There is an interesting new paper in the British Medical Journal looking at the long-term use of menopause hormone therapy (MHT).

The study, Menopausal hormone therapy and long-term mortality: nationwide, register-based cohort study, is from Denmark, where they have robust registries they can mine and produce far better observational studies than we can in America. In addition, as they have universal healthcare, the observational studies don’t have the wild differences in access to care based on socioeconomic status that we see in the United States. Another aspect of care in Denmark that makes this research especially compelling is that all prescriptions are logged in a central registry. The researchers leveraged all of these resources to look at the long-term safety of (MHT) regarding mortality.

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The study population was women born between 1950 and 1977 who were alive at age 45. If they took MHT, they were divided into groups based on the age when the hormones were started: 45-51, 52-56, ≥ 57 years. Women at higher risk of complications from MHT were excluded, such as those with a previous blood clot, breast cancer, or liver disease. The researchers were able to control for a number of variables that affect health outcomes, such as diabetes, heart disease, and recently being hospitalized. Other factors that were considered included marital status, number of deliveries, education level, income, and country of birth.

A unique aspect of this study is that in addition to using women who did not take MHT as controls, they also included siblings who did not take MHT as controls. As environmental factors have a major impact on health, being able to compare outcomes between those women who took MHT and those who did not, who may have shared a similar environment for many developmental years, adds to the strength of the study.

Mortality was chosen as the primary outcome. Obviously, risks and benefits may vary for a given individual, but at the population level, mortality is a good way to ask, “Is this therapy net positive, negative, or neutral?”

Over 800,000 women were included, and the average follow-up was 14.3 years. Just over 100,000 women filled at least one MHT prescription, more than 15,000 took MHT for 5-10 years, and over 7,000 women had 10 or more years of MHT use. This really shows the power of well managed databases, because these numbers are just not achievable in a clinical trial. Oral estradiol and norethisterone acetate was the most common therapy, accounting for 32.3% of prescriptions.

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With 12 million person-years of follow-up, the investigators found no “epidemiological evidence of excess mortality following menopausal hormone therapy use.” Meaning that overall, MHT was a net neutral for mortality. This includes use for 10 or more years. This is good news. Looking at some specific causes of death, MHT was also net neutral with respect to mortality from cardiovascular disease and cancer. This is all very reassuring. When people have symptoms, this study suggests that women at low risk for complications can take MHT for over ten years with no net negative. This study also suggests that there is no net positive with MHT when it comes to overall mortality, and so women who don’t take MHT are not missing out on a longevity benefit.

There was a trend towards a lower mortality for three groups: women using transdermal menopausal hormone therapy, women who used estrogen alone, and those starting MHT aged 52 years or older. However, the investigators stated we should exercise caution in over-interpreting these findings. We should take them at their word.

One group emerged who did have a benefit from hormone therapy: women who had their ovaries removed between ages 45-54. Menopausal hormone therapy was associated with a 27-34% decrease in mortality. Among the women who died during the follow-up period, the women who took MHT lived about 4 years longer on average than those women who had their ovaries removed and did not take hormones. This is not an unexpected finding, and so it supports the accuracy of the data mining used in the study.

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As this is all observational data, we cannot be definitive about the findings. However, the no benefit for mortality for the otherwise healthy women aligns with other data, as does the benefits of MHT for women who had their ovaries removed. Specifically regarding the women who had their ovaries removed and who took MHT, it is possible they were healthier to begin with in a way that the study couldn’t capture, or taking hormones may change behavior, meaning women who start MHT after they have their ovaries removed may be more likely to change their diet and exercise.

Regarding MHT after removing the ovaries, it is unlikely we will ever see a clinical trial, and ethically it is probably not even possible, and so observational data like this is likely the best we can do. The findings of this study suggest that we may need to take a closer look at the guidelines for hormone therapy after the ovaries are removed. The current recommendation is to take MHT until age 51 and then reconsider use based on symptoms and risk factors, but this study suggests that we may want to raise that age to 54.

Here is the visual abstract from the paper, which provides a nive summary. It’s one of the better visual abstracts that I’ve seen in a while.

Summary

This is a good quality observational study that adds to our body of knowledge about long term use of MHT: no net negative or positive when it comes to mortality for otherwise healthy women ages 45-54, even for those who take it for 10 or more years. The exception is women who have had their ovaries removed between the ages of 45 and 54 derive a significant benefit from MHT, and likely should use it until at least age 55.

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References

Mikkelsen A P, Bergholt T, Lidegaard, Scheller N M. Menopausal hormone therapy and long term mortality: nationwide, register based cohort study BMJ 2026; 392 :e085998

Protective Effect of Hormone Therapy Among Women With Hysterectomy/­Oophorectomy. Human Reproduction. 2017.

Chen L, Mishra GD, Dobson AJ, Wilson LF, Jones MA.Menopausal Estrogen-Alone Therapy and Health Outcomes in Women With and Without Bilateral Oophorectomy: A Randomized Trial. Annals of Internal Medicine. 2019.

Manson JE, Aragaki AK, Bassuk SS, et al.Association of Bilateral Salpingo-Oophorectomy With All Cause and Cause Specific Mortality: Population Based Cohort Study. BMJ. 2021. Cusimano MC, Chiu M, Ferguson SE, et al.

Rocca WA, Grossardt BR, de Andrade M, Malkasian GD, Melton LJ 3rd.. Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol 2006;7:821-8.

Cusimano MC, Chiu M, Ferguson SE, et al. Association of bilateral salpingo-oophorectomy with all cause and cause specific mortality: population based cohort study. BMJ2021;375:e067528. .

Manchanda R, Gaba F, Talaulikar V, et al., Royal College of Obstetricians and Gynaecologists. Risk-Reducing Salpingo-Oophorectomy and the Use of Hormone Replacement Therapy Below the Age of Natural Menopause: Scientific Impact Paper No. 66 October 2021: Scientific Impact Paper No. 66. BJOG2022;129:e16-34.

Is transdermal estradiol safer for the endometrium than other estrogens?

It’s not uncommon to hear the claim that “body-identical” or “bioidentical estradiol” is more physiologic, a framing that can be interpreted by patients as implying it has a reduced risk for cancer or other complications/side effects.

The fact that a hormone is produced by the body does not make it inherently safe. Any chemical produced by the body, when administered at the wrong dose or in the wrong context, can cause serious health issues. For example, insulin is a natural hormone, yet if someone took a large dose and did not need it, they could go into a coma and die.

Why make this claim? I suspect a big part of it is marketing, just as it was in the 1980s. But I would not be surprised if some doctors hold this false belief and then use it to justify the supposed safety of super-high doses of transdermal estradiol from an endometrial cancer perspective. So let’s take a look at the data and get to the truth, and excitingly, this is one of the situations where we actually have research to look at!

Since no one is really using ethinyl estradiol for menopause hormone therapy anymore, we’ll compare transdermal estradiol to Premarin.

The Basic Science

Estradiol drives endometrial cell division by binding to ERα, which triggers events that cause endometrial cells to divide. This is the fundamental mechanism underlying endometrial cancer risk. Any estrogen that activates ERα, regardless of its

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I’ve been asked a couple of times this week about the safety of progesterone for long-term endometrial protection with MHT. If two people have the same question, others likely do as well, so I thought it was worth a post.

Background

Oral micronized progesterone is metabolized in the gut and liver, significantly reducing the amount that actually reaches the bloodstream and, hence, is available to work in your body. In fact, the Prometrium label notes that “the absolute bioavailability of micronized progesterone is not known,” which is a pretty telling statement. In contrast, the structural differences with progestins (synthetic progesterone-like molecules) reduce metabolism in the gut and liver, resulting in higher, more sustained blood levels, making them more effective at suppressing ovulation (useful for contraception) and suppressing the endometrium. For a rundown of the difference between progestogens, progesterone, and progestins, head to this post for a refresher.

Before the WHI, almost all of the progestogens in menopause hormone therapy were progestins. When the WHI came out, and the combined arm (estrogen plus medroxyprogesterone acetate or MPA, which is a progestin) showed an increased risk of breast cancer, and the estrogen-only arm did not, the hypothesis was that the MPA/progestin may be a major contributor to breast cancer.

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Post WHI

After the WHI, people began to look for data to identify other hormone combinations that might be safer breast-wise. That’s when a large observational study from France, the E3N cohort (Étude Épidémiologique auprès de femmes de la Mutuelle Générale de l’Éducation Nationale), entered the picture. Over 80.000 postmenopausal women who were followed for an average of 8 years, and the breast cancer risk with oral progesterone-based MHT regimens was neutral, and it was increased with progestins by about 30% (which was in line with the increased breast cancer risk seen with the WHI). This single observational study was largely responsible for the swing to progesterone for breast safety.

However, in the E3N cohort, progesterone-based MHT regimens, when taken for five or more years, were associated with a 2.7-fold increased risk of endometrial cancer. It is this data from the E3N study that has raised concern about the long-term safety of oral progesterone for endometrial protection. While estrogen dosing was not reported, apparently typical French regimens at the time were standard doses. This is not a new study, it was published in 2014.

Let’s put the increased risk into perspective. The baseline lifetime risk of endometrial cancer is about 3 in 100 women. If someone is taking a progesterone-based regimen long-term, if the E3N results are valid, that lifetime risk could increase to 6–8 in 100. An individual might think this risk acceptable, but on a population level, the numbers add up. Also, endometrial cancer rates are rising, so that is another consideration.

Long-time readers of The Vajenda will have heard about the E3N cohort before. I have always maintained that if we accept the E3N cohort’s conclusions about progesterone and the breast (safer than a progestin), and about transdermal estradiol and risk of blood clots (no increase), then we need to accept their findings about endometrial cancer.

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What Randomized Trial Data Do We Have?

The E3N cohort is observational, so there may be other factors that explain the higher rate of endometrial cancer with progesterone over time.

Most clinical trials use endometrial hyperplasia as a surrogate marker because it tells us the endometrium has been exposed to too much estrogen without enough progestogen. It doesn’t mean that someone will develop endometrial cancer, but it means they could be on that road. It takes several years to develop endometrial cancer, so surrogate markers are a way to get results in a more timely fashion.

The first large-scale clinical trial with progesterone is the PEPI trial from 1995. Women were randomized to one of 5 medication regimens and one we are interested in is Premarin 0.625 mg daily and progesterone 200 mg/d for the first 12 days of each 28 day cycle. There was also a placebo arm, a Premarin only arm, and two arms with Premarin and different doses of progestins. At 3 years, the risk of endometrial hyperplasia was 24% with Premarin alone, but all three arms with a progestogen were equally protective. The rate of hyperplasia was < 1% for the progesterone arm. PEPI and several other small clinical trials set the stage for progesterone being a viable option to progestins.

Prometrium was FDA-approved in 1998. The package insert describes a 36-month, randomized, double-blind, placebo-controlled trial in 358 postmenopausal women specifically designed to evaluate oral micronized progesterone for the prevention of endometrial hyperplasia with MHT. The regimens studied were Premarin 0.625 mg daily plus 200 mg/day progesterone for 12 days per 28-day cycle, Premarin 0.625 mg daily, and placebo. With placebo, there was a 3% risk of hyperplasia, with Premarin plus 200 mg progesterone, it was 6%, and with Premarin alone, it was 64% (yes, 64%!).

This study appears not to be in the peer-reviewed literature. and there are no statistics to review, so it’s hard to say much about the 6% rate of hyperplasia. The PEPI data is methodologically strong (multicenter, blinded pathology review, published in JAMA), while the Prometrium registration trial data is opaque. We don’t know if there were baseline biopsies or how the samples were evaluated.

There is an FDA-approved combination of oral estradiol and progesterone MHT, Bijuva, and they submitted a 52-week endometrial safety study involving 1,835 postmenopausal women. The dose combinations were estradiol/progesterone 0.5 mg/100 mg and 1 mg/100 mg (the two FDA-approved doses) compared to placebo. This is about the same as a 25 mcg and a 50 mcg patch, respectively. Reassuringly, there were very low rates of endometrial hyperplasia: 1 case out of 303 women (0.33%) in the 0.5 mg/100 mg group and 1 case out of 281 women (0.36%) in the 1 mg/100 mg group, with 0 cases in the placebo group (0/92).

