Natural, Bioidentical, Plant-Based...Oh My!

Decoding the marketing behind menopause hormone therapy

PytyCzech/Getty Images

A lot of terms get thrown around when it comes to menopause hormone therapy (MHT). The big three are natural, bioidentical, and plant-based, which are used to imply there are products or classes of hormones that are inherently safer. For example, here is the first Google hit when I searched for “natural bioidentical HRT.” I didn’t even have to prompt it to include plant-based!

Natural, bioidentical, and plant-based, are not medical terms, rather they are marketing terminology, and if you have even a passing interest in menopause or MHT, you will be exposed to them, so it’s good to know exactly what they mean and don’t mean.

(If you are interested in understanding why experts prefer the term menopause hormone therapy or hormone therapy over HRT, please see this post).

Regardless of what people specifically mean when they use natural, bioidentical, or plant-based, the words themselves have an inherent and potent, yet ill-defined positive value. This is why they are so valuable for marketers–one hears or reads them and fills in the “goodness” blanks for themselves. This is what allows those terms to mean everything and nothing, all at the same time.

Natural

Natural is an incredibly malleable term. For example, I could say, regarding menopause, that the most natural thing is not to take any medication at all. After all, it is natural for the ovaries to stop ovulating, and unnatural to take a chemical made in a lab.

Regarding the marketing of MHT, natural is usually used to imply the product is the same as made by the body, and hence safer than a synthetic hormone.

From a chemistry standpoint, a natural hormone is one found in nature, and can be extracted unchanged from a human, animal, or plant source. Think of removing salt from salt water; by boiling a pan of salt water, we can evaporate the water, leaving the salt behind. The salt was always there, and the salt that was removed from the water is unchanged. In contrast, a synthetic hormone is not found in nature.

A synthetic hormone is not some abomination or Frankenhormone; scientists create synthetic hormones in an attempt to improve a specific quality or reduce a side effect of a natural hormone. The best example is the class of hormones called progestins. These are chemicals that act like progesterone. The first hormones for clinical use and experimentation in the lab were extracted from human urine or animal ovaries, but this was expensive and cumbersome and the natural progesterone produced this way was absorbed poorly and so was ineffective. It was only in the 1940s when scientists created progestins, molecules that are similar to progesterone and can be absorbed when taken orally, that the first hormonal contraception could be invented. The ability to formulate progesterone so it could be absorbed orally wasn’t discovered until the 1970s.

It’s true that some synthetic hormones have proven to be dangerous. The most notorious example is diethylstilbestrol (DES), which a synthetic estrogen that was recommended during pregnancy to prevent miscarriages and preterm labor and sadly ended up causing birth defects for the fetuses (although the scientist who discovered it apparently vigorously opposed its use in pregnant women). It’s also true that naturally occurring estrogens have proven to be dangerous. Premarin, a naturally occurring estrogen, was initially prescribed to women for menopause without a progestin or progesterone for 20 or so years before we realized it caused endometrial cancer. Both of these sad episodes in our medical history occurred before the modern approval process for pharmaceuticals was created.

Tamoxifen, which is used to prevent and treat hormone-receptor-positive breast cancer, is a synthetic hormone.

The critical takeaway here is that naturally occurring does not equal safe or effective and synthetic does not mean unsafe; robust studies and regulations are what help ensure our medications are safe and effective. Remember, giving a medication as a pharmaceutical is not the same as it being released by the body, especially when it is being given in menopause after the production of estradiol has greatly decreased and the production of progesterone has stopped. Hence, why studies are needed.

Here is a chart of the common naturally occurring and synthetic hormones used in modern MHT (either systemic or bloodstream therapy and local vaginal therapy):

For a hormone that is taken as a medication to be natural, by definition, it must come from a natural source and be unchanged. This means that to obtain natural estradiol, the hormone would have to be extracted from the urine of pregnant women or from the ovaries of cows or pigs, and to obtain natural estriol, placentas would be required. And to get natural estetrol (an estrogen found in fetal livers) would require fetal livers. I am sure everyone is seeing the issues here. It requires gallons of urine from pregnant women or lots of cow and pig ovaries to get even small amounts of the hormone. This is actually why early hormone research was slow, because the cost of acquiring the raw hormone was astronomical. And of course, I don't need to explain the ethical issues with getting natural estetrol.

The only natural hormone available as a pharmaceutical for use in MHT is Premarin, which is removed unchanged from the urine of pregnant mares. Pregnant mares, it turns out, make buckets of urine, and it is rich with several naturally occurring estrogens which, when extracted, make the drug Premarin.

