Are Bioidentical Hormones Safe?

 

In my last post, Why You Shouldn’t Care About Estrogen Dominance, I leaned heavily on an old friend who is a respected Obstetrician/Gynecologist.  She sees many more women for hormone replacement therapy (HRT) than I do as an Endocrinologist, and she explained that many of her patients come in requesting something “natural.”  She always asks them, “What does that mean to you?”  Invariably, there is a pregnant pause, followed by some awkward stammering, ending with the patient usually admitting that she just wants something “safe.”  That desire then forms the basis for further discussion with my friend, as both patient and doctor can agree that whatever treatment is instituted should be safe.

Of course, this begs the question: are compounded, bioidentical HRT regimens safe or risky?  Furthermore, are they any safer or riskier than manufactured, FDA-approved regimens?  In order to answer these questions, we need to do explore the nearly $1.6 billion/year bioidentical HRT industry.

Why Women Seek Out Bioidentical HRT

I always like to start with the “why” of a problem; if you don’t understand the “why,” you’ll flounder when it comes to figuring out how to deal with it.  While I’m not sure I needed a study to understand why women seek out bioidentical hormones, I found a very good one that describes what I’ve observed in practice over the years.

In their paper, Why women choose compounded bioidentical hormone therapy: lessons from a qualitative study of menopausal decision-making, Jennifer Jo Thompson et al found that women’s motivations could be boiled down to two overarching themes: “push” motivations that pushed them away from conventional HRT and herbals, and “pull” motivations that attracted women to compounded, bioidentical HRT (CBHT):

Push motivations focused on (1) fear and uncertainty about the safety of conventional HT, (2) an aversion to conjugated estrogens [HD: Premarin, made from mare’s urine] in particular, and (3) and overarching distrust of a medical system perceived as dismissive of their concerns and overly reliant on pharmaceuticals. Participants also voiced dissatisfaction with the effectiveness of herbal and soy supplements. Participants were attracted to CBHT because they perceive it to be (1) effective in managing menopausal symptoms, (2) safer than conventional HT, (3) tailored to their individual bodies and needs, and (4) accompanied by enhanced clinical care and attention.

If you’re a doctor reading this, I’m sure that the quote above jives with everything patients have told you over the years.  If you’re a woman researching HRT, perhaps one or more of the above statements describes your beliefs about HRT.  Either way, the article is worth a look.  It does a stellar job of helping the reader empathize and truly understand why women pursue CBHT.  I especially like the authors’ use of direct quotations from study participants, as they illustrate just how visceral women’s reactions can be to the issue of hormone therapy.  And, as I discussed in Top 10 Reasons Why Smart People Are Stupid About Their Health, people often make poor decisions when those choices are based on visceral reactions.

The rest of this piece will focus on women’s fear about the safety of conventional HT and their perception that CBHT is safer.  The next post in this HRT series will address the other push and pull motivations described by Thompson et al.

Let’s Talk About Safety

By now, you’ve all heard of the Women’s Health Initiative (WHI) clinical trials, which were discontinued in 2002 and 2004, citing risks (cardiovascular and breast cancer) that outweighed the preventive benefits (reduced fractures and colon cancers) of HRT.  What you may not know is that the risk estimates have been walked back over the last 16 years, as the WHI data has been parsed with greater nuance.  For example, in 50-60 year-old women taking combination estrogen-progestin therapy, the estimated additional risk of breast cancer is 3 cases per 1000 women on five years of therapy.  That is a very small absolute risk.  Further, in those 50-60 year-old women taking estrogen alone, it is estimated that there will be 2.5 fewer cases of breast cancer per 1000 women on treatment for five years.  Of course, headlines proclaiming “HRT is not as Bad as We Thought” are not nearly as sexy as “HRT Will Give You Cancer,” so the followup evaluation of WHI data is better publicized in medical journals than in the lay press.

To the detriment of clarity, the type of HRT used in WHI is no longer in common use.  In WHI, the synthetic progestin MPA was associated with excess breast cancer risk (as above).  Nowadays, we mostly recommend natural micronized progesterone instead, as there is limited observational data suggesting that it may not be associated with increased risk.  Regarding estrogen, we don’t use conjugated estrogens as much as we use estradiol; but, it is not known if the current formulations of estradiol carry less risk than conjugated estrogens.  Nor is it known whether lower doses of estradiol would be associated with less risk, when estradiol is used for longer periods of time (observational studies suggest increased risk when estrogen is used for > 10 years).

