Not All Menopausal Hormone Therapy is the Same (Part 3)

Defining Bioidentical and Explaining FDA Approval

Note: This post is US-centric. The regulations around menopausal hormone therapy differ by country and regulatory body.

What does bioidentical mean? 

Bioidentical refers to the molecular structure of the active ingredient of a product. A product is said to be bioidentical when the molecular structure of the active ingredient is exactly the same as the hormone your body produces. This link shows the structure of bioidentical progesterone and a synthetic progesterone (a progestin).

So, is bioidentical more natural?

No. “Natural” is a term that has long been associated with bioidentical products, but it is a misperception. Some bioidentical estrogen products are derived from wild yams. However, those yams are altered in a lab through a chemical process to create the final product. This is true for yam-derived bioidentical FDA-approved products and bioidentical compounded products alike.

Are bioidentical products safer? 

Not necessarily. While there is something logically appealing and mentally comforting about products that are more similar to what our body makes, in the case of estrogen there are no studies demonstrating that the bioidentical form of estrogen (i.e., 17-beta-estradiol) is safer or more effective than other estrogen-like products such as Premarin® (CEE). As Dr. Marcie Richardson, The Director of the Menopause Consultation Service at Atrius Heath, put it: “While there is an appealing, seemingly intuitive logic that a bioidentical molecule, more similar to the ones our bodies produce would be safer, there haven’t yet been studies that support this idea for estrogens.” Dr. Nanette Santoro, Chair of Obstetrics and Gynecology at the University of Colorado and a leading researcher on midlife women’s health underscored this point: “Based on the research that has been done to date, an estrogen is an estrogen is an estrogen, bioidentical or not.” The estrogen receptor is stimulated by all estrogens and that is how estrogen effects play out in the body.

Progesterone may be a different story. In 1995, a randomized-controlled trial compared different estrogen and progestogen (products that have progesterone-like effects) combinations on markers of cardiovascular health in 875 postmenopausal women. The trial demonstrated that bioidentical progesterone (Progesterone USP) had a more favorable impact on cholesterol and was better tolerated than Provera® (medroxyprogesterone acetate) — a synthetic (i.e., non-bioidentical) form.

In terms of comparing safety, there has not yet been a randomized trial that demonstrates that bioidentical progesterone is safer than progestins (synthetic, non-bioidentical). However, recent reviews of observational studies have raised the question of whether bioidentical progesterone is safer with respect to breast cancer risk than progestins like Provera (medroxyprogesterone acetate).^1,2

For those reading closely, you’ll note the use of three very similar words: progesterone, progestogen and progestins. Briefly, progesterone is the hormone your body produces, and progestogen is used to describe all products that have progesterone-like effects, including progestins. More on that here.

1. Asi N, Mohammed K, Haydour Q, et al. Progesterone vs. synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis. Syst Rev. 2016;5(1):121. Published 2016 Jul 26. doi:10.1186/s13643-016-0294-5

2. Stute P, Wildt L, Neulen J. The impact of micronized progesterone on breast cancer risk: a systematic review. Climacteric. 2018;21(2):111-122. doi:10.1080/13697137.2017.1421925

So then, what is the difference between an FDA-approved bioidentical hormone therapy product vs. a compounded bioidentical hormone therapy product?

There are two dimensions on which an FDA-approved product and a compounded product differ. One has to do with proof of safety and effectiveness and the other has to do with the manufacturing process.

1. Proof of safety and effectiveness

In order to become FDA-approved, there are several hurdles a potential therapy/product has to clear to prove its safety and effectiveness. Depending on the type of pharmacy (503A or 503B) that produced them, the compounded products are or are not subject to these same hurdles.

1. Recommendations by The Board on Health Sciences Policy within the National Academies of Sciences, Engineering, and Medicine, 1. p.53-54. Download available here.

2. The manufacturing process

FDA-approved products are made in batches according to a specified manufacturing process. This ensures the product is made exactly the same way with the same proportion of ingredients every time.

Here is way more detail than you need (don’t bother reading), but a quick glance at the following paragraph will convey how much is specified about the way  an FDA-approved product is made:

A list of all components used in the manufacture of the drug product (regardless of whether they appear in the drug product) and a statement of the composition of the drug product; the specifications for each component; the name and address of each manufacturer of the drug product; a description of the manufacturing and packaging procedures and in-process controls for the drug product; the specifications necessary to ensure the identity, strength, quality, purity, potency, and bioavailability of the drug product, including, for example, tests, analytical procedures, and acceptance criteria relating to sterility, dissolution rate, container closure systems; and stability data with proposed expiration dating. ¹

In contrast, most compounded products, those that are made by 503A pharmacies, are designed to be “one-offs” meaning that they are made to a specific prescription for a specific patient. A compounding pharmacist takes the active ingredient as specified by the prescription and mixes it with inactive ingredients. The precision of the process relies on the skill and expertise of that pharmacist. The products made by a 503B pharmacy are made in batches, but not by an FDA-approved process with required, manufacturing specifications as listed above.

1 .21 CFR § 314.50 – Content and format of an NDA, Legal Information Institute, Cornell Law School.

What are the other differences between a 503A and a 503B pharmacy?