Bioidentical

This term appears to have been invented by a functional medicine doctor as a way to distinguish his compounded estrogen preparations from Premarin, which had a hold on the market in the 1980s and 1990s. The tag line was “Premarin is natural for horses,” and of course his compounded concoction of three estrogens (estradiol, estrone, and estriol) and progesterone used hormones that were “natural” for women. Not exactly sure how estriol, a hormone that is basically a placental estrogen (levels outside of pregnancy are barely detectable if they are detectable at all) is natural for a woman who isn’t pregnant.

Bioidentical is a flexible term. Some us it to refer to estradiol and progesterone, and some use it to refer to all the estrogens that can be made by the human body, others use it to describe compounded hormones, while there are people who use bioidentical for complex hormone protocols with pellets or other compounded hormones that are based on monitoring blood levels. When a term is made up, it can be used for anything. Take a look at this text I recently received for BHRT training–BHRT stands for bioidentical HRT, and the HRT is delivered as pellets.

The FDA does not recognize bioidentical as a term and discourages its use, which is why you don’t typically see it attached to advertising from pharmaceutical companies for estradiol or progesterone.

The chemical structure of estradiol is C₁₈H₂₄O₂, whether it is made in a human ovary, a cow ovary, or in a lab. There isn’t a way to make estradiol “bioidentical,” whatever that means; it’s just estradiol. And the same goes for progesterone. “Bioidentical estradiol” and “estradiol” are the same thing; it’s just that people are supposed the think that adding the adjective “bioidentical” somehow makes a hormone better or safer. It’s either estradiol or it isn’t. It’s either progesterone or it isn’t. Bioidentical estradiol is a bit like saying an equine horse as if it’s a distinct thing from a horse.

What about using bioidentical to distinguish estradiol or progesterone from other hormone therapies, such as Premarin or the progestins? The problem is bioidentical used this way doesn’t tell us about safety. By this definition estriol is also bioidentical, so does that mean it is safe and effective for MHT despite relatively few studies? No. Also, bioidentical doesn’t inform about the delivery method. Transdermal estradiol is the recommended starting estrogen for MHT not because it is the same estrogen as produced by the ovary, rather it’s recommended because it is delivered in transdermal form and a wealth of observational data suggests this is has the lowest risk for blood clots and is essentially neutral for lipids. We don’t know if oral estradiol, also bioidentical, is safer in any meaningful way from Premarin, and in fact it is Premarin, that is associated with a reduced risk of breast cancer. Progesterone is recommended as the starting progestogen (a group that includes progesterone and progestins), not because it is the same hormone produced by the body, but because observational studies have linked it with a lower risk of breast cancer than the progestins.

There are times when Premarin is the preferred estrogen; for example, if an appropriate dose of estradiol isn’t treating hot flashes adequately or for someone with an elevated risk of breast cancer. And there are times when a progestin is recommended over a progesterone, for example, someone who still needs contraception and wants to use a levonorgestrel IUD (progestin), or someone at high risk of endometrial cancer, as progestins are better at reducing that risk. And of course, there is a transdermal progestin, but not a transdermal progesterone, and some people prefer that route.

The idea that bioidentical hormones are somehow better is problematic because the term can be used for several different types of therapies or protocols, some which are not recommended (compounded hormones, pellets, and hormone therapy guided by hormone levels).

In addition, rejecting hormone therapies that aren’t structurally the same as what the body makes denies women access to other important therapies that may be safer for them.

Bioidentical is also misleading, because it’s only transdermal estradiol that is believed to be the relatively safer therapy, not oral estradiol. And of course, we have very little data on using either oral or transdermal estriol and estrone for MHT. Oral estetrol is an active area of study, but we still know less than we do about estradiol.

The best therapy is the best one for the individual that has been studied and has robust data, and using a word that scares women away from other therapies or falsely implies safety is, in my opinion, bad medicine and patriarchal.

Plant-Based

I’m going to rock your world right now and tell you that EVERY hormone in MHT, except Premarin and bazedoxifene, is plant-based.

No, really!

Plant-based is a marketing euphemism for the process of semi-synthesis, which is how most hormones are produced. Semi-synthesis means the starting chemical is found in nature, but it is then modified in a lab to create a different chemical. Hormones can also be made by synthesis, which means the starting chemical is not found in nature. Whether estradiol is made by the ovary, by semi-synthesis, or by synthesis, the end hormone has the same chemical structure.

If it’s estradiol, it looks like this:

Natural estradiol, using the chemical definition, would mean the hormone would have to come from a human or an animal and that is prohibitively expensive and a logistical nightmare. Making hormones by synthesis is still too costly to produce at scale, so the only viable option for making estradiol, progesterone, and testosterone is semi-synthesis. This is also how the progestins and ethinyl estradiol, synthetic hormones, are made.