If you’d like to read about all the risks of HRT found in WHI, please do so at the Women’s Health Initiative site.  Be careful about differentiating between relative risk and absolute risk, as the relative risk numbers are the ones that initially sounded so scary, becoming less scary as we realized that the absolute risks were low.  Also note that the numbers you find there differ from some of the numbers I quoted above, as the numbers above are from independent, third party interpretations of the data.

The million-dollar question, however, is: are compounded, bioidentical hormones any safer than FDA-approved versions of estradiol and natural micronized progesterone?  First, let’s get one thing straight: most of the FDA-approved versions of estradiol and progesterone prescribed by conventional doctors are bioidentical.

Wait…what?

For the moment, let’s disregard the fact that the term “bioidentical” is a pseudoscientific neologism, promulgated by Alternative Medicine and compounding pharmacies in an effort to differentiate their product – a product that typically isn’t paid for by insurance, costing you more money out-of-pocket than an FDA-approved version of HRT.  Tabling all that…pharmacologic grade estradiol pills/patches/sprays/gels/etc and micronized progesterone have chemical structures identical to endogenous (internal) hormones.  By definition, they are bioidentical.  Not only that, these modern, FDA-approved, bioidentical hormones are derived from soy and plants – just like the hormones used in CBHT.  You know what that means, right?  FDA-approved HRT is bioidentical and natural.

So…if FDA-approved, standardized, bioidentical formulations exist, why does my Alternative Medicine practitioner recommend CBHT?  It must be safer, more effective, or both!

Today, we’re focusing on safety, so let’s stick to that issue.  If a compounded bioidentical product and an FDA-approved bioidentical product have the same doses of estradiol and micronized progesterone, then the risk would be identical.  It’s the same stuff, after all.  There is nothing magical or inherently safer about the hormones used by the compounding pharmacy.  But you would never know that, because compounded products are not required to carry the same warning labels as FDA-approved formulations.  Let me make this crystal clear: CBHT does not lack a warning label because it’s safer than HRT; it lacks a warning label because it isn’t forced by law to have one.

CBHT Has Poor Quality Control

Disturbingly, when independent labs have broken down and analyzed CBHT products, they have shown that the actual amounts of hormones can be anywhere from 60-270% of the prescribed dosage.  Let’s temporarily ignore the fact that these medications would never meet the FDA standard of being within 90-110% of the prescribed dose.  One of your biggest concerns should be that, when progesterone is under-dosed, you may be at higher risk of uterine cancer.  That’s because estradiol causes a buildup of the uterine lining that can lead to cancer – unless adequate progesterone is given to suppress the estradiol effect.  As long as you get enough progesterone, there should be minimal to no increased risk.

So, even if your prescriber tries to keep other health risks lower by writing for low doses of compounded estradiol and progesterone, you could still receive a medication with too little progesterone to protect against uterine cancer.  Or a medication with 2.5 times the desired amount of estradiol, thereby raising the risk of uterine cancer as well as several other undesirable endpoints.

Why would anyone want to take that chance, when there is a natural, bioidentical, consistent, FDA-approved product that is cheaper than the CBHT?

CBHT Uses Multiple Hormones of Uncertain Safety

Not only do CBHT medications fail to meet FDA standards for dosing consistency, they often combine multiple hormones: estradiol, estrone, estriol, dehydroepiandrosterone (DHEA), testosterone,  and progesterone.  These ingredients either have not been studied sufficiently to define risk, or they have been found to have risks, period.  But proponents of CBHT tout these products as clearly safer than conventional HRT.

Consider the case of estriol, a weak estrogen that is mainly produced by the placenta.  Compounding pharmacies seem to love estriol.  After all, what could possibly be more natural for a postmenopausal woman than jacking up her estriol to a level seen only in pregnancy?  Um, I can think of several things, but let’s table that for a second.  Estriol, despite being a weak estrogen, still appears to increase the risk of breast cancer and still increases the risk of uterine cancer.  Does that sound safer to you?