There have been several reviews over the past decade that have examined all the data, and most have a question mark about the long-term safety of progesterone for the endometrium. And for good reason, it’s just not studied in clinical trials beyond three years.

We have even less data for vaginal progesterone (more on that here).

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How Do We Explain the E3N Findings?

There are several possibilities:

• The findings are spurious. After all, it is observational data, and important information could be missing. However, if we discard the E3N findings, then we probably also need to discard the findings that progesterone is safer for the breast.

• Some people may metabolize progesterone differently, and perhaps their blood levels are even lower. Meaning, maybe there is an at-risk population.

• Micronized progesterone may simply not be as good at protecting the endometrium in the long-term.

• Sequential hormone therapy was common at the time in France (200 mg of progesterone for 12–14 days per month). The number of days of progesterone/progestin exposure is critical. During sequential regimens, the 16-19 days a month when there is no progesterone, the endometrium rebounds from the protective effect of the progesterone, and perhaps, cumulatively over the months and years, this adds up. This could mean that daily progesterone might be fine, and it was how the medication was taken, not the medication itself that was the issue. Some reviews question if sequential therapy is as protective as continuous.

• Some women may have been taking too much estrogen relative to the progesterone. We don’t know doses, so we can’t say.

• Compliance. Clinical trials are highly monitored, and medication use is tracked. It’s possible in the real world that women end up missing doses of progesterone, which may matter more when the medication has a weaker effect on the uterine lining. Taking a medication for 12-14 days a month is not intuitive, so you could see how doses might be missed, and if that were the case it would explain the E3N findings. This is one of the more popular theories.

Putting This in Context

All studies evaluating the endometrial safety of progesterone in MHT have used standard doses of estrogen, which is a lower dose than what many doctors with large online followings are advising women to take. Is the risk of endometrial cancer higher with higher doses of estrogen? Unknown. Should we increase the dose of progesterone? Doubling the dose appears to double the blood levels, but we don’t know that it doubles the endometrial protection as it is unstudied. Anyone taking a high dose of estrogen (75 mcg or 100 mcg patch or equivalent dose of anther estrogen) and 100 mg of progesterone a day may want to discuss the adequacy of this regimen for protecting the uterus with their menopause professional. I usually recommend a higher dose of progesterone or a progestin, but am upfront this is based on expert opinion.

Annual check-ins are important. People should asked whether they are having any unexpected bleeding, and, if so, it should be investigated.

People at higher risk for endometrial cancer may wish to consider a progestin, assuming they are at average risk for breast cancer. Those at high risk for breast cancer may wish to consider Duavee.

DO NOT rely on estradiol levels to tell you that you are not absorbing much estradiol, so don’t need to worry about the progestogen dose. Levels CANNOT tell us what is happening to the endometrium.

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One Final Thought

As with many things in medicine, care needs to be individualized, and we need to be honest when we don’t have complete answers. A lot of how we manage progesterone past 3 years is based on expert opinion.

If you are taking progesterone, make sure you are not missing doses. If you are, you may want to discuss a progestin with your menopause practitioner.

Some people might be hearing about this for the first time and wonder what’s up with that? Before starting MHT, a woman’s individual risk for breast cancer and endometrial cancer should be considered so the best choice can be made. This should be part of the MHT discussion

One major concern I have is that there is a big push from influencers, doctors on Instagram, and some telemedicine companies for high doses of estrogen and they also promote fake terms like “natural” and “bioidentical,” which is great for marketing, but it demonizes progestins, which may be the best choice for some people.

One piece of good news is that the PROBES study is currently enrolling, which should give us more information about both breast risk and endometrial risk with progesterone. The investigators are comparing 1 mg of oral estradiol with either 100 mg of progesterone a day to 1 mg of oral estradiol and 0.5 mg of norethindrone a day (a progestin). The biopsies from the lining of the uterus will include special testing to look for signs of increased cell division, which can determine if the lining is not getting enough protection from the progesterone.

And finally, there is no safety cut-off per se at five years with progesterone, but five years is good time to pause and consider if you are getting enough endometrial protection.

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References

1. Piette PCM. The Pharmacodynamics and Safety of Progesterone.

   Best Practice & Research. Clinical Obstetrics & Gynaecology. 2020.

2. Tasci Y, Polat OG, Ozdogan S, Karcaaltincaba D, Seckin L, Erkaya S. Comparison of the efficacy of micronized progesterone and lynestrenol in treatment of simple endometrial hyperplasia without atypia. Arch Gynecol Obstet. 2014 Jul;290(1):83-6.

3. Fournier A, et. al. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008;107:103–111.

4. Fournier A, Dossus L, Mesrine S, et al.Risks of Endometrial Cancer Associated With Different Hormone Replacement Therapies in the E3N Cohort, 1992-2008. American Journal of Epidemiology. 2014.

5. Tempfer CB, Hilal Z, Kern P, Juhasz-Boess I, Rezniczek GA. Menopausal Hormone Therapy and Risk of Endometrial Cancer: A Systematic Review. Cancers. 2020.

6. Sjögren LL, Mørch LS, Løkkegaard E. Hormone Replacement Therapy and the Risk of Endometrial Cancer: A Systematic Review. Maturitas. 2016.

7. Stute P, Walker LJ, Eicher A, et al.Progestogens for Endometrial Protection in Combined Menopausal Hormone Therapy: A Systematic Review. Best Practice & Research. Clinical Endocrinology & Metabolism. 2024.

8. Stute P, Neulen J, Wildt L.The Impact of Micronized Progesterone on the Endometrium: A Systematic Review. Climacteric : The Journal of the International Menopause Society. 2016.

9. Chlebowski RT, Aragaki AK, Pan K, et al.Menopausal Hormone Therapy and Ovarian and Endometrial Cancers: Long-Term Follow-Up of the Women’s Health Initiative Randomized Trials. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2024.

10. Gompel A. Progesterone and Endometrial Cancer. Best Practice & Research. Clinical Obstetrics & Gynaecology. 2020.

11. Ylikorkala O, Joensuu JM, Siitonen H, Mikkola TS. Progestogens in Menopausal Hormone Therapy: A Double-Edged Sword. Seminars in Reproductive Medicine. 2025.

12. Lundell C, Stergiopoulos N, Blomberg L, et al. New Breast and Endometrial Safety of Micronised Progesterone Versus Norethisterone Acetate in Menopausal Hormone Therapy (PROBES): Study Protocol of a Double-Blind Randomised Controlled Trial. BMJ Open. 2024.

Some women in perimenopause who are taking estrogen-containing oral contraceptives (the pill) report hot flashes. Either they were doing well, and now the hot flashes have “broken through,” or they started the pill specifically for both hot flashes and bleeding control/contraception, and the hot flashes have persisted. I have heard from several of these women that they have been dismissed with a “that can’t be possible,” as their pill contains ethinyl estradiol, which is a very potent estrogen, and technically has “more” estrogen than menopause hormone therapy (MHT). However, there are several possibilities that theoretically could explain hot flashes on the pill.

Not on the pill? Wait! This post will still be helpful if you have been told that it’s important to check your estradiol levels on MHT or if you are on menopause hormone therapy and are still getting hot flashes.

Fair warning, as there are very few studies looking at oral contraceptives for perimenopause, a lot of what I am proposing is hypothesis, or my best guess based on the neurobiology of menopause and the pharmacology of various hormones. I feel it is always important to be honest when we are in a “best guess” scenario.

What We Know About Ethinyl Estradiol for Hot Flashes

Ethinyl estradiol is a synthetic estrogen, meaning it is not found in nature. (Fun fact, it is made by semi-synthesis, so it is “plant-based.”) It is estradiol that has been chemically modified to resist metabolism by the liver, making it much more potent and longer-lasting than estradiol. Ethinyl estradiol also resists breakdown in other tissues. This means it provides better suppression of ovulation and also helps prevent the abnormal bleeding that can happen with long-term use of progestins.

While comparing estrogens is challenging, a general estimate is that 5 mcg of ethinyl estradiol is roughly equivalent to 0.3-0.5 mg of oral estradiol, which is considered low-dose therapy. Most oral contraceptive pills have 20-35 mcg of ethinyl estradiol. As this is unstudied and the metabolism of estradiol and ethinyl estradiol are very different, we should not assume the relationship is linear as the dose of ethinyl estradiol increases.

There is one 12-week study comparing two different doses of ethinyl estradiol (we’ll look at the 5 mcg dose, to make it easier) combined with norethindrone acetate. The drug reduced hot flashes by 70%, but placebo reduced them by 48%, so the actual benefit attributable to the medication is about 20 percentage points, in line with other estrogen therapies. But, honestly, it’s hard to make a direct comparison. It’s also important to note this is a relatively short-term study.

There is a study from the 1970s with a 50 mcg pill for women with a hysterectomy and had their ovaries removed. This is not perimenopause and it’s a dose we don’t use anymore. All we can really say from that study is the pill was better than placebo. There is also double-blind trial with a 20 mcg ethinyl estradiol pill, and while hot flashes improved, it was not statistically significant vs placebo. And there is an observational study of a 30 mcg pill, which found 90% of perimenopausal women using an oral contraceptive had complete relief of symptoms after two months, versus 40% who were not taking the pill. This was not a clinical trial or a blinded study, and I can’t access it (not digitized), so this is a summary of the results from another paper.

We know very little about how well ethinyl estradiol works for hot flashes, so it’s not as if we have really robust data to put anyone’s concerns about persistent hot flashes in perspective.

For our purposes here, we will consider someone taking continuous pills, meaning no placebo. Because if you are taking estrogen in the pill for 21 days and then 7 days of placebo, breakthrough hot flashes would not be considered a medication failure, rather, an expected outcome.

With that preamble, what are the potential explanations for breakthrough hot flashes on a continuous ethinyl estradiol pill? Assuming non menopause-related hot flashes have been ruled out.

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Metabolic Differences Between Ethinyl Estradiol and Estradiol. Take Note, This Also Explains One of the Reasons Estradiol Levels Are Not Useful.

Ethinyl estradiol is a more potent estrogen than estradiol, but not because it binds better to estrogen receptors; rather, it is relatively resistant to breakdown in the body compared with estradiol. This means more ethinyl estradiol hangs around in the body and is available to bind to estrogen receptors.

While ethinyl estradiol is resistant to breakdown in the liver and other tissues, we do not know whether that effect also applies to KNDy neurons (pronounced “candy”) in the brain, which are the neurons that help regulate temperature and play a central role in hot flashes. The research simply hasn’t been done, and when we don’t have studies, we can’t know and shouldn’t make definitive statements. And of course, there can be genetic differences in metabolism, so it’s possible there may be a difference in how ethinyl estradiol is metabolized in the brain that only affects some people.

We also don’t know if the high-dose ethinyl estradiol in the pill (20-35 mcg) works differently on the brain compared with a 5 mcg dose, as medications can sometimes have different effects at different doses.

Ethinyl estradiol differs metabolically in another important way. All estradiol, oral or transdermal, is converted to estrone. This is reversible, so estradiol can move back and forth between estrone and estradiol. With oral estrone, there is anywhere from a 3:1 ratio to a 6:1 ratio of estrone to estradiol, and with transdermal, it’s 1:1. Now, intuitively, you might think, “Well, estrone is weaker, so transdermal should be better.” Not so fast! Estrone acts as a reservoir, so the body can draw on it when needed and produce more estradiol. Think of estrone like money in the ATM and estradiol as money in your wallet. The money can flow both ways. This is one reason why estradiol levels can’t tell you how much total estrogen has been absorbed: they don’t reflect the estrone reservoir (your ATM balance).

Ethinyl estradiol does not participate in the estrone reservoir as it can’t be converted into estrone. Basically, there is no reservoir or bank balance for lean times. It’s possible that a steady baseline exposure to estrogen, which is assisted by the estrone reservoir, is more important for treating hot flashes than actual levels. This might matter for someone who might have the genetics that allows them to metabolize ethinyl estradiol faster than the norm.

Let’s step back from the pill and think about someone with persistent hot flashes on a 100 mcg estradiol patch, which is a high dose. Say they have an estradiol level of 24 pg/ml, which is lower than typical for that dose. That level tells you nothing, because there are several possible explanations:

• Poor absorption? Possibly. Maybe this person just doesn’t absorb transdermal products well.