In the 1940s, the chemist Dr. Russell Marker discovered a class of compounds in certain plants called sapogenins, and structurally they share some similarities with hormones. The first one that proved useful was found in yams and is called diosgenin. The initial process for converting diosgenin into a hormone is known as the Marker Degradation. It is a multi-step process involving chemicals such as acetic anhydride heated to 200°C, chromic acid, and sodium hydroxide (lye)…NOT a mortar and pestle, and the body most certainly can’t convert these plant chemicals into hormones.

Today, most hormones are made from diosgenin or stigmasterol extracted from soybeans grown in China. Pharmaceutical estradiol and progesterone are about as plant-based as petroleum or coal. Look, when words don’t really have a meaning, they can mean anything!

The first sex steroid that was used pharmaceutically was norethisterone, a progestin (a synthetic hormone that acts like progesterone). It was used in the first birth control pill that was developed in the 1950s. Progestins are made from testosterone, so testosterone is produced by semi-synthesis and then further chemically modified to create a progestin.

And there is one final twist to the story. Carbon atoms have two naturally occurring isotopes: 12C and 13C (12C has six neutrons and 13C has seven neutrons). Humans make estradiol (and other estrogens), progesterone, and testosterone from carbon atoms that come from a variety of plant and animal sources. These hormones made by the body have varying 12C/13C ratios that reflect the diverse sources of carbon in the diet. Hormones made in a lab by semi-synthesis all have one carbon source, soybeans, and so the 12C/13C ratio is fixed. This doesn't matter as far as the body is concerned, but if you are a chemistry nerd, the term bioidentical likely also irks you because it’s inaccurate.

Natural, Bioidentical, Plant-Based…Oh My

Since the terms natural, bioidentical, and plant-based lack clear definitions and are often used to falsely imply safety, it’s best to avoid the term or marketeers that use them. However, given they are everywhere, I realize this may not be practical, and this chart is my codex or way of categorizing natural, bioidentical, and plant-based hormones using the best scientific terms (although when words are malleable, science-ish is probably better):

It’s important to point out that estrone and estriol have really only been studied for vaginal use. And as estriol is made by the placenta and estetrol by the fetal liver, it’s pretty hard to see how the concept of “bioidentical” is of any relevance to an individual in menopause who is not pregnant.

Bioidentical estradiol and estradiol are two terms that mean exactly the same thing.

And the reality is that plant-based simply means soybeans grown in China that are then subjected to a multistep chemical process. However, I know the people who market their “special” hormones as plant-based would have you believe that their formulation begins with plants cultivated in unique microclimates that maximize phytonutrient potency. That harvesting is performed during the narrow circadian window when enzymatic activity peaks, ensuring optimal molecular integrity. And that they use a proprietary extraction process — calibrated to preserve the sapogenin structures and capture the plants’ full spectrum of bioactive constituents. The result is a highly concentrated, clinically inspired blend designed to support the body’s innate cellular resilience and promote balanced hormonal harmony. The reality is if someone is selling estradiol or progesterone, be it marketed with the terms bioidentical and/or plant-based, they got the raw hormone from the exactly the same places as Big Pharma.

Natural hormones (Premarin), pharmaceutical versions of naturally occurring hormones (one definition of bioidentical), and synthetic hormones all have their place, so beware of the marketing. At the end of the day, “natural,” “bioidentical,” and “plant-based” sound comforting — but they’re just marketing terms, not medical ones. The safest hormone therapy is the one where you have worked with your physician to find the studied, regulated and tested formulation that works for you, not the one with a fanciful origin story.

References

Pinkerton JV, Constantine GD. Compounded non-FDA-approved menopausal hormone therapy prescriptions have increased: results of a pharmacy survey. Menopause. 2016 Apr;23(4):359-67. doi: 10.1097/GME.0000000000000567. PMID: 26645819; PMCID: PMC4819678.

Seeman JI. Russell Earl Marker and the Beginning of the Steroidal Pharmaceutical Industry. Chem Rec. 2023 Apr;23(4):e202300048. doi: 10.1002/tcr.202300048. Epub 2023 Mar 30. PMID: 36995067.

Bhavnani BR, Stanczyk FZ. Misconception and concerns about bioidentical hormones used for custom-compounded hormone therapy. J Clin Endocrinol Metab. 2012 Mar;97(3):756-9. doi: 10.1210/jc.2011-2492. Epub 2011 Dec 28. PMID: 22205711.

Regine Sitruk-Ware. Pharmacological profile of progestins. Maturitas 2004; 47:277-283. ISSN 0378-5122.

Strauss JF, Barbieri RL (13 September 2013). Yen and Jaffe's Reproductive Endocrinology. Elsevier Health Sciences. pp. 256–. ISBN 978-1-4557-2758-2.