So why does CBHT often include multiple forms of estrogen?  Well, it is well known that the three circulating estrogens in premenopausal women have different biologic potencies.  Estradiol (E2) > Estrone (E1) > Estriol (E3).  In the presence of E2, E1 and E3 function as competitive inhibitors because they all bind to the same estrogen receptor.  Custom-compounding advocates interpret this to mean that E2 needs to be “balanced” by adding E1 and E3.  This is why Biest has E2 + E3 in a 20/80 ratio, and Triest has E1 + E2 + E3 in a 10/10/80 split.  Is there any medical evidence to support the notion that E2 must be antagonized by E1 and/or E3 in order to relieve menopausal symptoms or prevent any disease?  No.  Is there any evidence that these products are safer than FDA-approved estradiol/progesterone?  No.

Does it All Come Down to Dose and Route?

If we apply some common sense, we can surmise that lower doses of hormones may be associated with less risk.  But what do we use as a yardstick when talking about CBHT?  In other words, “lower than what?”  The compounded creams, pellets, subdermal implants, and other non-FDA-approved vehicles have doses of hormones that cannot be directly compared to the doses of pills studied in WHI and other clinical trials.  We also know that the consistency, absorption, and pharmacokinetics of these compounded medications are going to be variable and unpredictable.  Further, there is no testing that can correlate a specific hormone level with a degree of risk (more about those worthless salivary tests in the next post of this HRT series).  Bottom line: you can hope that your CBHT dose is high enough to relieve your symptoms, but low enough to not increase your risk beyond the risk of FDA-approved HRT.  But in my opinion, hope is not a strategy.  A strategy would be to use a standardized preparation of known risk, at the lowest dose that relieves symptoms.  Given that we don’t use conjugated estrogens and MPA much anymore, the closest you can get to a regimen of “known risk” would be estradiol and natural micronized progesterone.

Regarding the route of administration, it is true that avoiding the oral route for estradiol replacement is desirable for many women.  Transdermal and other non-oral therapy appears to have a lower risk of blood clots, stroke, and high triglycerides, when compared to oral therapy.  Fortunately, we have access to FDA-approved, bioidentical estradiol patches, which are applied either once weekly or twice weekly, depending on the manufacturer.  Because E2 levels remain fairly stable on the patch, symptoms tend to be well-controlled.

As for progesterone, we have FDA-approved formulations that can be given orally, vaginally, via IUD, or via a combination patch.  There appears to be no sensible rationale for using compounded progesterone creams or gels with uncertain pharmacokinetics, because the risk of underdosing is uterine cancer – not an acceptable risk in my opinion.

Compounding Pharmacies Have Inadequate Oversight

In 2016, The Endocrine Society published an excellent Scientific Statement about compounded bioidentical hormones.  Some of the information in this post is sourced from that publication.  I don’t think I could say any better what they said about the big-picture problems with compounding pharmacies, so I will quote it here:

Historically, the pharmaceutical practice of compounding has fallen into a “gray” area between state and federal oversight. The bulk of oversight regarding compounding pharmacies (recordkeeping, certification, and licensing) falls to state pharmacy boards, whereas the FDA only inspects compounding pharmacies when there is a complaint (14). Compounding pharmacies do not have to register with the FDA as drug manufacturers and do not have to report adverse events. As a result of this regulatory laxity, compounding pharmacies are not held to the same rigors as manufacturers of FDA-approved substances. As such, they traditionally make indirect claims of safety that are not evidence based. There have been a series of attempts by different organizations and societies, including The Endocrine Society (15), to point out examples of inappropriate compounding practices. The FDA has provided consumer information and even issued warnings on occasion (1617). Concerns about the safety of compounded hormones reached a climax in 2010, when 750 cases of fungal meningitis, including 64 deaths, were attributed to corticosteroid preparations from a New England compounding pharmacy (18).

 

As of January 2014, the Pharmacy Compounding Accreditation Board, which requires compliance with strict quality regulations and periodic renewal (19), only accredited a small minority of the 7500 compounding pharmacies in the United States…

 

…compounding pharmacists prepare, assemble, and package custom-compounded bioidentical hormone products as gels, creams, lotions, sublingual tablets, subdermal implants (pellets), suppositories, and troches according to a provider’s prescription. The contents, concentration, quality, and sterility are not subject to regulatory oversight. There are no large, long-term, randomized, double-blind, placebo-controlled studies that have determined the effectiveness, safety, or adverse effects of custom-compounded bioidentical hormones (20).

 

Custom-compounded hormone products are not legally required to include the “black box” warnings that all FDA-approved estrogens provide, such as increased risks of myocardial infarction (MI), stroke, invasive breast cancer, pulmonary embolism, and deep vein thrombosis in postmenopausal women (20). That does not mean that such risks are not present. Overdosing or underdosing is a chronic concern, because little is known about the pharmacokinetics of these products, leading to variable exposure to estrogen or progestin and either a lack of efficacy from underdosing or risk of harm from overdosing.