• A temporary absorption issue? Possibly. Meaning the test was done in the morning. The test is just a snapshot in time and may not reflect the whole experience.

• The level was done 2-3 days into the life of the patch. Levels vary significantly between the first 24 hours and the day the patch is changed.

• The estrone reservoir is robust. This means more estradiol is converted to estrone, so a lot of estrogen is actually entering the system, but the test can’t detect it because it’s only measuring estradiol.

• The test is an immunoassay; it is unreliable.

Regardless of the bullet points above, studies have not linked estradiol levels with hot flashes, so the results are useless to begin with. There is so much individual variation, and there is no “level” we are shooting for because of all of these unique metabolic issues. In addition, estradiol levels can’t tell us about receptors. If you think of estradiol as a key and the estradiol receptor as a lock, levels don’t tell you how well the key turns the lock.

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Progestins May Counteract Estrogen

Oral contraceptives contain relatively high doses of progestins and progesterone/progestins tend to raise body temperature. It’s possible that the progestins in oral contraceptives partially counteract the beneficial estrogen effect of estrogen on KNDy neurons.

Let’s back up and think about the thermoneutral zone (yes, very Star Trek). This is the range of core body temperatures between the sweating and shivering thresholds, where the body maintains temperature through passive mechanisms (meaning without sweating or shivering). Think of a thermostat in your house: the heat turns on when the temperature drops to 65 °F, and the air conditioning turns on at 75 °F. This means the thermoneutral zone os between 65 and 75 °F. During menopause, the thermoneutral zone narrows, and for some women it can be almost nonexistent, so even a tiny fluctuation in core temperature triggers a heat-dissipation response, i.e., a hot flash. If progestins produce tiny fluctuations in core temperature, then they are antagonizing the beneficial effect of the estrogen. Estrogen can’t stop all hot flashes, so with more hot flashes overall because of a slightly higher body temperature, there is more opportunity for breakthrough.

Not All Hot Flashes Are Estrogen

Estrogen normally keeps KNDy neurons calm and quiet. When estrogen levels drop, these neurons become overactive and hypersensitive, narrowing the thermoneutral zone. Estrogen in MHT helps to calm the KNDy neurons, restoring the thermoneutral zone back to a wider set point.

It turns out that estrogen is not the only factor that affects the KNDy network; inflammation, metabolic signals, stress hormones, and other signaling systems also play a role. These other systems explain how some antidepressants can help with hot flashes. We aren’t giving them because women are depressed, but because serotonin can be involved. This also explains why cognitive behavioral therapy (CBT) can help: the adrenergic system (the alert and respond network) is also involved.

It’s important to know hot flashes can be more than estrogen, or that the system can be influenced by more than estrogen. If a woman has KNDy instability from these other factors, estrogen alone, even at high doses, may not fully stabilize the system. This could explain why some people not only have hot flashes on the pill, but also on MHT, which is why we treat symptoms, not numbers.

The Pill May Reflect Their Optimal Response

Estrogen therapy is very effective for hot flashes, but is not 100% effective. And there is a lot of variability person-to-person. It’s possible that someone who is getting break through hot flashes on the pill is simply reaching their limits of estrogen therapy. Meaning, switching to another form of estrogen may not offer any change. As this is understudied, we just can’t say what percentage of women will find the pill relatively ineffective.

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What To Do?

If a woman has hot flashes while taking the estrogen-containing pill, believe her!

While there are several potential, physiologically sound reasons, none of these theories of mine have been tested, but that’s not much different from using the pill, when you think about it. The pill should work in theory, so we use it. And, there are theories why the pill might not work for some women.

With all of this in mind, here are some options I recommend for someone experiencing hot flashes from the ethinyl estradiol pill (assuming they are taking it continuously and not having 7 days off every 28 days):

• A different estrogen. If someone needs contraception and likes the pill, consider the estetrol pill or an estradiol-based pill, if available. Estetrol doesn’t participate in the estrone reservoir, but it has a very long half-life, and so it hangs around providing good tissue levels. Anecdotally, I have had good responses with Nextellis.

• Change the progestin. Consider switching to an ethinyl estradiol pill with a different progestin if the pills mentioned above are cost-prohibitive. Perhaps a different progestin may not have the same effect on thermoregulation.

• Switch to a drospirenone-based progestin-only pill. This provides suppression of ovulation and control of the perimenopause hormonal chaos. Oral or transdermal estrogen can be added to treat the hot flashes.

• Stop the pill and switch to a hormonal IUD, which will control bleeding, but not the ovulatory chaos, and then add in transdermal or oral estrogen. Keep in mind that 30% of cycles in perimenopause have high levels of estrogen, a phenomenon called LOOP ovulation, and adding more estrogen while still ovulating can make some women feel worse. For more on LOOP ovulation, check out this post.

• Switch to standard MHT, but understand that it doesn’t provide contraception, may result in more bleeding issues (I say may because it’s not a guarantee), and there is still the LOOP ovulation issue to contend with.

• Don’t change anything, and discuss other strategies for hot flashes that work through non-estrogen mechanisms, such as cognitive behavioral therapy, gabapentin, or paroxetine.

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In Summary

There are several sound, but admittedly untested, reasons why an ethinyl estradiol pill may not work for hot flashes.

• The unique metabolism of ethinyl estradiol

• Individual genetic variations

• The progestin component may partially counteract estrogen’s benefits

• Non-estrogen inputs to KNDy neurons (inflammation, stress, metabolic signals) may dominate

When we don’t have clinical trials to guide us, if you understand the physiology, you can make some educated guesses while waiting for the science to catch up.

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There have been a lot of questions about progesterone and endometrial cancer risk, so look for that post up next.

References

Norethindrone/ethinyl estradiol MHT Package insert

Dennerstein L, Burrows GD, Hyman G, Wood C. Menopausal hot flushes: a double blind comparison of placebo, ethinyl oestradiol and norgestrel. Br J Obstet Gynaecol. 1978 Nov;85(11):852-6.

Shargil AA. Hormone replacement therapy in perimenopausal women with a triphasic contraceptive compound: a three-year prospective study. International Journal of Fertility. 1985 ;30(1):15, 18-28. PMID: 2862116.

Casper, R.F. ∙ Dodin, S. ∙ Reid, R.L. The effect of 20 μg ethinyl estradiol/1 mg norethindrone acetate (Minestrin), a low-dose oral contraceptive, on vaginal bleeding patterns, hot flashes, and quality of life in symptomatic perimenopausal women. Menopause. 1997; 4:139-147

Shargil AA. Hormone replacement therapy in perimenopausal women with a triphasic contraceptive compound: a three-year prospective study. Int J Fertil. 1985;30(1):15, 18-28. PMID: 2862116.

Goldzieher JW. Selected aspects of the pharmacokinetics and metabolism of ethinyl estrogens and their clinical implications. Am J Obstet Gynecol. 1990 Jul;163(1 Pt 2):318-22.

Rance NE, Dacks PA, Mittelman-Smith MA, Romanovsky AA, Krajewski-Hall SJ. Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes. Front Neuroendocrinol. 2013 Aug;34(3):211-27. doi: 10.1016/j.yfrne.2013.07.003

Freedman RR. Menopausal hot flashes: mechanisms, endocrinology, treatment. J Steroid Biochem Mol Biol. 2014 Jul;142:115-20. doi: 10.1016/j.jsbmb.2013.08.010.

Guerin J, Engelmann A, Mattamana M, Borgelt LM. Use of hormonal contraceptives in perimenopause: A systematic review. Pharmacotherapy. 2022 Feb;42(2):154-164. doi: 10.1002/phar.2657.

Sun Y, Wang H, Wang W, Lu J, Zhang J, Luo X, Luan L, Wang K, Jia J, Yan J, Qin L. Glutamatergic and GABAergic neurons in the preoptic area of the hypothalamus play key roles in menopausal hot flashes. Front Aging Neurosci. 2022 Oct 14;14:993955

Sriprasert I, Kono N, Karim R, Hodis HN, Stanczyk FZ, Shoupe D, Mack WJ. Factors Associated With Serum Estradiol Levels Among Postmenopausal Women Using Hormone Therapy. Obstet Gynecol. 2020 Oct;136(4):675-684. doi: 10.1097/AOG.0000000000004006.

For those who are interested in my free talk on Menopause Hormone Therapy: The basics, sponsored by the BC Women’s Hospital, you can sign up here: https://zoom.us/webinar/register/WN_1qRsV4sDQ2qpKqW-e5p-2w#/registration

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There’s a new claim circulating that when it comes to menopause hormone therapy (MHT), oral progesterone is bad for brain health and vaginal progesterone is the way to go. I received multiple direct messages from women panicking that they needed to switch from oral to vaginal progesterone as “vaginal progesterone was better for the brain.”

Let’s walk through the data, because I’ve taken a very deep dive to give you all the facts. And yes, I even tackled rectal progesterone. If you just want the summary, head to the section at the end marked “Final Thoughts.”

Is Oral Micronized Progesterone “Bad” for the Brain?

Let’s start with the first part of the claim.

One of the most important modern studies of menopausal hormone therapy is the Kronos Early Estrogen Prevention Study (KEEPS). KEEPS enrolled more than 700 women who were within three years of menopause and randomly assigned them to hormone therapy or placebo. The study followed participants for four years.

The hormone therapy groups were either Premarin 0.45 mg or an estradiol patch 50 mcg, and both used the same progesterone regimen: oral micronized progesterone, 200 mg daily for 12 days each month.

KEEPS also included a cognitive substudy, KEEPS-Cog, which evaluated memory, executive function, mood, and other brain measures. Researchers later followed those participants for about ten years. The results showed no cognitive harm from short-term menopausal hormone therapy, including no concerning changes on MRI.

When people claim we don’t have good data on oral progesterone and brain health with menopause therapy, that simply isn’t true. We have four-year clinical trial data evaluating brain health and 10-year follow-up data. If progesterone impacted memory or cognition, we would have seen worse outcomes in the hormone therapy arms, and we did not.

But What About Allopregnanolone?

One of the claims about oral progesterone being “bad” for the brain is based on effects from oral progesterone metabolites (like allopregnanolone). These metabolites can affect GABA-A receptors, which can make people feel sleepy or less anxious. Studies looking at 400 mg or higher doses of progesterone have shown side effects like sedation, and the belief is this is primarily via these metabolites.

Allopregnanolone has a bit of a paradoxical response curve, meaning that at low concentrations (similar to luteal phase levels), about 3-8% of women can have anxiety, irritability, negative mood (so there is a group of susceptible individuals), and high concentrations produce the sedative/calming effects. Individual differences in metabolism are likely why some women report unpleasant and potentially intolerable side effects from progesterone.

Side effects and being “bad for the brain” are two very different things. Based on KEEPS, we know that taking 200 mg of oral progesterone for 12 days per month does not adversely affect mood, cognition, or brain health in the short-term or long-term.

Is Vaginal Progesterone “Better” for the Brain?

Allopregnanolone (and other metabolites) are produced in the liver. With oral progesterone, all the progesterone is absorbed quickly and passes through the gut to the liver, a process called the first-pass effect (the liver gets the first pass at the drug). This produces a spike in progesterone and its metabolites. When progesterone is given in the vagina, it enters the bloodstream via veins that supply the uterus and

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Today is International Woman’s Day, and I can’t think of a better way to honor and respect the day than to share a clinical trial that looks at testosterone and quality of life, as this topic is such a source of much misinformation online.

Remember, misinformation is the patriarchy as it robs women of agency.

Can testosterone improve the quality of life for premenopausal women with diminished ovarian reserve? That is the question a group of investigators sought to answer in a recently published double-blind, randomized, placebo-controlled trial.

What is Diminished Ovarian Reserve and Why Use Testosterone?

According to the American Society for Reproductive Medicine (ASRM), ovarian reserve is “the number of oocytes [eggs] remaining in the ovary, or oocyte quantity (oocyte number). Markers of ovarian reserve include hormone levels and sonographically measured features of the ovaries.”

Diminished ovarian reserve (DOR) is when a woman of reproductive age has regular menstrual cycles, but her response to ovarian stimulation for fertility care is reduced compared with that of women of the same age. It’s crucial to note that DOR primarily predicts poor response to fertility medications rather than absolute inability to conceive.

