Since the publication of the Women’s Health Initiative (WHI) study results were reported in 2002, many doctors and patients alike have firmly held a strong belief that hormones are “dangerous” for women. Despite many published “Mia culpas” regarding the misreporting regarding this data, and in fact numerous reports of true benefits in women, this misperception has held firm.
During the last two decades, a substantial number of patients and their prescribing doctors switched patients’ hormonal therapies for the FDA approved synthetic products to compounded bio-identical hormonal therapies, with the belief that these therapies would be “safer”. This caused the FDA and many medical associations, which both 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 that prescribe them.
There appears to however, be a change in the tide, which one can only hope will continue. In the last few months, two articles have been published that are challenging the “conventional wisdom” regarding hormones in general and compounded therapies specifically.
The first article, “Breast Cancer Prevention: Time for Change” by Dr. Chlebowski et al, JCO Oncology Practice, Volume 17, issues 12 pages 709-717, discusses the WHI overall study and the WHI dietary modification trial and true results related to breast cancers. The analysis showed that women under-going conjugated equine therapy had positive clinical outcomes compared to placebo in breast cancer rates and in fact, in the WHI trial showed a reduction of actual deaths from breast cancer by 40%. This has not been demonstrated for any other pharmacologic intervention including aromatase inhibitors and SERM’s.
In the March 14th, 2022 International Menopause Society (IMS) e-letter, a commentary was published that illustrated these findings and the author called for a re-evaluation of hormones in particular when is comes to breast cancer prevention and hormone therapy replacement. This is particularly surprising given the historical negative stance regarding hormones by the IMS.
The second and most recent article, “Safety and efficacy of compounded bio-identical hormone therapy (cHRT) in perimenopausal and postmenopausal women: a systematic review and meta-analysis of randomized controlled trials” by Yi Liu et al. Menopause Volume 29, No. 4 2022pp 465-482, discusses the findings of 29 published randomized control trials comparing cBHRT with a placebo or an FDA approved product.
In the 29 studies, 1,808 perimenopausal and post- menopausal were evaluated. They were on non-sterile compounded formulations of either topical creams or gels, vaginal suppositories, oral tablets or capsules etc. The hormones that were studied include testosterone, estriol, estradiol progesterone and DHEA. Primary outcomes included safety and efficiency outcomes. The safety outcomes looked at indirect measures of cardiovascular disease (lipids and glucose metabolism) and efficacy outcome of vaginal atrophy symptoms. Other secondary items were assessed were post-treatment endometrial thickness, and risk of adverse events, vasomotor symptoms, the change of serum hormone levels and the change of bone mineral density.
The authors found that cBHRT used in primarily short term RCT’s 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 as was the only hormone studied that showed an increase in androgenic side effects (which were mild) at the most commonly prescribed dose of 25mg.
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 articles, suggested that although the absorption was influence by the types of hormones, routes, and strengths, there was consistent trends across the studies that were deemed to have “moderate to high certainly of evidence” by the authors.
Compounded combination of oral estradiol 2mg with progesterone 100mg 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 300mg or topical progesterone at 40mg may have significant systemic absorption. Topical testosterone at 10mg significant increased both total and free testosterone levels. Vaginal androgens may also increase corresponding serum androgen levels when doses reached several milligrams. Oral DHEA at 50 to 100mg lead to consistent elevations of the serum DHEA and DHEAs.
This study 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 NAMS, “Menopause” published this analysis itself is an interesting turn of events. The organization and its leaders have been very vocal in its disparagement of compounded therapies.
I suspect that the tide if turning with more and more women and providers joining forces to showcase the long-standing safety and utilization of compounded product which have largely filled a huge void by the commercial sector for women. I hope this is a sign of things to come and that compounded therapies made by reputable and highly regulated compounded pharmacies will get to step into the “sunlight” of patient care.