Summary

You have a choice.  You can use hormone replacement therapy that is natural, bioidentical, of known and consistent potency, with well-studied pharmacokinetics, at the lowest dose that resolves your symptoms to mitigate risk.  Or, you can use hormone replacement therapy that is synthesized by someone in the back room of an unregulated compounding pharmacy, of unknown and inconsistent potency, with unknown pharmacokinetics, at a dose that may or may not confer excess risk.  I implore you to make a sensible choice.

 

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Image Credit: Photo by Christin Hume on Unsplash

7 Replies to “Are Bioidentical Hormones Safe?”

  1. Excellent!

    During my years as an OBG, I heard the same statements from patients repetitively. Sadly, most were not interested in factual summaries, but rather most wanted emotionally comforting responses.

    “Don’t confuse me with facts, my mind is made up”.

    1. Yes, that’s why I found Thompson’s paper so interesting. She and her colleagues do an excellent job describing how women view the choices involved in HRT – using the women’s own words. They also describe how the significant time spent by prescribers of CBHT and compounding pharmacists seems to lead to greatly enhanced trust and satisfaction with therapy. Makes me wonder: if we had that much time, would patients trust “conventional medicine” more?

  2. Wow, what a wonderful and appreciated post. If I was a doctor I’d want to have this ready to hand out to patients. If, after that, they still opt for CBHT then that’s their decision. “Religious” debates can’t be won. As a doctor you’ve done your level best to inform and prescribe the best treatments in your arsenal.

  3. Thanks for wading in on this. I don’t share your trust in government regulation, as it’s not capable of eliminating human fallibility. Still, lack of consistency of dosage could be a big problem if we’re trying to do right by our bodies and it may be that, today, there is more quality assurance with FDA-approved HRT. So at the very least we’d need to look into the quality assurance practices of our compounding pharmacy.

    Three questions: (1) What is the latest evidence you have that progesterone is required to prevent uterine cancer? Are the studies based on the estradiol used today? (2) If progesterone is required, are you saying it’s estrogen-dose dependent? (3) Why is the only goal to alleviate symptoms vs. try to optimize dosage of estrogen for, e.g., disease-prevention purposes? Is that simply because we don’t really know the risks of taking substantial doses of estrogen for long periods of time? How do you deal with the risks of taking estrogen, indefinitely, for your transgender patients?

    Thanks again!

    1. So at the very least we’d need to look into the quality assurance practices of our compounding pharmacy.

      I suspect that every compounding pharmacy will tell you that they double- and triple-check their work. Good luck figuring out who’s telling the truth. To your questions:

      1. With any significant amount of any type of estrogen exposure (though I cannot quote you a dose threshold for “significant”), the uterine lining will hypertrophy without concomitant progesterone therapy. Basically, if there is enough estrogen of any type in the bloodstream to alleviate menopausal symptoms, one should assume there is enough to stimulate endometrial hypertrophy.

      2. No. The doses of progesterone available are fairly standard, and are not graded depending on how much estrogen one uses.

      3. There is not enough evidence that a certain dose of estrogen is optimal to prevent osteoporosis, colon cancer, etc. In fact, there is evidence from WHI that estrogen therapy is not good enough at preventing disease to recommend it as a therapy for such. Therefore, its only indication nowadays is for relief of symptoms, because the balance of evidence suggests there are other, better ways to prevent/treat disease (bisphosphonates for osteoporosis, for example).

      As for MTF transgender care, I have a risk/benefit discussion with everyone before starting therapy. But, since the hands-down best way to treat gender incongruence is with cross-hormone therapy, the risks are usually acceptable to the person. They need to be screened for breast cancer, like all women, but again – they are usually willing to accept any risk to become who they were meant to be.

  4. Great article!

    Can you please do one about testosterone treatment in men who have normal serum testosterone but have self-diagnosed with “low T”?

    Where I practice, there are many self-proclaimed “hormone experts” and “anti-aging” experts who will prescribe testosterone to anyone with a penis and a pulse, regardless of lab results. Often these are done via phone consultation. I have a hard time convincing my patients of how dangerous this is, because they feel better on the injections (that is, until they stroke out or have an MI, which has happened to 2 of my patients).

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