There is a hypothesis that testosterone might be helpful in improving the response to IVF for women with DOR. For example, animal studies have shown that androgens might amplify the ovarian response to medications used in IVF, slow follicular loss, and promote follicular growth. There is also data suggesting that androgens might increase the number of oocytes (eggs retrieved). In addition, women with diminished ovarian reserve have, on average, lower levels of testosterone.

Medically this is all interesting, but we do not know if this association with testosterone is causation or correlation. Might lower levels of testosterone for women with DOR be the result of the declining number of eggs and/or egg quality? Yes. Might the same “thing” (for lack of a better word) that leads to diminished ovarian reserve also lead to low levels of testosterone. Yes. And we also don’t know the implication of lower testosterone as there is no lower level of testosterone for women below which symptoms or medical conditions develop.

The biological rationale for testosterone supplementation during IVF is therefore a sound hypothesis, but the studies available were low quality. In fact, a 2025 meta-analysis of studies found that, when restricted to high-quality randomized controlled trials, there was no benefit of testosterone on pregnancy rate.

The next step, when there is a sound hypothesis but no robust data, is to design and implement a high-quality randomized controlled trial. And so, to evaluate a possible improved response to IVF with testosterone, a multi center randomized double blind placebo controlled trial was carried out, where women with DOR received transdermal testosterone or placebo for about 9-10 weeks as part of the preparation for their hormonal stimulation with IVF.

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That’s All Very Interesting, But What Does It Have to Do with Well-Being?

The investigators built evaluating quality of life into the study design. It’s an interesting, and important decision, because diminished ovarian reserve is linked with lower quality of life and also with lower levels of testosterone. It makes sense to try to get data here too, if possible.

The investigators designed the study so the impact of testosterone on quality of life was a pre-planned secondary outcome, meaning that while they were collecting data on fertility outcomes, they were also collecting data on quality of life.

The clinical trial was conducted at eight clinics in three countries (Spain, Belgium, and Denmark). Women were randomized into two groups, one that received a 1% testosterone gel that delivered 5.5 mg of testosterone per day vs. a second that received a placebo gel. The women took the testosterone or placebo gel for their first menstrual cycle in the study and then for the next 35 days (about 9 weeks of testosterone in total).

The investigators used a scale called FertilQoL, which is a validated patient-reported outcome measure designed to assess how infertility affects a person’s quality of life. It captures the emotional, relational, and social impacts of infertility as well as experiences with fertility treatment. It is widely used in infertility research and clinical settings to measure outcomes that extend beyond pregnancy rates.

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What Were the Findings?

The study was halted prematurely because testosterone did not improve IVF outcomes. A point was reached at which it would not be possible to demonstrate a statistically significant response, so the study was terminated early. Clinical pregnancy rates for testosterone were 15.7% vs 14.9% for placebo.

For the well-being aspect of the study, there was data on 106 women who received testosterone and 107 who received placebo. As expected, the testosterone levels remained low for the women on placebo (average 0.6 nmol/L or 17.3 ng/dL) and rose to the upper end of normal.just above normal for the testosterone group (average 3.2 nmol/L or 92.3 ng/dL). There was no difference in quality of life between the testosterone and placebo groups for any domain measured by the FertilQoL.

What are the Study’s Weaknesses?

The investigators used an immunoassay, which may be less accurate at low levels than mass spectrometry, so that may affect the validity of the testosterone levels, especially at the lower end.

While the FertiQoL is a validated scale, we don’t know what change represents something that is meaningful or beneficial.

The study may not have been long enough; 9 weeks is relatively short, although benefits are typically seen by 8 weeks in most studies.

The trial was powered to detect a difference in clinical pregnancy rate (the primary outcome) and was ended early, so the researchers did not enroll the target sample size. No power calculations were reported for the secondary outcome of quality of life (this is typical), but it means there may not be sufficient statistical power to make conclusions about testosterone on quality of life.

There is also an inherent limitation with evaluating secondary outcomes. The authors acknowledged the limitation, stating: “QOL was a secondary outcome in this trial, and participants were not recruited based on a low QOL.” Here are a couple of ways that a secondary outcome could introduce potential problems:

1. The average total FertiQoL in the study was 73-74 which is on par with the general IVF population. This is a higher score than is seen when people have depression or anxiety. It’s possible there isn’t much room to move with these results, creating a ceiling effect, making it harder to detect a treatment benefit (assuming one exists).

2. If participants have the full spectrum of quality of life scores (not just those with low scores), any treatment effect in a subgroup who might actually benefit gets diluted by the majority who had no room to improve or didn’t need improvement.

Is it possible the dose wasn’t high enough? The investigators kept the testosterone level at or close to the upper limit of normal. Going higher risks greater side effects, such as hair loss on the head, facial hair, voice changes, acne, and an enlarged clitoris. So this is hard to consider this a fault.

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A Small Detour to Discuss How Outcomes Get Abused By Marty Makary and Some Influencers

This study brings up an important topic, secondary outcomes. A secondary outcome, as mentioned above, is pre-specified in the trial design. A questionnaire or blood test or whatever outcome is decided upon, and then the data is collected along the way along with the data for the primary objective for the study. It provides good hypothesis generating data, and it stronger when it is supported by the body of literature, but we want to be careful about drawing sweeping conclusions from secondary outcomes.

There is also something called a post-hoc analysis, meaning, the study did not specifically control for or collect data about an outcome, but after the fact, investigators sift through the data to see what they can piece together. Post hoc analyses carry a much higher risk of false positives because investigators can (consciously or unconsciously) search through the data until they find a “significant” result. This is sometimes called “p-hacking.”

A secondary outcome, while imperfect, at least demonstrates that the investigators committed to examining that endpoint before seeing the results. It is a post-hoc analysis of the DOPS study that Marty Makary and others wave around as “poof” that menopause hormone therapy prevents cardiovascular disease. It’s absurd, and I’d argue it’s misogyny, because it rests on telling women they should accept very weak, potentially extremely flawed data as science.

How Does this New Study Fit With The Body of Research?

This is the question we should be asking with every new study.

This paper is not the only randomized-placebo controlled trial to fail to show a benefit of testosterone for quality of life and/or mood. Several studies have used validated tools to measure mood and/or depression in response to testosterone:

• In 2008, a 16 week randomized-double blind placebo controlled trial where 261 women ages 35 to 46 years with libido-related concerns were evaluated with three different doses of transdermal testosterone or a control group. Well-being was evaluated as well as impact on libido. There was no benefit on well-being. Quality of life/wellbeing was a secondary outcome measure.

• In 2014, a study of 44 women ages 35-55 years with decrease in libido related to antidepressants were randomized to a group with a 300 mcg testosterone patch for 12 weeks or placebo group for 12 weeks. While testosterone improved libido for the women, there was no change in general well being or depression. How can testosterone impact libido and not well-being? They are different outcomes, and that is why it’s important to use validated scales so we can be sure where a benefit actually lies. Quality of life/wellbeing was a secondary outcome measure.

• Also in 2014, 128 women with primary ovarian insufficiency were randomized to a 150mcg testosterone patch group or placebo group and after one year of use there was no difference in mood or wellbeing. This is the study that provides the strongest argument against testosterone as it was a 12-month study and Quality of life/wellbeing was a PRIMARY outcome.

The only data that show benefit for mood and well-being are smaller, lower-quality studies. It is important, as the science progresses, that we do not get anchored to lower-quality data simply because it supports a bias about wanting testosterone to be the answer.

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Putting it All Together

I know many people will wonder, how can people feel fine when their testosterone levels are in the low normal range or not have any improvement when their testosterone levels rise from low to high normal?

Here are some things to consider, which I think are very important given the over promotion of testosterone as a menopause-fountain of youth:

• Levels don’t tell the whole story. Testosterone has a rich intracrinology, meaning we don’t know what is happening inside the cell. There may be a myriad of adaptations inside the cell which we simply can’t measure, so what is going on in the blood may be meaningless.

• No study has shown a testosterone level below which symptoms or diseases emerge for women. Low levels may be just fine, remember, adrenal glands continue to make testosterone. So what some doctors are calling “low” and in need of supplementation may simply be in the normal range.

• Based on the data we have, it’s not likely that testosterone is helping to improve libido because it is replacing a hormone that is missing. Rather, it is likely working in the same way that most medications work, because increased libido is simply an effect of the drug.

I know influencers and doctors hype testosterone online and in the office, but I don’t see these results in my practice. In fact, I do a lot of testosterone de-prescribing of people who have been on it for some time and and are clearly not getting the desired result. It’s important to remember that many medications we use in perimenopause and menopause have a very robust placebo response. I always show this slide from KEEPS when I am giving talks, as it shows the impact of both of the estrogen arms (transdermal estradiol and Premarin) as well as the placebo arm, and durable nature of the placebo response. In every metric there is drastic placebo response, and for irritability, estrogen and the placebo were indistinguishable for 48 months! About a 75% improvement!

If testosterone is essential for mood or well-being, it is reasonable to hypothesize that women with diminished ovarian reserve who generally have lower testosterone levels might benefit the most from therapy. This was a good group to study the impact of testosterone.

This study adds another piece to the body of evidence suggesting that testosterone therapy for premenopausal women (and women with primary ovarian insufficiency and those in early menopause) does not meaningfully improve overall well-being. However, it’s also important to add that we can really only have a low certainty in this conclusion, because most of the data is from secondary outcomes.

For me, the findings reinforce two important lessons in women’s health research: plausible biological mechanisms do not guarantee clinical benefit, and enthusiasm for hormone therapies should not outpace the strength of the evidence supporting them.

While the literature in the area is most secondary outcome measures (with the exception of the 12 month trial for primary ovarian insufficiency), and are not definitive, the best quality data all supports no effect for testosterone. That is why it is so irritating to see testosterone so over promoted. The data is trending to no effect, and telling women they should ignore that in the face of anecdotes is the opposite of science.

Women deserve science and an accurate representation of that science, not marketing. Anything less is the patriarchy.

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References

1. Testing and interpreting measures of ovarian reserve: a committee opinion. ASRM

https://www.asrm.org/practice-guidance/practice-committee-documents/testing-and-interpreting-measures-of-ovarian-reserve-a-committee-opinion-2020/?gad_source=1&gad_campaignid=23473204753&gbraid=0AAAAADnmRYbSeruEgfXZCWFkg9eX0T3G4&gclid=CjwKCAiAtq_NBhA_EiwA78nNWIQubY5c2lMHkc26S4umHjZ0PPIhytzJ_BF3rJd2lcICjMQH-R2e0xoCKOEQAvD_BwE

2. Conforti A, Carbone L, Di Girolamo R, et al. Therapeutic management in women with a diminished ovarian reserve: a systematic review and meta-analysis of randomized controlled trials. Fertil Steril. 2025

3. Gleicher N, Kim A, Weghofer A, et al. Hypoandrogenism is Association With Diminished Functional Ovarian Reserve. Human Reproduction. 2013.

4. Lin LT, Li CJ, Tsui KH. Serum Testosterone Levels Are Positively Associated With Serum Anti-Mullerian Hormone Levels in Infertile Women. Scientific Reports. 2021.

5. Neumann K, Kayser J, Depenbusch M, Schultze-Mosgau A, Griesinger G. Can a quality-of-life assessment assist in identifying women at risk of prematurely discontinuing IVF treatment? A prospective cohort study utilizing the FertiQoL questionnaire. Arch Gynecol Obstet. 2018

6. Kitchen H, Aldhouse N, Trigg A, Palencia R, Mitchell S. A review of patient-reported outcome measures to assess female infertility-related quality of life. Health Qual Life Outcomes. 2017

7. Davis S, Papalia M-A, Norman RJ, et al. Safety and efficacy of a testosterone metered-dose transdermal spray for treating decreased sexual satisfaction in premenopausal women. Ann Intern Med 2008

8. Fooladi E, Bell RJ, Jane F, Robinson PJ, Kulkarni J, Davis SR. Testosterone improves antidepressant-emergent loss of libido in women: findings from a randomized, double-blind, placebo-controlled trial. J Sex Med. 2014

9. Guerrieri GM, Martinez PE, Klug SP, et al. Effects of physiologic testosterone therapy on quality of life, self-esteem, and mood in women with primary ovarian insufficiency. Menopause. 2014

I addressed the “why” about the hormone shortages in this previous post and also had a discussion about it with Dr. Hollie Wakelyn PharmD, BCACP, MSCP, who is a pharmacist and menopause expert that you can watch here. She gave us a wealth if information, so I do hope you listen.

