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Women's Health Spotlight: Hormone Replacement Therapy and the Endocannabinoid System

The use of compounded bioidentical hormone replacement was originally developed in 1939 for women who had undergone radical hysterectomies. The longest-studied type of hormone replacement therapy (or HRT as it is commonly known), it was primarily utilized in Europe and Australia until about 2011, when innovators in the field of integrative and functional medicine started reintroducing the therapy into the United States. A reintroduction made necessary by HRT’s controversial path to acceptance.

n the United States, hormone replacement therapy began in the 1960s and later gained traction in the 1990s with The Women’s Health Initiative, a long-term national health study funded by the National Heart, Lung, and Blood Institute. It was one of the first clinical trials on chronic postmenopausal conditions. In 2002, the first results were released, and the study was prematurely halted, when the initial results indicated HRT may have more detrimental effects than benefits.

This widespread publicity created panic and new guidance to doctors prescribing HRT. Since that time, review of the WHI trial analyses and new studies demonstrated that the use of HRT in younger women or in early postmenopausal women had a beneficial effect on the cardiovascular system, reducing coronary disease and all-cause mortality. Further studies on the use of compounded Bio-Identical Hormone Replacement Therapy (BHRT) subcutaneous pellet therapy have indicated that it may benefit the recipients in bone, brain, and breast health.

In a new study from The Journal of Clinical Investigation, researchers point to evidence that there is a “critical window” for women where hormone replacement can reduce the depression- and memory-loss-related symptoms associated with menopause. Researchers examined hormone levels, biochemical regulators of CB1, and mice’s ability to adaptively learn after ovariectomized mice were induced into menopause. Through their research, Zhang, et al. discovered that activating CB1 receptors may prolong this window.

In the study, estrogen administration was beneficial for the mice, improving learning and reducing memory loss, but only if administered immediately after deprivation via ovariectomy. These beneficial effects were not seen when treatment was given three months after the onset of the menopause model, suggesting the so-called “time window of opportunity” in hormone therapy. Upon cotreatment with CB1 receptor agonists, however, the hormone treatment became more effective, and the window of opportunity was prolonged.

While the experimental methods cannot be directly translated to humans, the interplay between sex hormones and the endocannabinoid system is increasingly recognized as relevant to health and medicine. Anecdotally, our providers are seeing better results from their patients that combine BHRT therapy with a full spectrum hemp extract, particularly cannabigerol (CBG).

Dr. Michael Jelinek, MD, notes, “My patients report back that they are feeling better when they start CBG before hormone replacement. Those that are being treated with BHRT, and are also using Formula30A, are reporting better outcomes to their hormone optimization when it comes to anxiety, sleep, and energy. If you give women that are on hormones CBG, they do better.” Additional research must be conducted before conclusions of any statistical significance may be drawn, but what we already know about CBG may shed some light on this mechanism.

The phytocannabinoid cannabigerol was first described by Goani and Mechoulam in 1964 and is one of the approximately 113 different cannabinoids identified in the Cannabis sativa plant. CBG is synthesized in plants via the decarboxylation of cannabigerolic acid (CBGA), which also serves as the precursor to Δ9-tetrahydrocannabinolic acid (Δ9-THCA), cannabidiolic acid (CBDA), and cannabichromenic acid (CBCA), and thereby the more commonly known, nonacidic forms of Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), and cannabichromene (CBC).

Due to this rapid conversion, CBG naturally occurs in low concentrations (~10% cannabinoid content), except in the case of rare chemotypes (> 0.3%) with mutations that alter cannabinoid conversion, such as those used to create Formula30A CBG extracts. CBG has been shown to have varied levels of affinity for CB1 and CB2 receptors, with studies indicating it is a partial agonist for both. Based on the findings from Zhang, et al., it is possible that CBG’s interaction at the CB1 receptor site is partially responsible for these anecdotal results.

Additionally, CBG is an inhibitor of cellular uptake for anandamide (AEA), which is also colloquially known as the “bliss molecule.” This may also attribute to the beneficial effects reported, particularly as CB1 antagonists have been shown to reduce the anxiolytic effects of AEA reuptake inhibitors. Additionally, according to Costa, et al., “Changes in anandamide (AEA) levels affect reproductive events and has already been suggested as a biomarker of reproductive potential of male and female gametes… This study supports the idea that ECS balance is crucial for folliculogenesis and oocyte quality as dysregulated AEA levels may compromise female fertility.

Clearly, the endocannabinoid system is intricately intertwined throughout the vast majority of our body processes. Identifying the ways in which it interacts with our hormones as we age is vital for seeking better long-term outcomes with HRT. As for those already implementing CBG in their patient care? “I think for all patients on hormone replacement therapy,” concludes Dr. Jelinek, “that the practitioner should consider starting CBG before hormone replacement, or at the same time. Personally, if push came to shove… I will not go without CBG.”


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