madman
Super Moderator
Abstract
Importance: More information is needed about the efficacy and safety of compounded bioidentical hormone therapy (cBHT) in the published literature. A thorough synthesis of existing data is not currently available.
Objective: To provide a systematic review and meta-analysis of the existing evidence related to the safety and efficacy of commonly prescribed cBHT preparations in perimenopausal and postmenopausal women.
Evidence Review: PubMed, ClinicalTrials.gov, and The Cochrane Central Register of Controlled Trials were searched. Randomized controlled trials (RCTs) comparing cBHT with placebo or FDA-approved products in perimenopausal or postmenopausal women were eligible. The risk of bias was assessed by the Cochrane risk of bias tool. The primary safety outcome was a change in lipid profile and glucose metabolism, and the primary efficacy outcome was the change in vaginal atrophy symptoms. The secondary outcomes included the change in endometrial thickness, risk of adverse events, vasomotor symptoms, change in serum hormone levels, and change in bone mineral density.
Findings: A total of 29 RCTs reported in 40 articles containing 1,808 perimenopausal and postmenopausal women were included. Two risk factors of cardiovascular disease, lipid profile, and glucose metabolism, were evaluated with cBHT. The results showed that compounded androgen was not associated with the change in lipid profile or glucose metabolism. There was no change in endometrial thickness or serious adverse events. There were more androgenic side effects with compounded dehydroepiandrosterone compared with placebo as expected. Other safety measures including clinical cardiovascular events, endometrial biopsy, and risk of breast cancer were not studied. cBHT in the form of compounded vaginal androgen was found to significantly improve vaginal atrophy symptoms (SMD 0.66 [95% CI, 1.28 to 0.04]; I 2¼ 86.70%). This finding was supported by the association between compounded vaginal androgen and improved female sexual function scores. The changes in serum hormone levels were also evaluated. Despite the variations in absorption from different types of compounded hormones, routes, and strengths, the trends were consistent with published data from FDA-approved products.
Conclusions and Relevance: This review found that cBHT used in primarily short-term RCTs is not associated with adverse changes in lipid profile or glucose metabolism. cBHT in the form of vaginal androgens appears beneficial for vaginal atrophy symptoms. There are insufficient RCTs of cBHT to assess the clinical risk of breast cancer, endometrial cancer, or cardiovascular disease. Long-term studies with clinical endpoints are needed.
In 2002, the Women’s Health Initiative reported the health risks of oral conjugated equine estrogen with medroxyprogesterone acetate in postmenopausal women.1 Since then, a substantial group of postmenopausal women using hormone therapy (HT) made the decision with their treating physicians to switch from synthetic hormones to bioidentical hormone therapy. Some physicians and patients determined that compounded bioidentical hormone therapy (cBHT) was appropriate. Several nationwide surveys showed a significant decline in prescriptions of FDA-approved hormone products over the past decade, in contrast with continuous growth in cBHT. It was estimated that 1 to 2.5 million US women are cBHT users, and 26 to 33 million cBHT prescriptions were filled each year.2-4 The new trend in HT raised concerns and discussions surrounding cBHT. The most prominent advantages of cBHT are its personalized approach and the flexibility in making customized strengths and dosage forms. Black box warnings are required on all FDA-approved estradiol and topical testosterone products, and Federal law exempts all compounded drugs from such labeling requirements. However, besides the absence of boxed warnings, other safety considerations regarding cBHT arose among physicians. These safety concerns included the increased risk of endometrial cancer, inconsistency of drug content, incomplete adverse events reporting, and unknown risk of cardiovascular disease, mostly from survey findings, case reports, nonrandomized studies, and expert opinions.5,6 Because of concerns regarding cBHT, in 2018, the FDA requested the National Academies of Science, Engineering, and Medicine (NASEM) to evaluate the available evidence of cBHT regarding safety and effectiveness.5 Thirteen clinical trials with relevance to the safety and effectiveness of cBHT were highlighted and discussed by the NASEM committee. A conclusion was reached that there was a lack of high-quality research to establish the safety and effectiveness of cBHT.5 Furthermore, the highest level of evidence, a systematic review and meta-analysis had not been published.