In this post I will provide some practical tips for managing an estrogen shortage, should you encounter one. Look for an upcoming post on options for managing a progesterone shortage.

Look for a Different Pharmacy

In the United States, I recommend checking Cost Plus Drugs. Currently they have five of the six possible doses of an estradiol patch that is generic for Climara, and four of the five possible doses of an estradiol patch that is generic for Vivelle-Dot. They also have all four doses of an estradiol gel (generic for Divigel) and oral estradiol as well. You can search by “estradiol,” and see what products and doses are available, and they are transparent about pricing.

Just ask your doctor to write a prescription and you send it in. They don’t take insurance, but their generic prices are very reasonable for the United States. Some people find their medications are cheaper here than through their drug plan.

Costco is another potential source to consider.

Switch from a Generic to a Name Brand

Brand names tend to be less affected by supply chain issues, although admittedly, this isn’t always the case. One downside is that brand names are more expensive. Ask your pharmacist if they have brand names in stock. And yes, you can ask. You can also ask for a specific generic if you prefer that brand. With the matrix patches, the drug is in the adhesive, and the adhesives vary company to company; some people who are sensitive to hormones may notice a difference depending on the origin of their patch. I just add a note to my prescriptions when my patients prefer a specific generic, although they may not always be available.

If you ask for a switch, just remember, there is no guarantee you health insurance will pay for your preference. Just an FYI.

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Switch to a Dose-Equivalent, but Different Transdermal or Oral Therapy

If you are using a patch, consider a gel or spray or even the vaginal ring as these are all transdermal options. Everyone seems to forget about the ring, although to be fair, it only comes in two doses. The ring is good for 3 months, which makes it a convenient option for many women, especially for travel. It is only available as a brand name, so that may be an issue for some. See the table below for conversions.

Another option that is often forgotten are the combinations patches, which have both transdermal estradiol and a progestin, Climara Pro® (0.045 mg estradiol and 0.015 mg levonorgestrel) and the Combipatch (transdermal estradiol 0.05 mg and transdermal norethindrone 0.25 mg or 0.14 mg). I prescribe these patches a fair bit, mostly for women with peanut allergies, those who feel too sleepy on progesterone or who have other progesterone-related side effects, and those who prefer transdermal therapy. It’s nice to have both products transdermal with one application.

Oral estradiol is not usually hard to find, but if by some chance it is, there is always oral Premarin.

Here is a conversion chart, which I created from reviewing several reputable pharmacy sites, the average estradiol levels in package inserts, information from several menopause societies, and the few studies that exist. Understand that these products are rarely studied head to head, so some of this is an informed “best guess.” It’s important to note that it’s difficult to establish bioequivalent doses between transdermal and oral estrogens as oral estradiol results in an estrone to estradiol ratio of 5:1 in the blood, versus with transdermal estradiol the ratio of estrone to estradiol is about 1:1. Consider this table as a launching point for a conversation with your health care professional.

Estradiol Dosing: Common Equivalences*

*Approximate equivalencies across formulations. Individual dosing should be guided by symptoms and clinical response. Also, different matrix patches may have different absorption kinetics as the estrogen is combined with the adhesive, and the adhesive may differ brand to brand.

(Yes, I know that the conversions from transdermal to oral are different in the UK, but the patch to oral conversion is what is commonly used in the US, but again, direct conversions are hard because these products are metabolized differently).

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Consider a Different Dose of Patch and Adjust Accordingly

If you can’t get a 0.05 mg patch, but a 0.375 is available, consider a switch. Or use two of the 0.025 mg patches.

If you have been on MHT for a while and are several years post menopause, you may be able to lower your dose and not have side effects. Over time, it is a good idea to consider reducing the estradiol dose for people on high dose therapy. All of the safety data is for women on moderate or lower dose therapy, and moderate and lower dose therapy will be plenty protective for bones.

Cutting Patches

Cutting a patch to get one that works for you dose-wise is also an option. While officially it is advised against, there are papers describing this method as the very small doses that are needed in some cases just don’t exist, but it’s crucial to know that not all patches can be cut, so (like a good tailor) check twice and cut once! Estradiol patches are either matrix, meaning the medication is in the adhesive, or reservoir, meaning it is a liquid with a rate-limiting membrane. A reservoir patch cannot be cut as the medication will seep out, rendering the patch useless. A matrix patch can theoretically be cut in half, although companies rarely have this data available. They don’t want you cutting a patch; they want you to buy a new one in the new strength.

One study shows that matrix estradiol patches can be cut as long as the second half is used within a month. I definitely tell my patients they can cut their matrix patches, because sometimes people start on one dose and they have too many side effects, and who wants to throw away 2 boxes of patches! A circular patch should just be cut in half. This diagram is from BC Children’s Hospital, with instructions on how to cut a rectangular patch in half or even in quarters (I think quarters would be challenging, but obviously, when options are limited like in a shortage, people need to make do with what they have).

I believe Estraderm is the only reservoir patch, so this or any generic equivalent cannot be cut. Always double-check with the product monograph that your patch is matrix, before cutting. Here is my trick for remembering:

Matrix can be Made smaller. Reservoir Resists cutting.

Here is a screenshot from the Estraderm product monograph, which describes the “rate-limiting membrane,” a.k.a reservoir, meaning it is not safe to cut.

Here is the same information from the Climara patch, which describes an “adhesive matrix,” so it’s okay to cut.

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Switch to an Oral Estrogen

While we believe transdermal has the lowest risk of clots, oral estradiol and Premarin are fine options for people at low risk for cardiovascular disease. Oral estrogen isn’t an option for someone with an ASCVD score greater than 5% (read more here) or for someone at high risk of blood clots. I’d also be concerned about switching someone who is age 65 or older to oral therapy (cardiac risks and risks of clots rise with age). The decision to convert to an oral estrogen should be made in consultation with your own medical professional.

In Perimenopause, Consider a Low Dose Oral Contraxceptive

Many people in perimenopause actually do better with hormonal contraception, especially if bleeding, mood swings, and breast symptoms are what is most bothersome. There is a lot of pill hate, and that that takes an excellent option away from women. Perimenopause is when women have LOOP ovulation (here is a video explainer), and those symptoms are typically best treated with hormonal contraception that suppresses ovulation. Also, traditional MHT can make bleeding worse in perimenopause.

I hope you found these tips practical and relevant, and any changes you make should be in consultation with your own health care professional who knows your unique needs.

Stay tuned for a post on progesterone shortages.

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References

Ankarberg-Lindgren C, et al. Estradiol matrix patches for pubertal induction: stability of cut pieces at different temperatures. Endocr Connect. 2019;8(4):360

Martin KA, Barbieri RL. Preparations for menopausal hormone therapy. UpToDate. 2023.

Santoro N, Allshouse A, Neal-Perry G, et al. Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study. Menopause 2017;24:238-246.

Kuhl H. Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005;8(Suppl 1):3-63.

Endocrinology Advisor, Oral and Transdermal Estrogen Dose Equivalents https://www.endocrinologyadvisor.com/clinical-charts/oral-and-transdermal-estrogen-dose-equivalents/

Converting Between Estrogen Products. The Pharmacists’ Letter/the Prescriber’s Letter. 2009:25, Number 251109.

The United States Senate Committee on Homeland Security and Governmental Affairs. Short Supply, the Health and National Security Risks of Drug Shortages.

Pharmacokinetics and Pharmacodynamics of Transdermal Dosage Forms of 17 Beta-Estradiol: Comparison With Conventional Oral Estrogens Used for Hormone Replacement. American Journal of Obstetrics and Gynecology. 1985. Powers MS, Schenkel L, Darley PE, et al.

Biologic Effects of Transdermal Estradiol. The New England Journal of Medicine. 1986. Chetkowski RJ, Meldrum DR, Steingold KA, et al.

Pharmacokinetics of Percutaneous Estradiol: A Crossover Study Using a Gel and a Transdermal System in Comparison With Oral Micronized Estradiol.

Obstetrics and Gynecology. 1991. Scott RT, Ross B, Anderson C, Archer DF.

We had a great conversation about the medication supply chain, the opacity of the system, the nuances of menopause hormone therapy, and the very misused term, bioidentical. I also reminisced about Dixon’s pharmacy in Winnipeg (that is, as the kids say, a deep cut). If you know, you know.

If you want to know why we have shortages, and why it’s not just MHT, check out this post.

I discussed LOOP ovulation in the live. I have an explainer about that here for anyone who wants a refresher.

Check back tomorrow for an updated post about tips and tricks for switching between estrogen products to manage the shortage.

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I’ve seen a lot of posts recently on social media about hormone shortages. I wrote about this back in 2023, but given there are so many new subscribers, and many of the posts I’ve seen on social media don’t explain the full picture, I felt the topic was due for an update. If you don’t want all the back story, skip to the summary at the end.

This is not an issue unique to the United States or Canada. There have been estrogen and/or progesterone shortages in many parts of the world on and off for several years. This also isn’t a hormone-only issue. Many drugs have been in short supply. Between 2021 and 2022, the number of drug shortages jumped 30%. In late 2024 there were 277 shortages, down from 323 in early 2024, which was apparently an all time high. Drug shortages are so problematic that there is a tracker (currently estradiol patches and injections are listed, but progesterone is not), and there are 194 drugs that are reported as being impacted by shortages as of February 13, 2026.

Drug shortages are not usually something that is resolved after a few months. In the United States, when we experience a drug shortage, it’s typically in short supply for about 1.5 years, but it can be longer, depending on the class of drugs. For example, for chemotherapy drugs, it’s 878 days; for hormones, it’s 1,201 days. More than fifteen drugs essential for critical care have been in short supply in the United States for over a decade. This is a major health issue, and the fact that the government has essentially taken a laissez-faire attitude is disgusting. So please, do not limit your outrage to menopause hormone therapy!

The fragility of supply chains and the lack of clarity around them is such an issue that in 2022, the National Academies of Science, Engineering, and Medicine send a report to the government on the subject. The fragility of the drug supply chain is currently being discussed by the United States Special Committee on Aging.

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The devastation of Hurricane Maria triggered a major drug crisis in 2017, as many critical medications or components of U.S. medications are made in Puerto Rico. The New York Times reported that 13 drugs made by a single manufacturer were in short or critical supply due to the hurricane. I remember we were very short on local anesthetics at the time. There were also a lot of medication shortages during the early days of COVID-19, as factories were understaffed and supply chains were affected in general.

Depending on the drug, the supply chain may be more fragile. When a medication is made by only one manufacturer, or even in a single factory, if there is a natural disaster, there is a serious issue. Most manufacturing is highly specialized, so it’s not possible, for example, to all of a sudden start making estradiol at a plant that makes penicillin, in the same way that a factory that makes shoes can’t all of a sudden start making socks. Some factories do make more than one drug, and so if they are required to scale up on one, shortages of another drug may be a consequence.

Here is an example of a single factory issue, which has halted production of Brexafemme, an antifungal medication that is effective for resistant yeast infections. There was a factory-related issue leading to potential contamination of the drug with another medication. Production had to be stopped. Even when the issue is fixed, it takes time and money to get the FDA’s go-ahead to get back up and running. It’s a brand-name medication, so there is no competitor. While the drug was off-market, the makers of Brexafemme appear to have sold the drug to GSK, possibly to help facilitate getting back into production (bigger companies likely have a better ability to work with the FDA), so that may add to the delay. Everything is so opaque; all I (and my suffering patients) can do is wait for the company to sort out the issue and get production back online.

The United States relies heavily on China for many drugs, including most antibiotics, so trade wars can also threaten drug supplies and affect prices. About 94% of APIs that eventually become medications in the United States come from China or India.

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Special Issues with Hormones

For the hormones in MHT, it begins with soybeans, which are the source of stigmasterol, the starting raw ingredient for semi-synthesis. If there is a crop failure, which is becoming more common with climate change, this can affect production, and recovery can take an entire growing season or possibly longer. I believe that only two countries supply soybeans for hormones: China and India (it’s all so opaque, so it’s hard to be 100% certain). The fewer the sources, the greater the risk of supply chain interruption.

