The Clinical Utility of Compounded Bioidentical Hormone Therapy A Review of Safety, Effectiveness, and Use (2020) / Chapter Skim
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7 The Safety and Effectiveness of Compounded Bioidentical Hormone Therapy
7 The Safety and Effectiveness of Compounded Bioidentical Hormone Therapy
Pages 137-172
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From page 137... ...
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)
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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.
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From page 139... ...
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.
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From page 140... ...
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 indicaion.
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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)
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; FSDS-R schedule: of sexual function vaginal (FSDS-R) , scores (P = 0.02)
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criteria Rating Scale women: Higher that no serious Absence of a testosterone women described (MRS) testosterone doses adverse events Initial dose randomized on somatic, correlated with occurred n = 300 varied across Total scores control group or psycho- greater improvement patient based and psycho- comparison group logical and Race/ethnicity in MRS total score on their weight logical, urogenital not reported (P < 0.05)
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vasomotor symptoms compounded n = 90 All received vasomotor (12 months) daily found in treatment preparation (assigned)
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: assessed: had been taking outcomes, and symptoms (50–100 mg) little to no 53.7 years hot flashes, Premarin for 10 statistical analysis and improvement in night sweats, years, which the of results testosterone symptoms insomnia, researchers believe perivaginal Multiple dosage lack of may have caused cream forms of treatments energy, the development of (subset of patients Participants low libido, breast cancer in this switched from began with a and minor patient Bi-est cream to 0.5 gm twice stiffness or sublingual route)
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TABLE 7-1 Continued Main Outcomes Relevant to the Serious Adverse Author Objective Study Design Population Treatment Other Notes Measure Committee's Charge Events Limitations 146 Mahmud, Treatment arm 2010 2: Transdermal (continued) Bi-est cream (estradiol 1 mg plus estriol 4 mg per gram)
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Race/ethnicity not reported Age (mean) : 55.6 years Narkwich- Determine Randomized, Women Oral DHEA; Exclusion Number of Treatment did not Author reported No power ean effect of double-blind, receiving IVF 75 mg/day; criteria oocytes improve the response that no serious calculation to et al., 2017 DHEA on placebo- with diminished 12 to 20 weeks described retrieved; live to controlled ovarian adverse reactions determine sample In-Vitro controlled ovarian reserves before starting birth rates; hyperstimulation or occurred size Long Fertilization pilot trial ovarian mRNA oocyte quality or live Treatment protocol (IVF)
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(MFI-20) ; result of treatment increased risk of between resulting in patient trial Health- (P < 0.001)
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45–69 years comparison of No significant baseline and difference between post dosing levels treatment maturation Posttreatment index, pH, and maturation values clinical were significantly examination higher for 300 μg group (P = 0.005) NOTE: AI = aromatase inhibitor; BMD = bone mineral density; DHEA = dehydroepiandrosterone; ER = estrogen receptor; FSDS-R = Female Sexual Distress Scale– Revised; 149 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.
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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.
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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 7 Ovesterin, approved drug product in Sweden (https://vardgivarwebb. egionostergotland.se/ r Startsida/Verksamheter/Regiondirektor/Rad-och-kommitteer-/Lakemedel-new/RekomenderadeLakemedel/Gynekologi11 [accessed April 3, 2020]
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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.
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. 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.
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.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.
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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)
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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
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From page 157... ...
. 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)
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From page 158... ...
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)
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From page 159... ...
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 ( tephenson et al., 2013)
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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)
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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. 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.
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From page 162... ...
." 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 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)
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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)
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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.
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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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2017. Effi cacy and safety of transdermal testosterone in postmenopausal women with hypoactive sexual desire disorder: A systematic review and meta-analysis.
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2014. Breast cancer, aromatase inhibitor therapy, and sexual functioning: A pilot study of the effects of vaginal testosterone therapy.
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1994. A comparative multicenter study of the effects of continuous low-dose estradiol released from a new vaginal ring versus estriol vaginal pessaries in postmenopausal women with symp toms and signs of urogenital atrophy.
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2017. Long-term hormone therapy for perimenopausal and postmenopausal women.
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2014. The effectiveness of sublingual and topical compounded bioidentical hormone replacement therapy in postmenopausal women: An observational cohort study.
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2013. The effects of com pounded bioidentical transdermal hormone therapy on hemostatic, inflammatory, im mune factors; Cardiovascular biomarkers; quality-of-life measures; and health outcomes in perimenopausal and postmenopausal women.
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2011. Topical testosterone for breast cancer patients with vaginal atrophy related to aromatase inhibitors: A phase I/II study.
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