Menopausal HRT Series: Is bioidentical estrogen the safest option?

This post was written by our guest author, Dr. Tori Hudson, ND.

Read about bioidentical estrogen in part 4 of our Menopausal HRT blog series. This series will focus on classic myths that can lead to depriving women of hormones they may need, prescribing insufficient doses of progesterone in combination with systemic estrogen, the subject of bioidentical hormones and compounding, and more.

Myth: Bioidentical estradiol is safe and non-bioidentical conjugated equine estrogen (aka Premarin) is not.

The term bioidentical hormone therapy is defined as an exogenous hormone that is the same molecule as the endogenous hormone. Bioidentical hormones are made from compounds in either soy (beta-sitosterol) or wild yam (diosgenin), and then converted in a manufacturing laboratory to the desired hormone. When the result is a hormone biochemically identical to endogenous, it is called bioidentical. Bioidentical hormones can either be an FDA-approved big pharma hormone, or a compounded hormone, including estradiol, estrone, DHEA, and micronized progesterone. There are compounded bioidentical hormones that are not available to women from big pharma, including testosterone, estriol, and pregnenolone. This article will not argue the case of compounded bioidentical hormones except to say that there are bioidentical hormones, formulations, and deliveries that are not available through big pharma. Compounding of hormones can produce individualized doses, combinations, and delivery systems that are not possible with FDA-approved big pharma options. There is also the issue of inert ingredients.  Compounded hormones can be made greener and cleaner when it comes to excipients, additives, and preservatives. For example, an FDA-approved estradiol tablet contains not only bioidentical estradiol but also colloidal silicon dioxide, corn starch, dibasic calcium phosphate, lactose monohydrate, magnesium stearate, and sodium starch glycolate. In addition, the 1 mg also contains FD&C blue no. 1 aluminum lake and D&C red no. 27.

Compounded hormones in pills, troches, and creams do have other ingredients, depending on which pharmacy and the options used. Some may be more desirable/preferred than others, as compounding pharmacy options also include propylene glycol, petrolatum bases, ethanol, sweeteners, choice of oils for capsules (olive, vitamin E, almond, sesame, medium chain triglycerides, grape seed), and fillers in most capsules, which vary but can include microcrystalline cellulose, lactobacillus, lactose, even sodium lauryl sulfate.

When it comes to patient sensitivities, and possibly other influences of foreign inert ingredients in our medicines, working with the compounding pharmacy to select the most inert option for your patients can make a difference.

Compounded bioidentical hormones have come under scrutiny from the FDA, NAMS, and the National Academy of Sciences, Engineering and Medicine (NASEM). In September 2018, the FDA announced a partnership with the NASEM. The FDA asked the NASEM to assess the clinical utility of compounded bioidentical hormone therapy (cBHT), whether the available evidence for safety and effectiveness supports use of cBHT drug products to treat patients, and to determine the specific patient populations that might require cBHT in lieu of an FDA-approved product. In July 2020, the committee released a report with key recommendations:

• Limit use of cBHT to: documented allergy to active pharmaceutical ingredient of FDA-approved drug; or documented medical need for a different dose or product from those approved by FDA.
• Add cBHT and doses to the FDA Difficult to Compound List: estradiol, estriol, estrone, DHEA pregnenolone, progesterone, testosterone, and ALL pellet therapies
• Increase education for prescribers, compounders, marketers, or dispensers of cBHT
• Increase state regulation and certification of prescribers using evidence-based guidelines
• Advocate for improved federal and state oversight of cBHT for safety and efficacy
• Needs standardized package and labeling for cBHT (boxed warnings)
• Transparency of financial relationships and conflicts of interest
• Increase research on safety and efficacy of cBHT

While the NASEM recommendations are processed by state and federal regulators, NASEM (and de facto NAMS) advises practicing clinicians to take action to reduce the effects on patient well-being of the existing double standard in regulation of cBHT production and distribution:

• Endeavor to restrict the use of cBHT preparations to designated exceptions (FDA-approved testosterone can be titrated for women)
• Advise the patient that cBHT is not FDA-approved and what that means regarding lack of proof of safety and efficacy
• Explain that FDA-approved bHT is available in a range of preparations and doses
• Distribute a copy of boxed warnings for FDA-approved bHT to those using cBHT
• Report adverse events to the FDA
• If a new patient is using cBHT, document discussions of safety concerns and NASEM recommendations
• Persist in encouraging a transition to FDA-approved bHT
• Establish detailed history of cBHT type, doses, route of administration, and duration
• Evaluate bleeding history and consider endometrial monitoring; endometrial cancer risk could be increased
• Maintain a low threshold to measure serum hormone levels initially and up to a year after pellet insertion

NAMS states, “Situations in which compounded bioidentical hormones could be considered included allergies to ingredients in a government approved formulation or dosages not available in government approved products.”

When it comes to benefits and risks of estradiol vs CEE, risk/safety is considered the same if given in comparable doses. When it comes to bioidentical progesterone vs progestins, please reread myth #1 in this series, as progesterone does appear to have a better safety profile in terms of breast cancer risk than a progestin.

There is some weak evidence that estradiol is slightly more effective for depression and anxiety in perimenopausal/menopausal women than conjugated equine estrogen. There is a small amount of evidence that oral estradiol has a lower hazard ratio for stroke than does conjugated equine estrogen.

Other than that, it is currently a stretch to make any factual statements that bioidentical estradiol, whether a compounded or FDA-approved product, is safe, and that CEE or synthetics are not safe. That said, I do think there is something to what we might call the metabolic footprint, and another, the environmental footprint. Might there be an as-of-yet unknown impact in other body systems from exogenous compounds compared to endogenous molecules? Perhaps even more worth pondering is the impact of what we excrete into our environment over decades and generations. We know the drugs humans consume, such as SSRIs, have been detected in our waterways. These molecules are foreign to fish and plant species as well as the animals that consume those fish and plants. What may be the long-term impact of this?

This is the final part of my Menopausal HRT blog series. Thanks for following along and learning more about the nuances of hormone replacement therapy. In the words of “NYPD Blue” (my favorite TV show while in medical school) during the morning shift patrol briefing to his fellow colleagues: “Let’s be careful out there.”

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