There are two countries that dominate the world market in converting stigmasterol from soybeans into the raw hormone or API: China and India. As they grow the soybeans, it makes sense that they have developed the infrastructure to make the API. Israel and The Netherlands are also large scale producers of hormone APIs. Other countries produce hormone APIs on a smaller scale, for example EUROAPI (in France and Hungary) and Novartis in Switzerland. This doesn’t appear to be for export.

When most companies are relying on two countries for an API, a supply chain issue can become a world-wide shortage. This is a case of having all the eggs in one basket for two steps in the process. One environmental issue (crops) or one factory-related issue (API), and overnight, a significant supply issue can occur.

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It’s important to remember that the stigamasterol used for estradiol and progesterone is also used to make hormones in birth control pills, patches, rings, and hormone IUDs, as well as testosterone. If levonorgestrel, for example, is more profitable for an API-manufacturer than estradiol, they may prioritize the product with the better profit margin.

Why do most APIs for MHT in American come from China and India? These countries have regions with mature biopharmaceutical ecosystems with well-established expertise in steroid synthesis and API manufacturing. There are also vertical supply chains that can also produce the finished products, such as patches or pills. Integrated supply chains helps lower costs. Building an ecosystem like this has largely been abandoned in the United States.

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The origins of the product that you use are largely unknowable. The final product that you swallow or apply to your skin, from Big Pharma or Big Generic, may be manufactured in a the company’s own factory in one country from an API sourced from another country, such as China, India, or the Netherlands. Or, they may even contract with a foreign manufacturer to produce the entire product. You can look up where the product you buy in America is made (not the API, but the final product) with this tool from ProPublica called Rx Inspector. The only hormone in MHT that is made entirely in North America is Premarin, the API all comes from Canada and the drugs are manufactured in Michigan.

For a foreign manufacturer to sell an API for U.S. drugs, the facilities must be registered and inspected by the U.S. Food and Drug Administration and demonstrate compliance with manufacturing standards. Making hormones like estrogen and progesterone is challenging, so this kind of oversight is crucial. Ramping up to meet the standards cannot happen overnight, so when there is a major shortage, it’s not as if a new supplier can quickly appear on the scene and start churning out API.

Factories can also fail inspections, and even more disturbingly, have serious safety issues and still be allowed to ship raw ingredients! This is primarily a generic-related issue, and some people have wondered if people who all of a sudden have a reaction to a drug where they were using the generic fine for years or an issue when there was a switch from brand to generic, that it could be the result of a poor product. This report on the issue from ProPublica is disturbing (it is not about MHT per se, but rather systemic issues). The finished product may have been through three factories (more if you consider adhesives in patches or other non active, but still essential, ingredients). Even more troubling, is that Pro Publica reports that the FDA has allowed factories with serious issues to continue supplying APIs and medications to the United States. The biggest issue here is likely mold or other contaminants that may harm humans, or that may impact the stability of the final product. The Rx Inspector tool mentioned above also tells you in there have been issues with FDA inspected factories.

There are also contract issues to consider. API makers don’t sell on a casual, open market. Most supply is locked into long-term contracts for several years, and brand-name Pharma companies are more likely to have priority clauses with dedicated production slots and backup suppliers, which is built into their higher price (they are paying more per kg per API to guarantee delivery). If capacity drops, brand-name products have more protection.

Some large generic manufacturers make their own API. Teva Pharmaceuticals is vertically integrated, so they can produce their own raw hormones (APIs) and then make the final product, which obviously provides a secure supply chain, but if they have a shortage, they still need to buy from elsewhere. In the United States, it appears that Teva makes most of their final products on the mainland or in Puerto Rico. Mylan/Viatris, another producer of generics (they make estradiol patches) as well as products with norethindrone and ethinyl estradiol, bought an Indian API manufacturer back in the 2000s, so they are vertically integrated as well, and according to the Pro Publica, they also make their final estrogen products in the Unites States. However, there may be times when these large generic manufacturers need additional APIs from other sources, which may affect their supply. Sandoz is a major manufacturer of generics, and they make their final estradiol products for the Canadian market in Canada. Sandoz was the generics division of Novartis, becoming its own company in 2003, so it had a strong global manufacturing infrastructure. Some of its raw hormone is vertically integrated, but they may also need an external backup.

There are also smaller-to-midsize generic manufacturers, but they are typically less able to tolerate supply disruptions. They are usually the cheapest products, but when there is an API shortage, they may be dropped first. As they don’t make their own raw hormones and will be secondary customers to Big Pharma and the big generics, they either have to weather the storm, or they fold.

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In the United States, the API source is locked in with the drug approval, meaning each finished drug, whether it is brand-name Prometrium or generic oral micronized progesterone, is approved using specific API suppliers that were part of its application. This make sense when you consider the inspections that are supposed to happen. If there is an API shortage, a company can’t typically just switch to another supplier; they usually need to submit a request to the FDA. This can be expensive and may not be worth the money if they expect the shortage to be short-lived (although if the same supplier is already approved for that API, the application may be less cumbersome and expensive). This is one reason that Big Pharma, with its locked-in API contracts and back-up, and large generic companies that make their own APIs, have more protection with shortages.

There is another issue with generics. They are often made in response to direct customer product orders. In Canada, provincial governments issue orders (which is why some provinces may have shortages and others do not), and in the United States, most ordering is from massive wholesalers (e.g., McKesson, AmerisourceBergen, Cardinal Health) and Pharmacy Benefit Managers (PBMs). These entities predict how much of the supply of drug A or B they will need. If they predict incorrectly, there are shortages. Consequently, there aren’t warehouses of pre-existing generic drugs available to fill the gap when there is a supply chain issue. This means that pharmaceutical shortages can result from poor order forecasting by agencies that didn’t anticipate the need. And companies may have ramped down, for example when prescriptions dropped off post WHI, and ramping back up takes time.

The unfortunate reality is that there have been lots of shortages of critical medications, and the hormones in MHT are sadly just more on a long list. Government agencies need to address this because it’s a major health concern.

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Summary: The Supply Chain is Fragile and Governments are not Doing Enough

Making hormones is highly specialized, and there are several steps where problems in production can occur, from obtaining the raw product, to factory-related issues with the API, or in producing the finished product.

High regulatory barriers needed to ensure a safe product means it is extremely hard to add a new estradiol or progesterone API manufacturer or switch suppliers quickly when there are issues. Disturbingly, some factories can fail inspection and keep supplying product to the United States.

Companies have complex contracts for obtaining APIs and may be tied to their API, so when issue in the supply chain occurs, even when there is money and demand, there may be limited flexibility in finding new sources.

These issues largely exist because drug purchasing policies have prioritizied lowest price over reliable production. Remember, in the United States pharmacy benefit managers are raking in money because of this system.

Geopolitical issues can also affect hormone supply. A trade war with China would affect a major source of many APIs.

Poor ordering on the part of governments, wholesale companies, and pharmacy benefit managers is also an issue. Contracts for purchasing APIs are usually for several years, so when ordering underestimates the need, the manufacturers that rely on other companies for raw hormones, may not in a position to get more API until they negotiate their next contract.

API shortages could also be related to prioritizing other hormones with a better financial return.

The opacity in the system is maddening, so explaining why there are issues right now is not possible. It’s not as if people haven’t been sounding the alarm for years about America’s dependence on other countries for medications, so the government is largely to blame here, and the issue is far beyond MHT. Anesthetics and antibiotics are also produced by very fragile supply chains that rely heavily on other countries.

If you are experiencing a medication shortage, please don’t blame your pharmacist. They have nothing to do with it and no control over the system. They would love to give you your medication if it is available.

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Look for two more posts in this series. Options for working around estrogen shortages, and options for working around progesterone shortages. And I will be hopefully doing a live with a pharmacist, so please leave questions (I will let you know the date and time).

References

Serchen J, Hilden D, Silberger JR. Bolstering the Medication Supply Chain and Ameliorating Medication Shortages: A Position Paper From the American College of Physicians. Annals of Internal Medicine. 2025.

Aronson JK, Heneghan C, Ferner RE.Drug Shortages. Part 2: Trends, Causes and Solutions. British Journal of Clinical Pharmacology. 2023.

Fox ER, Sweet BV, Jensen V.Drug Shortages: A Complex Health Care Crisis. Mayo Clinic Proceedings. 2014.

National and Transnational Drug Shortages: A Quantitative Descriptive Study of Public Registers in Europe and the USA.

BMC Health Services Research. 2022. Ravela R, Lyles A, Airaksinen M

Ventola CL. The drug shortage crisis in the United States: causes, impact, and management strategies. P T. 2011 Nov;36(11):740-57. PMID: 22346307; PMCID: PMC3278171.

Ankarberg-Lindgren C, et al. Estradiol matrix patches for pubertal induction: stability of cut pieces at different temperatures. Endocr Connect. 2019;8(4):360

Martin KA, Barbieri RL. Preparations for menopausal hormone therapy. UpToDate. 2023.

Santoro N, Allshouse A, Neal-Perry G, et al. Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study. Menopause 2017;24:238-246.

Kuhl H. Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005;8(Suppl 1):3-63.

Endocrinology Advisor, Oral and Transdermal Estrogen Dose Equivalents https://www.endocrinologyadvisor.com/clinical-charts/oral-and-transdermal-estrogen-dose-equivalents/

Converting Between Estrogen Products. The Pharmacists’ Letter/the Prescriber’s Letter. 2009:25, Number 251109.

The United States Senate Committee on Homeland Security and Governmental Affairs. Short Supply, the Health and National Security Risks of Drug Shortages.

MENOAMAZING™: The Art of Turning Weak Data Into Menopause Miracles.

Sadly, this seems to apply to a lot of content about both estrogen and testosterone, because it feels as if I am regularly sent articles that are promoted on social media as AMAZING evidence of their magical powers, but when I take a closer look, these articles and the claims on social media don’t hold up. And this is very problematic, because many of these papers are waved around in videos on Instagram and TikTok as if they are a veritable menopause Rosetta Stone, containing the magical key to being fracture-free, heart-attack-free, dementia-free, wrinkle-free, as well as the secret to longevity. You know, the basic fountain of youth.

The truth is, medical research varies significantly in its relevance to patient care, and it’s rare that a single study changes things, because the scientific method builds on a body of knowledge. While a well-designed clinical trial is usually worth discussing, those of us interested in science communication must be very careful with context and explain how any study fits with what we know. We must be especially mindful of how we discuss retrospective and database studies in menopause. One, because this is what we call observational data, which can only tell us about correlation, not causation, so it doesn’t help us much when it comes to tying outcomes to a medication. Unfortunately, many times I see these observational studies spoken about in such a way that could lead the audience to mistake the work as a clinical trial. And two, because women with more money and/or those who are healthier are more likely to have access to hormone therapy, this means in observational studies, the women taking hormones are primed to have a better outcome, which could be mistaken as a benefit of the hormone therapy.

An unfortunate example of this hype machine occurred a few months ago regarding an abstract presented at the Menopause Society meeting in October. This was a database study that, at best, is of use to researchers in designing future studies and should have no role in patient care (I wrote about it here). Then again, being amazing, and ground-breaking, even when that is not the case, is what gets attention on social media, not accurate discussions about database studies and their limitations.

In addition, there are papers that have serious methodological flaws, and one wonders how they were published in the first place. (Sadly, an open secret in science is that the only reason a paper hasn’t been published is that the lead author has not hit “send” enough times.) And so, before we, as health communicators, discuss a study publicly, we should assess both its relevance to the field and its quality. And with that, I bring you the study on testosterone therapy and hip fractures I will discuss, which was sent to me the other day.

The study is titled “A Matched Retrospective Analysis: The Relationship Between Testosterone Replacement Therapy and the Incidence of Hip Fractures,” and is published in the Journal of the American Academy of Orthopedic Surgeons. I would have rejected it had I been a reviewer. I cannot understand how someone could read this article and think it is worth discussing with the public.