We conducted a deep and thorough literature search and identified some studies that have not been cited by others in this field, including the NASEM committee. To obtain a comprehensive view of the safety and efficacy of commonly prescribed cBHT preparations, and to evaluate the robustness of evidence for using cBHT, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to examine the safety and efficacy of cBHT in perimenopausal and postmenopausal women. In this review, the analyzed safety outcomes included two risk factors of cardiovascular disease, endometrial thickness, and adverse events. There were no available data on other measures of safety such as breast density on mammography, breast cancer, or clinical cardiovascular events. The primary efficacy outcome is vaginal atrophy symptoms. Change in serum hormone levels was also evaluated as a secondary outcome to provide information on absorption.
RESULTS
*Search results and study characteristics
*Risk of bias within studies and publication bias
*Primary safety outcome analysis—the risk factors of cardiovascular disease
*Secondary safety outcomes analysis—endometrial thickness and adverse events
*Primary efficacy outcome analysis—change of vaginal atrophy symptoms
*Other secondary outcomes analysis—vasomotor symptoms, change of serum hormone levels, and BMD
DISCUSSION
*Summary of the main findings
*Agreements and disagreements with other reviews
*Strengths and limitations
*Applicability
CONCLUSIONS
In this systematic review and meta-analysis of primarily short-term RCTs in perimenopausal and postmenopausal women, and recognizing the limits of the available evidence, cBHT was found beneficial with respect to vaginal androgens without showing major safety concerns for lipid profile, glucose metabolism, endometrial thickness, or severe adverse events. Consistent trends in changes in serum hormone levels were observed across included studies. There are not enough published clinical trials to assess the effects of cBHT on hot flashes and no benefits were found on BMD in current short-term studies. More long-term studies are needed to draw conclusions on the clinical cardiovascular events, the risk of breast cancer, endometrial cancer, and the prevention of bone loss.
Importance: More information is needed about the efficacy and safety of compounded bioidentical hormone therapy (cBHT) in the published literature. A thorough synthesis of existing data is not currently available.
Objective: To provide a systematic review and meta-analysis of the existing evidence related to the safety and efficacy of commonly prescribed cBHT preparations in perimenopausal and postmenopausal women.
Evidence Review: PubMed, ClinicalTrials.gov, and The Cochrane Central Register of Controlled Trials were searched. Randomized controlled trials (RCTs) comparing cBHT with placebo or FDA-approved products in perimenopausal or postmenopausal women were eligible. The risk of bias was assessed by the Cochrane risk of bias tool. The primary safety outcome was a change in lipid profile and glucose metabolism, and the primary efficacy outcome was the change in vaginal atrophy symptoms. The secondary outcomes included the change in endometrial thickness, risk of adverse events, vasomotor symptoms, change in serum hormone levels, and change in bone mineral density.
Findings: A total of 29 RCTs reported in 40 articles containing 1,808 perimenopausal and postmenopausal women were included. Two risk factors of cardiovascular disease, lipid profile, and glucose metabolism, were evaluated with cBHT. The results showed that compounded androgen was not associated with the change in lipid profile or glucose metabolism. There was no change in endometrial thickness or serious adverse events. There were more androgenic side effects with compounded dehydroepiandrosterone compared with placebo as expected. Other safety measures including clinical cardiovascular events, endometrial biopsy, and risk of breast cancer were not studied. cBHT in the form of compounded vaginal androgen was found to significantly improve vaginal atrophy symptoms (SMD 0.66 [95% CI, 1.28 to 0.04]; I 2¼ 86.70%). This finding was supported by the association between compounded vaginal androgen and improved female sexual function scores. The changes in serum hormone levels were also evaluated. Despite the variations in absorption from different types of compounded hormones, routes, and strengths, the trends were consistent with published data from FDA-approved products.