503A pharmacies are smaller organizations that can only create a product when they have a specific prescription for a specific patient. 503B pharmacies can both create a product for a specific prescription and can also create large amounts of common prescriptions and store them for later sale. The 503B organizations, often called “outsourcing facilities,” are also permitted to sell across state lines, 503As are not. To become a 503B, a pharmacy voluntarily registers annually with the FDA and undergoes inspections on a risk-based schedule, and must report adverse events (see table above). 503A organizations are subject to the regulation of their own state’s boards of pharmacy and those regulations vary from state to state. As of February 2020, only 73 pharmacies in the US were registered as 503Bs. ¹ This link lists each 503B organization when their last inspection was and whether they’ve been issued any warnings.

1. Recommendations by The Board on Health Sciences Policy within the National Academies of Sciences, Engineering, and Medicine 3. p. 57 (download is available here.)

So, are products from 503B pharmacies FDA-approved?

No, and this is an important but subtle distinction. When a pharmacy registers as a 503B organization, the FDA inspects the facility. This allows 503B organizations to make batches of products and sell them beyond state lines. Some sellers then use the phrase “made in an FDA-approved facility” and this is a true statement. However, products from a 503B pharmacy have not undergone the rigorous testing required to become an FDA-approved product (refer to the table above). These products lack testing for safety and effectiveness, an understanding of how long the active ingredients stay in your body, they don’t have the same labeling requirements and they are not required to include black box warnings about cancer-causing ingredients.

As you look back at the differences in the table above, you’ll see that there are considerably fewer safety assurances with a compounded product — from either type of organization — than with an FDA-approved one.

What are the third-party certifications that some compounding pharmacies mention on their websites? 

Within the compounding industry, there are two third-party certifications a pharmacy can get to demonstrate compliance with a set of safety protocols and standards. They are called The Pharmacy Compounding Accreditation Board (PCAB) and The Joint Commission Medication Compounding Certification (MCC). Most pharmacies list these accreditations if they have them.

How can I tell if a hormone therapy product is bioidentical?

The generic name of bioidentical estrogen is “17-beta-estradiol.” The generic name of bioidentical progesterone is “progesterone USP”. You should find these listed on the label. You can see all of the available hormone therapy products (bioidentical and non-bioidentical) and their brand names here: hormone therapy chart. Note: Often you have to pay out-of-pocket for compounded products whereas FDA-approved products may be covered by insurance.

How can I tell if a bioidentical hormone therapy product is FDA-approved?

You can get an FDA-approved product only by prescription from your healthcare provider. Products that are sold in health food stores, on Amazon, or other online retailers are not FDA-approved. If you are getting a prescription from your healthcare provider and are unsure if it is FDA-approved, ask! There are several FDA-approved bioidentical products available, and they come in many forms: oral (pills, tablets), creams, sprays, patches and gels.

Remember, your healthcare provider may recommend a compounded product when FDA-approved products are not available in a required dose or if you are allergic to one of the ingredients in a product.

So, are compounded products dangerous?

It’s not compounding in and of itself that presents risk, rather the risk is in the lack of regulation and therefore the lack of assurance you get that a compounded product has certain, safe ratios of ingredients and that it’s made in a sterile process without contaminants.

Here are the risks with compounded HT products:

• Exact ingredient ratios: It’s important that you are getting enough progestogen (either progesterone or a progestin) with your estrogen to protect your uterus from cancerous overgrowth. Therefore, your assurance that there is a precise combination of ingredients is important.
• All ingredients FDA-approved: Some frequently prescribed compounded products have ingredients that have not been FDA-approved as safe.
• Sterile products: While they were not products for hormone therapy, and injectables are in a different class from creams and gels, many concerned with the safety of compounding in general, point to the contaminated steroid injections of Methylprednisolone Acetate made at the New England Compounding Center in 2012.¹ 

1. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/press-releases/january-31-2018-new-england-compounding-center-pharmacist-sentenced-role-nationwide-fungal

There are compounding pharmacies and pharmacists that follow their own and industry-established guidelines to ensure the safety of their products. However, as a consumer without the assurance of FDA approval and a regulated manufacturing process and with products that contain multiple ingredients, it’s really hard to know what is safe. For this reason, we wanted to share these latest findings from the expert committee.

Ok, if you are still with us, here are those takeaway bullet points you deserve!

1. Compounded hormone therapy should be used in only two situations: when a patient is allergic to one of the ingredients in a product or when a required dose is not available in an FDA-approved product.
2. A July 2020 report, extensively researched by a NASEM independent committee, concluded there is not sufficient evidence for the safety and effectiveness of compounded bioidentical hormone therapy (cBHT) to warrant its use, except in the two situations mentioned above) and in light of two factors:
3. There are FDA-approved forms of bioidentical hormones (estrogen and progesterone) that have been extensively studied for safety and efficacy.
4. There is little research about the safety and effectiveness of compounded bioidentical hormone therapy (cBHT). More is needed.

Keep in mind that most drugs we take have some risk with their associated potential benefit. Discussing the benefits and your unique risks with a healthcare provider before starting a new therapy is important. We hope this article provides the information you need to have a more informed conversation about menopausal hormone therapy.

Still have questions? Submit them here:

Acknowledgments, gratitude, and disclosures

We are grateful to Marcie Richardson, MD, Nancy Woods Ph.D., Nanette Santoro MD and Nancy Reame Ph.D. for their input, feedback and review of this article.

Disclosure: Nancy Reame, one of our advisors, was a member of the NASEM committee that developed the July 2020 report.

In case you missed them:

Part I: Hormone Therapy Overview, Defining Compounding and New Information from an Expert Committee

Part II: The Women’s Health Initiative and its Impact on Hormone Therapy Usage