The Purpose of the Study

To explore the relationship between testosterone therapy and hip fractures…for women AND men. And given the numbers, mostly men (about 25% of participants were women). Yes, this is a study about hip fractures that includes women and men, and a lot of the data was lumped together, as if women and men have the same biology when it comes to bone health, fracture risk, and prescribing testosterone. I had to go to the supplement (leave the main paper for an appendix in another document) to find out how many women were included.

If anyone who promoted this article has also complained about women not being studied separately from men…well, oh, the hypocrisy. The investigators should have separated the results into two papers; it is absurd to consider women and men together when it comes to hip fracture and/or use of testosterone.

Le grand sigh.

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The Methods

The researchers used something called the PearlDiver Mariner165 Database to find men and women who had been prescribed testosterone therapy for at least three months and control groups who were matched by age, sex, smoking, and a few other variables that were available in the database. They then looked at the rate of hip fracture over 2 years.

This is an administrative claims database that captures billing codes for procedures, diagnoses, and dispensed medications submitted to insurance companies (including Medicaid and Medicare). It has the usual billing code database issue: the researchers depend on everyone entering the billing codes correctly, so they may over record or under record diagnoses and confounders. Billing code databases are useful for scanning large numbers of people to look for signals; they are not useful for drawing conclusions.

What is especially relevant here is that the PearlDiver database has no demographic data, which is problematic because based on what we know from other research, it is very likely those women who received testosterone were different demographically from those who did not, as women who are healthier and wealthier are far more likely to be prescribed testosterone therapy. This is a major confounder that this database could easily miss or underestimate.

There are some other serious issues. One is a fatal flaw, and others are severe limitations of the database:

The fatal flaw: The authors did not control for estrogen use. No, really. Most women who take testosterone are likely also taking estrogen, and as estrogen is associated with a lower risk of hip fractures, it’s nothing short of shocking that it wasn’t included. If the authors could pull the testosterone prescriptions, they could have pulled the estrogen prescriptions. This alone makes the data unusable if you are trying to isolate the impact of testosterone; it must be separated from the known positive impact of estrogen. For this reason alone, I would have rejected the study. Why did they not include estrogen prescriptions? They did not say.

The decision to ignore estrogen was a big, what the f*ck, for me. To make sure I hadn’t missed something (because, really, this is astounding!) after reading the paper several times, I did a word search for words beginning with estr- (as that would catch estradiol, conjugated equine estrogens, and estrogen). Only estrogen is mentioned, twice, and that is in the discussion, where the authors acknowledge the role of estrogen in bone health.

Other issues are database-related, and illustrate why we can’t imply cause and effect or draw conclusions from this paper:

1. The data on testosterone is almost certainly incomplete. Many women get testosterone therapy in the form of pellets or from concierge practices outside of their insurance, so this testosterone use will be completely missed by the database.

2. They did not control for the age of menopause. This is not available in the database.

3. There is no information on the testosterone dose.

4. There are no testosterone levels.

5. The investigators controlled for osteoporosis, but this was based on billing codes rather than DEXA scan results. Studies examining the accuracy of billing codes show that they miss a substantial proportion of patients with true osteoporosis while incorrectly identifying many patients without osteoporosis.

6. There is no information on activity levels. It is highly possible, and probably likely, that the women who used testosterone were overall healthier and more physically active than those who did not. People who are more physically active tend to have more muscle mass, which is protective against osteoporosis and falls, a major cause of hip fractures.

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The Results

Honestly, it doesn’t really matter given the lack of estrogen, but we’re here!

There were 301,724 matched pairs, meaning 301,724 testosterone-users and 301,724 non-users. There were 76,610 matched pairs of women: 76,610 taking testosterone and 76,610 not taking testosterone. The authors reported about a 50% reduction in hip fractures overall among women taking testosterone versus those not taking it. It sounds impressive, and I am sure that number was flashed on social media as breaking news, but it’s not a reliable number given all the limitations of the study and the database.

The paper divides women into four age groups: 35-45, 45-55, 56-65, and 66-75 years. There was no difference in hip fractures between the 35-45 and 45-55 year age groups, although the absolute numbers of hip fractures over 2 years were very low in these age groups, limiting analysis. Let’s confine ourselves to the 55-65 years and 66-75 years age groups. This includes a total 43,252 women who used testosterone and 43,252 controls. The results suggest a 51% reduction in hip fractures for women taking testosterone who are 56-65 years, and a 31% reduction for those ages 66-75 years.

These numbers seemed awfully high to me for 2 years or less of testosterone, so I pulled the WHI for comparison. The reduction in hip fractures with five years of estrogen and progesterone was 33%. I just do not believe that two years or less of an unknown dose of testosterone is as effective or more effective than five years of estrogen in preventing fractures. Extraordinary claims require extraordinary evidence, which is lacking here. (I’m always happy to be proven wrong with a quality clinical trial.)

I also wanted to compare the fracture rate in the control group in this new paper with that of the placebo group in the WHI, which were women of average health. Among the control group in this new study, 195 of the 43,252 women aged 55-75 years had a hip fracture over 2 years, and if I did my math right, that means the rate of hip fracture rate was 22.5 per 10,000 women per year. The rate of hip fracture among the placebo group in the WHI was 16 per 10,000 women per year. This means the control group in the database study had just over 40% higher annual rate of hip fracture when compared to the placebo in the WHI, which could support the hypothesis that women who did not get a testosterone prescription had a higher baseline risk of hip fracture.

Can We Take Anything Away from this Study?

No.

As I noted earlier, this study has a fatal flaw: it fails to consider estrogen use, and it would be logical to assume that the majority of women taking testosterone were also taking estrogen. In addition, the PearDriver database lacks important demographic data, which, even if we had estrogen data, would severely limit any conclusions. In any study like this, I would always expect the hormone therapy group to have better outcomes, as they are likely to be wealthier and have access to hormones, and people who are in poorer health may not be candidates for health reasons.

It is true that there are some studies showing that after menopause, higher levels of testosterone are associated with a decreased rate of fracture, but higher testosterone levels do not mean that testosterone therapy will be effective for bone health. Are testosterone levels higher because women are healthier, or are the higher levels helping bone health? We can’t say without a placebo-controlled trial. There are some small clinical trials looking at testosterone and bone density, but the results are conflicting. The 2019 systematic review and meta-analysis of testosterone therapy that included 36 randomized controlled trials comprising 8,480 participants found insufficient data to draw conclusions about testosterone’s effects on bone health. And this new study is of too low quality to contribute to the discussion in any meaningful way. We are at the point where a clinical trial is needed to say anything valuable about testosterone and bone health.

PearlDiver is valuable for analyzing healthcare utilization patterns and identifying trends, it has no value for clinical care. Pre-social media, this kind of nothing-burger study would get published, and no one would hear about it other than the research community, who may find it useful to consider when designing other observational studies or clinical trials. But then came the internet, social media, and meno-influencers and now there are hundreds of thousands of eyeballs, sometimes millions, directed towards research that just isn’t ready for prime time, but hyped like it is.

Often when I write a post about an article like this, I’m accused of being too negative, but I’m just being accurate. It would be nice if people didn’t promote papers like this; but when they do, I feel it’s important to give people the full picture. I want to point out that I also review studies that I think are worthy of sharing because they may change clinical care or they add significantly to the body of knowledge. I’d like to highlight a couple of those posts.

This post on the randomized trial looking at partner treatment for bacterial vaginosis.

And this post, and this one from just a month ago, both looking at the shingles vaccine and dementia risk. The data discussed in these posts comes from database studies, so they can be useful. But even here, I’m always cautious about pointing out that the data is observational, because facts matter.

It’s simply wrong to suggest to any woman that this database study looking at testosterone prescriptions and hip fractures should be used as evidence to support the use of testosterone for bone health, and I’m sick of low-quality studies being dressed up as evidence and presented as life-changing menopause science for click-bait.

Women deserve better.

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References

Peresuh SJ, Arcand PH, Confessore J, Parvaresh-Rizi A, Testa EJ, Quinn M, Avellino G, Arcand MA, Daniels AH. A Matched Retrospective Analysis: The Relationship Between Testosterone Replacement Therapy and the Incidence of Hip Fractures. J Am Acad Orthop Surg. 2026 Feb 1;34(3):e370-e375. doi: 10.5435/JAAOS-D-24-01334. Epub 2025 Jul 3. PMID: 40627853.

Cauley JA, Robbins J, Chen Z, et al. Effects of Estrogen Plus Progestin on Risk of Fracture and Bone Mineral Density: The Women’s Health Initiative Randomized Trial. JAMA. 2003;290(13):1729–1738. doi:10.1001/jama.290.13.1729

Islam RM, Bell RJ, Green S, Page MJ, Davis SR. Safety and Efficacy of Testosterone for Women: A Systematic Review and Meta-Analysis of Randomised Controlled Trial Data. The Lancet Diabetes & Endocrinology. 2019;7(10):754-766.

A new review article (a systematic review and meta-analysis) has been published in The Lancet Healthy Longevity evaluating studies about menopause hormone therapy (MHT) and the risk of mild cognitive impairment or dementia. The researchers combed through the literature, but because they were only considering more rigorous studies, only 15 studies were considered for the systematic review and 10 for the meta-analysis. To stick with the highest quality evidence, the study authors only included randomized controlled trials, non randomised trials, and prospective observational studies where women were followed over time.

This rigor is important, as lower quality studies are often included in analyses. Examples might include studies that define MHT use with a simple yes/no questionnaire and nothing else is known about the type of hormones or the duration of therapy, or a study where the age of menopause was not determined by a validated method, or one where the diagnosis of dementia was based on coding for billing and not on an actual evaluation. All of this vagueness further degrades the quality of observational data. If we are going to have any hope of sorting out if a medication has a cause and effect, we need to know precisely what medication was taken and for how long and if that effect (dementia or not) actually occurred.

The only randomized controlled trial that specifically looked at dementia that was included in this paper is the Women’s Health Initiative Memory Study (WHIMS), an ancillary study of the WHI, and it did not show a benefit. On the contrary, it found and increased risk for dementia for women starting oral Premarin and or medroxyprogesterone at age 65 and older. It’s important to note that this is a regimen that is rarely used today, and beginning MHT past age 65 doesn’t inform us what the risks may be for 50-year-olds. The investigators were careful not to count the WHI more than once. In other review articles and meta-analyses this has not always been the case, as there are several ancillary WHI studies.

The findings? The authors of the new paper conclude there is no evidence to support that MHT raises or lowers the risk of mild cognitive impairment or dementia in post-menopausal women. They caution that the “certainty of evidence ranged from moderate to very low.” More work is clearly needed with more modern approaches to MHT, such as transdermal estrogens, oral progesterone, and starting close to the age of menopause (to name but a few considerations). Still, not drawing a conclusion about benefit or risk is a very important point. The highest quality data (such as it is) doesn’t say either way, so neither should we.

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Many of you might wonder how this paper stacks up against a couple of recent meta-analyses, one from 2023 (Nerattini et al) and another from 2025 (Mosconi et al). Both of these papers found a slight benefit for women taking estrogen-only MHT. For example the Nerattini review found a 32% reduction in dementia for women on estrogen-only MHT (only using observational data) and a non statistically significant reduction for those on combined MHT (estrogen plus a progestogen). The 2025 paper included 46 case-control or cohort studies, and showed an 11.3% reduction in the risk of Alzheimer’s Disease or dementia, with estrogen only therapy more beneficial than estrogen plus a progestogen. I had expressed my issues with the 2023 Nerattini paper in a previous post. About the 2025 paper, the authors of The Lancet Healthy Longevity article state:

We found no evidence for a therapeutic window of timing for MHT for cognitive protection. Unlike the Mosconi study, we applied risk of bias assessments and used stricter inclusion criteria, excluding cross-sectional studies and poorly defined case-control designs to minimize bias and overestimation of effects. We used GRADE to assess certainty and carefully reviewed overlapping cohorts. To avoid double counting we included only one RCT from the Women’s Health Initiative, whereas other reviews included six reports from four distinct trials. While the reviews led by Nerratini and colleagues and Mosconi and colleagues suggest that MHT might be protective if initiated in midlife, we remain cautious, highlighting evidence gaps and the need for further well-designed studies to clarify timing formulation and duration effects.