Conclusions and Relevance: This review found that cBHT used in primarily short-term RCTs is not associated with adverse changes in lipid profile or glucose metabolism. cBHT in the form of vaginal androgens appears beneficial for vaginal atrophy symptoms. There are insufficient RCTs of cBHT to assess the clinical risk of breast cancer, endometrial cancer, or cardiovascular disease. Long-term studies with clinical endpoints are needed.
In 2002, the Women’s Health Initiative reported the health risks of oral conjugated equine estrogen with medroxyprogesterone acetate in postmenopausal women.1 Since then, a substantial group of postmenopausal women using hormone therapy (HT) made the decision with their treating physicians to switch from synthetic hormones to bioidentical hormone therapy. Some physicians and patients determined that compounded bioidentical hormone therapy (cBHT) was appropriate. Several nationwide surveys showed a significant decline in prescriptions of FDA-approved hormone products over the past decade, in contrast with continuous growth in cBHT. It was estimated that 1 to 2.5 million US women are cBHT users, and 26 to 33 million cBHT prescriptions were filled each year.2-4 The new trend in HT raised concerns and discussions surrounding cBHT. The most prominent advantages of cBHT are its personalized approach and the flexibility in making customized strengths and dosage forms. Black box warnings are required on all FDA-approved estradiol and topical testosterone products, and Federal law exempts all compounded drugs from such labeling requirements. However, besides the absence of boxed warnings, other safety considerations regarding cBHT arose among physicians. These safety concerns included the increased risk of endometrial cancer, inconsistency of drug content, incomplete adverse events reporting, and unknown risk of cardiovascular disease, mostly from survey findings, case reports, nonrandomized studies, and expert opinions.5,6 Because of concerns regarding cBHT, in 2018, the FDA requested the National Academies of Science, Engineering, and Medicine (NASEM) to evaluate the available evidence of cBHT regarding safety and effectiveness.5 Thirteen clinical trials with relevance to the safety and effectiveness of cBHT were highlighted and discussed by the NASEM committee. A conclusion was reached that there was a lack of high-quality research to establish the safety and effectiveness of cBHT.5 Furthermore, the highest level of evidence, a systematic review and meta-analysis had not been published.
We conducted a deep and thorough literature search and identified some studies that have not been cited by others in this field, including the NASEM committee. To obtain a comprehensive view of the safety and efficacy of commonly prescribed cBHT preparations, and to evaluate the robustness of evidence for using cBHT, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to examine the safety and efficacy of cBHT in perimenopausal and postmenopausal women. In this review, the analyzed safety outcomes included two risk factors of cardiovascular disease, endometrial thickness, and adverse events. There were no available data on other measures of safety such as breast density on mammography, breast cancer, or clinical cardiovascular events. The primary efficacy outcome is vaginal atrophy symptoms. Change in serum hormone levels was also evaluated as a secondary outcome to provide information on absorption.
RESULTS
*Search results and study characteristics
*Risk of bias within studies and publication bias
*Primary safety outcome analysis—the risk factors of cardiovascular disease
*Secondary safety outcomes analysis—endometrial thickness and adverse events
*Primary efficacy outcome analysis—change of vaginal atrophy symptoms
*Other secondary outcomes analysis—vasomotor symptoms, change of serum hormone levels, and BMD
DISCUSSION
*Summary of the main findings
*Agreements and disagreements with other reviews
*Strengths and limitations
*Applicability
CONCLUSIONS
In this systematic review and meta-analysis of primarily short-term RCTs in perimenopausal and postmenopausal women, and recognizing the limits of the available evidence, cBHT was found beneficial with respect to vaginal androgens without showing major safety concerns for lipid profile, glucose metabolism, endometrial thickness, or severe adverse events. Consistent trends in changes in serum hormone levels were observed across included studies. There are not enough published clinical trials to assess the effects of cBHT on hot flashes and no benefits were found on BMD in current short-term studies. More long-term studies are needed to draw conclusions on the clinical cardiovascular events, the risk of breast cancer, endometrial cancer, and the prevention of bone loss.
