosages. However as noted in Chapter 6, cBHT inconsistencies in compounded formulations can increase the risk of bioavailability-related adverse reactions.

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 7-2Adverse Events Discovered During an FDA Inspection

Adverse Event	Number of Events Identified
Acne	11
Amenorrhea	1
Breast cancer	154
Cellulitis	529
Deep vein thrombosis	40
Endometrial cancer	21
Enlarged clitoris	6
Facial hair	7
Hair loss	30
Heart attack	37
Other complications	427
Pellet extrusions	2,335
Prostate cancer	25
Stroke	31
Voice deepening	2

: SOURCE: FDA, 2019a.

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.

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Footnotes

1: There are a number of articles with relevance to multiple hormones. In its search efforts, the committee identified other published studies that have tangential relevance to the committee's charge; however, only the studies with greatest pertinence were reviewed in this report. As such, the reference list for this chapter represents the most relevant data and is not an inclusive list of all articles reviewed.
2: Stakeholder submissions are available through the National Academies Public Access File.
3: See Ernst and Pittler (2006) and Kim (2013) for an additional discussion.
4: Compounded drugs prepared for investigational new drug trials are subject to Current Good Manufacturing Practice (CGMP) requirements under Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act).
5: The committee was unable to identify any studies of adequate methodological rigor aimed at determining the safety and effectiveness of pregnenolone compounded preparations.
6: For additional discussion on labeled indications and contraindications for FDA-approved drug products, see Chapter 8, Table 8-1.
7: Ovesterin, approved drug product in Sweden (https://vardgivarwebb.regionostergotland.se/Startsida/Verksamheter/Regiondirektor/Rad-och-kommitteer-/Lakemedel-new/RekomenderadeLakemedel/Gynekologi11 [accessed April 3, 2020]).
8: Estring, FDA-approved drug product (NLM, 2020).
9: Synapause, approved drug product in the Netherlands (WHO, 2018).
10: For additional discussion on labeled indications and contraindications for FDA-approved drug products, see Chapter 8, Table 8-1.
11: At the time this report was written, testosterone was available by prescription in eight FDA-approved drug products for hormone therapy in males for conditions associated with symptoms of deficiency or absence of endogenous testosterone. These products could be prescribed in one of the following forms: gel, transdermal patch, buccal system tablet, and pellet (see Chapter 5 for additional information on hormone products).
12: For a further discussion on the compounded hormone preparations and their use, see Chapters 5 and 8.
13: Although this study is a large observational study, the participant-specific dosing regimens prevent the committee from creating a table that could accurately capture the published data.
14: See FDA's Guidance for Industry, Adverse Event Reporting for Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act, October 2015. See https://www.fda.gov/media/90997/download (accessed May 15, 2020).
15: These adverse event reports were identified in the FAERS database by the study sponsor—FDA. FDA identified adverse events reports that relate to the use of a cBHT by reading through report descriptions of all entries marked as compounded. It is important to note that there may be other FAERS cases related to the use of a cBHT, but if the necessary indication box for compounded medications was not checked during the data entry process, then those cases would not be represented in the full data set.

Boxes

BOX 7-1FDA-Approved Hormone Therapy Indications

The natural aging process and the correlated decrease in steroid hormone levels are linked to symptomology associated with menopause and male hypogonadism. The use of hormone therapy products has been one way in which clinicians have sought to alleviate the symptoms brought on by the natural aging process.

Estrogen hormone therapy (either estrogen alone in the absence of a uterus or estrogen plus progesterone in the presence of a uterus) is FDA approved for treating the following four indications: (1) vasomotor symptoms; (2) genitourinary symptoms (vaginal atrophy); (3) bone loss prevention; and (4) hypoestrogenism induced by hypogonadism, primary ovarian insufficiency, or castration. Dehydroepiandrosterone (DHEA) hormone therapy has been FDA approved for treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, attributable to menopause. Testosterone hormone therapy is FDA approved for treating conditions associated with a deficiency or absence of endogenous testosterone in males. Pregnenolone is not an active ingredient in FDA-approved hormone therapy products.

SOURCES: FDA, 2020a; NAMS, 2017.

Conclusion 7-1

There is limited and mixed quality evidence to suggest that estriol may be effective in treating certain menopausal symptoms; however, there is insufficient evidence to inform conclusions regarding the safety of estriol. Well-designed and properly controlled clinical trials are needed to clarify the potential clinical utility of estriol.

Conclusion 7-2

There is insufficient evidence to determine the safety and effectiveness of compounded estriol in comparison to bioidentical hormone therapy products approved by FDA or similar international bodies.

Conclusion 7-3

There is a dearth of high-quality evidence—data from studies that would meet FDA's requirements for granting regulatory approval to a drug product—available to establish whether compounded bioidentical hormone therapy preparations are safe and effective for their prescribed uses.

Conclusion 7-4

Well-designed and properly controlled clinical trials are needed to provide reliable evidence about the safety and effectiveness of compounded bioidentical hormone therapy preparations.

Conclusion 7-5

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.

Conclusion 7-6

There are concerns with the voluntary and incomplete nature of adverse events reporting for compounded preparations. The lack of an easily accessible safety database limits assessment of the frequency, type, and severity of adverse events related to the use of compounded bioidentical hormone therapy. Improved monitoring of adverse events are required to characterize the safety of these compounded preparations.

Bookshelf ID: NBK562865

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