Since the Women’s Health Initiative (WHI) study results were reported in 2002, many doctors and patients have had a strong belief that hormones are dangerous for women. Despite many published “mia culpas” regarding the misreporting of these data and numerous reports of true benefits in women, this misperception has held firm.
The rise of compounded bioidentical hormone therapy
During the last two decades, a substantial number of patients and their prescribing doctors switched patients’ hormonal therapies from the FDA-approved synthetic products to compounded bioidentical hormone replacement therapy (BHRT). They believed these compounded bioidentical therapies would be safer.
This trend caused the FDA and many medical associations—both of which are largely supported by the pharmaceutical industry—to question the clinical utility and safety of compounded hormonal therapies. Subsequently, there has been much backlash on compounded products and the providers who prescribe them.
New publications challenge conventional thinking about HRT and breast cancer prevention
In the last few months, two published articles challenged conventional wisdom about hormones in general and compounded therapies specifically.
Article #1: Breast cancer prevention: Time for change
The first article, “Breast Cancer Prevention: Time for Change” by Dr. Rowan Chlebowski et al (JCO Oncology Practice, 2021; Volume 17, Issue 12: pages 709-717), discusses the WHI study, the WHI dietary modification trial, and true results related to breast cancer.
The analysis showed that women undergoing conjugated equine therapy had positive clinical outcomes in breast cancer rates compared to placebo. In fact, the WHI trial showed a reduction in actual deaths from breast cancer of 40%. This has not been demonstrated for any other pharmacologic intervention including aromatase inhibitors and SERMs.
A commentary illustrating these findings was published in the International Menopause Society (IMS) e-letter on March 14, 2022. The author called for a reevaluation of hormone replacement therapy in relation to breast cancer prevention. This is particularly surprising given the historical negative stance regarding hormones by the IMS.
Article #2: Safety and efficacy of compounded bioidentical hormone therapy
The second and most recent article, “Safety and efficacy of compounded bioidentical hormone therapy (cHRT) in perimenopausal and postmenopausal women: a systematic review and meta-analysis of randomized controlled trials” by Dr. Yi Liu, et al (Menopause, 2022; Volume 29, No. 4: pages 465-482) discusses the findings of 29 published randomized control trials comparing compounded BHRT with a placebo or an FDA-approved product.
Study population and outcomes
In the 29 studies, 1,808 perimenopausal and postmenopausal women were evaluated. They were on non-sterile compounded formulations of either topical creams or gels, vaginal suppositories, oral tablets, or oral capsules. The hormones that were studied included testosterone, estriol, estradiol, progesterone and DHEA.
Primary outcomes included safety and efficiency outcomes. They evaluated indirect measures of cardiovascular disease (lipids and glucose metabolism) and an efficacy outcome of vaginal atrophy symptoms. Other secondary items assessed were post-treatment endometrial thickness, risk of adverse events, vasomotor symptoms, change in serum hormone levels, and change in bone mineral density.
Safety findings
The authors found that compounded BHRT used in primarily short-term randomized controlled trials is not associated with adverse changes in lipid profiles or glucose metabolism. In addition, vaginal androgens in particular showed benefits with respect to vaginal health and sexual function without adverse effects. DHEA was the only hormone studied that showed an increase in androgenic side effects (which were mild) at the most commonly prescribed dose of 25 mg.
Pharmacokinetic findings
One of the biggest concerns cited by critics of compounded hormones is the attainable serum levels and possible inconsistencies. The pharmacokinetic studies evaluated in this article suggested that although the absorption was influenced by the hormone type, route, and strength, there were consistent trends across the studies that had “moderate to high certainty of evidence,” according to the authors.
These trends include:
- The compounded combination of 2 gm oral estradiol with 100 mg progesterone significantly increased serum estradiol levels, and the levels remained in the physiologic range for reproductive-aged women.
- Compounded vaginal estrogen at 10 ug or 25 ug is unlikely to increase serum estradiol, while vaginal progesterone at 300 mg or topical progesterone at 40 mg may have significant systemic absorption.
- Topical testosterone at 10 mg significantly increased both total and free testosterone levels. Vaginal androgens may also increase corresponding serum androgen levels when doses reach several milligrams.
- Oral DHEA at 50 mg to 100 mg leads to consistent elevations of serum DHEA and DHEAS.
What these results mean for compounded bioidentical hormone replacement therapy
This meta-analysis was the first of its kind to evaluate the safety and efficacy of compounded BHRT. Although the studies were small, short in duration, and did not address sterile products (injectables and pellets), they are very reassuring.
The fact that the journal of the NAMS, Menopause, published this analysis is an interesting turn of events, as the organization and its leaders have been very vocal in the disparagement of compounded therapies.
The evolving future of HRT
It appears that the tide is turning for hormone therapy. More and more women and providers are joining forces to showcase the long-standing utilization and safety of compounded products.
Hopefully, this is a sign of things to come, and that compounded therapies made by reputable and highly regulated compounding pharmacies will get to “step into the sunlight” of patient care.
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