It is important to point out that there are a variety of ways that lower quality studies are more likely to overestimate a benefit with MHT. We need to move beyond the lower quality studies when we’re discussing potential therapies. While these studies absolutely have their place in forming hypotheses and designing better quality studies, they can’t help physicians or their patients make informed decisions.

Now this new paper doesn’t mean the issue is settled. Far from it. It means we don’t yet have the kind of data we need to draw any conclusions.

Even though MHT for prevention of dementia is not in the guidelines and we have no solid clinical trials or solid observational data supporting MHT for prevention of dementia (otherwise, this new review and meta-analysis would have a different conclusion), many women are confused as there are a lot of claims about MHT and dementia and brain health. Here are just a few examples with very large reaches:

• The widely promoted 2024 M Factor Documentary, which was shown on PBS, interviewed Dr. Mary Claire Haver, who stated about MHT, “We know it’s protective against neuro dementia.”

• Dr. Rhonda Voskuhl, a neurologist from UCLA was on Oprah’s menopause special in April, 2025, and likened menopause to a “neurodegenerative disease.” Dr. Voskuhl is the inventor of a therapy, compounded estriol (PearlPAK™), that women supposedly need for their degenerating, menopausal brains. The product’s website claims it can “treat cognitive decline during perimenopause and menopause.”

(Side note: There are no clinical trials, prospective observational studies, or even retrospective studies for estriol and menopause-associated cognitive decline that I can find, and they are not listed on the CleopatraRx website as of Dec 26, 2025.)

• Dr. Kelly Casperson (a urologist) recently shared a clip on Instagram (October 2025) with Louisa Nicola (a neurophysiologist) where Nicola claims that the “female’s brain literally eats itself during menopause if you don’t replace it with hormone replacement therapy.” The clip went viral, which is no surprise given both have large followings on social media and the claim was, well, wild.

  The brain has metabolic shifts in menopause, but it is not a sign the brain is destroying itself, it’s a sign of adaptation. If you want to hear an excellent rebuttal of this claim, The Brain Docs (a great follow on Instagram) interviewed Dr. Lisa Mosconi on this Instagram live to clear it up. And obviously, if it were so clear that the brain “eats itself” (can’t believe I’m typing that) without menopause hormone therapy, surely this new review focusing on high quality studies would have shown a difference in dementia between those women who used MHT and those who did not, and so their brains quietly performed self-zombieism.

Looking at the three examples listed above, it’s understandable why women might believe that menopause hormone therapy and/or compounded estriol has been definitively proven to prevent dementia in large-scale, quality studies. In fact, here’s a comment on my Instagram when I debunked the brain eating itself claim.

Is anyone else just super confused still? Do we take HRT or not? All the voices on IG are only complicating the message

Statements like “we know,” and “designed to treat,” and “the brain literally eats itself” sound pretty definitive. People hear these claims, and then they hear other experts and the various society guidelines stating that the highest quality research shows that we should not be prescribing MHT for prevention of dementia and it creates a false balance. You have one group saying we know something for sure about protecting yourself from something that is very scary, and another saying that we need more research and cannot be definitive at all, which, to the algorithm, is like hearing a parent say eat your vegetables. BORING!

Even if we were to ignore this new paper that sticks with the highest quality data and confine ourselves to the Nerattini, 2023, and Mosconi, 2025 papers, we’d have to say that that because the studies are all so different, there may (heavy emphasis on may) be a signal for estrogen only therapy, but more work is needed before making recommendations. Still not very definitive and still not protective against self-brain eating.

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So what’s the harm with over-hyping MHT for dementia?

Women should not be misled, and honestly, that’s reason enough. I have heard from many women with no symptoms that they have specifically started MHT for prevention of dementia. I also believe it’s cruel to women who can’t take MHT, as the social media chorus can make them feel hopeless about their long-term health.

If women falsely believe that MHT protects against dementia, that may change lifestyle habits that we know for a fact do protect against dementia. For example, it may make them more likely to have alcohol (a risk factor for dementia), because they have been led to believe they are protected by MHT.

Mistrust of the guidelines and the true experts who develop them is another potential fallout. The false balance makes it look as if there are two sides, one where the guidelines are out of date and the experts at the medical professional societies must be wrong, and hence the guidelines are not to be trusted, and the other with algorithmically friendly information that “they” don’t want you to know.

We do not have the data to make any conclusions about MHT and prevention of mild cognitive impairment or dementia, which is why the guidelines are what they are. And while many people may want it to be otherwise, wishful thinking is not science.

It’s fascinating to me how definitive some people are about MHT and dementia, despite the data that we have. In contrast there is the shingles vaccine where we have several, high quality observational studies that indicate the vaccine may have a positive effect on reducing dementia (far better data than we have for MHT and dementia, and I still used the word “may”), and I have yet to be fed a video with a doctor or neuroscientist making bold claims about the vaccine preventing dementia. Hopeful, intriguing, and promising, I’ve seen, but nothing definitive. It’s fascinating how hormones seem to feed the algorithm, and the shingles vaccine doesn’t. Then again, there doesn’t appear to be a bustling business in selling supplements, memberships, or compounded vaccines to help with the shingles experience.

While it’s true that we need quality studies, designing long term randomized trials to answer this question is fraught with challenges, and so it’s likely that we will need to rely on quality observational studies. The good news is this is an active area of research.

Social media algorithms reward definitive opinions about preventing something scary, like dementia. Most of us have a bias towards action, it’s just here the better action for the brain isn’t taking MHT for dementia prevention, it’s doing the things that science shows are effective (read more here), which also happen to mostly not be that easy to monetize and of little interest to the algorithm.

This is not about being “pro-MHT” or “anti-MHT,” it’s about being clear about what the highest quality data shows, because that is the only way that women can have the informed consent that they deserve. Science moves forward by asking careful questions, designing studies to answer those questions, and respecting uncertainty as a potential outcome, not by declaring victory before the data exist.

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References

1. Melville M, He L, Desai R, et al. Menopause hormone therapy and risk of mild cognitive impairment or dementia: a systematic review and meta-analysis. Lancet 2025.

2. Nerattini M, Jett S, Andy C, Carlton C, Zarate C, Boneu C, Battista M, Pahlajani S, Loeb-Zeitlin S, Havryulik Y, Williams S, Christos P, Fink M, Brinton RD, Mosconi L. Systematic review and meta-analysis of the effects of menopause hormone therapy on risk of Alzheimer’s disease and dementia. Front Aging Neurosci. 2023 Oct 23;15:1260427. doi: 10.3389/fnagi.2023.1260427. PMID: 37937120.

3. P. M. Maki & N. G. Jaff (2022) Brain fog in menopause: a health-care professional’s guide for decision-making and counseling on cognition, Climacteric, 25:6,570-578, DOI: 10.1080/13697137.2022.2122792

4. Henderson St. John JA, Hodis HN, et. al. Cognitive effects of estradiol after Menopause. A randomized trial of the timing hypothesis. Neurology 2016. Aug 16;87(7):699-708.

5. Espeland MA, Shumaker SA, Leng I, et. al. Long-Term Effects on Cognitive Function of Postmenopausal Hormone Therapy Prescribed to Women Aged 50 to 55 Years. JAMA Intern Med. 2013;173.

6. Mark A Espeland, Stephen R Rapp, JoAnn E Manson, et. al. Long-term Effects on Cognitive Trajectories of Postmenopausal Hormone Therapy in Two Age Groups J Gerontol A Biol Sci Med Sci 2017 Jun 1;72(6):838-845.

7. Beam CR, Kaneshiro C, Jang JY, Reynolds CA, Pedersen NL, Gatz M. Differences Between Women and Men in Incidence Rates of Dementia and Alzheimer’s Disease. J Alzheimers Dis. 2018;64(4):1077-1083. doi: 10.3233/JAD-180141. PMID: 30010124; PMCID: PMC6226313.

8. Gleason CE, Dowling NM, Kara F, et al. Long-term cognitive effects of menopausal hormone therapy: Findings from the KEEPS Continuation Study. PLOS Medicine, November 21, 2024. https://doi.org/10.1371/journal.pmed.1004435

9. Faubion LL, Mak E, Kara F, et al. Long-term effects of 4 years of menopausal hormone therapy on white matter integrity. Menopause. 2025 Jul 22;32(9):818–28. doi: 10.1097/GME.0000000000002562. Epub ahead of print. PMID: 40694740; PMCID: PMC12382724.

This question comes up a lot.

We have no long-term clinical trials, so we must rely on observational studies and clinical opinion, both of which have limitations. While we do have long-term follow-up from the WHI, data beyond the 5-7 years that the women took the hormones is observational because when the medication part of the trial ended, hormone therapy was stopped, and the women were told which arm of the study they were in. It is possible that knowing you were in the arm that had the medication, which at the time the media was calling a cause of cancer, may have changed health behaviors going forward.

The 2022 Menopause Society Guidelines state, “Of note, the continued use of hormone therapy in healthy women aged older than 65 years at low risk for breast cancer and CVD (cardiovascular disease) is limited by insufficient evidence regarding safety, risks, and benefits.” This conclusion is primarily based on expert opinion due to the lack of data. The gist of the recommendation is that we think people who are at low risk for complications can continue hormones past age 65 if they still feel they need them. However, it’s important to be honest. The data we have has a lot of limitations.

There is a recent observational study of hormone therapy use after age 65 that many people quote as proof of safety, and I previously wrote about it here and here. But we can’t make conclusions about cause and effect from this paper. In addition, there are some odd findings, such as vaginal and low-dose estrogen being associated with a statistically significant reduced risk of lung and colon cancer, but not estrogens that are absorbed into the blood. This phenomenon is simply not biologically plausible, and of course if there is one anomaly like this, it makes me wonder about the utility of the database. A study like this is best thought of as a search for signals to design future research that can more accurately examine the data, not as a source of definitive proclamations.

I also think it’s important to point out that this paper shows an increased risk of breast cancer for both MHT with a progestin and MHT with a progesterone. Other observational data suggests no increased risk of breast cancer with progesterone, while other data shows a small increased risk with progesterone, but still lower than a progestin, and here this new paper shows the risk is actually slightly higher with progesterone vs. progestin. As all of our information about progesterone being lower risk for breast cancer is observational, we just need to be mindful about speaking in absolutes.

When I am discussing the long-term use of MHT with a patient, I reevaluate the risks and the benefits based on the best literature, the dose and route (oral or transdermal), and the reasons why someone is taking MHT. It’s not much different than the conversation I have with a patient when starting them on MHT in the first place.

Here’s a closer look at my approach.

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Step 1: Reevaluate Risks

The risks of some medical conditions increase with age or may change because of other interventions or medications. The three risks that are the most applicable for long-term use of MHT are breast cancer, blood clots, and heart disease.

Breast Cancer:

The overall risk depends on the hormone regimen:

• Combined hormone therapy: For women ages 50-59, this translates to an

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The word on the street is that the FDA is poised to make an announcement about menopause hormone therapy on Monday. I’ve already addressed what I think about the misinformation and back-room deal-making here, here, and here, so I thought I’d address in more detail a claim about testosterone that was presented at the meeting. Specifically, the claim that testosterone can help women recover from hip surgery.

Here is the quote:

“Your high-functioning older sister breaks a hip, as one in six American women will. Thirty percent will die, and only half fully recover. In 2025, a study showed women given a female dose of a safe, inexpensive drug were 50% less likely to need a cane or a walker, 6 months after a hip fracture. Wouldn’t you want her to have access to that amazing medication? That medication, Testosterone, was first developed in 1935. Ninety years later, your sister still can’t get it.”

If this were true, I would want such a therapy if I were ever to break a hip. But, how accurate is the claim?

Here’s a video summary for those who don’t want the deep dive.

If you also want the full meal deal, please read on…

The claim appears to be based on this study, “Combining Exercise Training and Testosterone Therapy in Older Women After Hip Fracture,” by Binder et al., published in JAMA Network Open in 2025. This clinical trial tested the hypothesis that supervised exercise combined with a supraphysiologic dose of testosterone (above the normal range) delivered via a topical gel would yield greater gains in mobility in women with persistent functional impairments after hip fracture repair wen compared with supervised exercise alone. The primary outcome measure, used by the investigators to determine the success or failure of testosterone therapy, was improvement in distance walked over 6 minutes compared with baseline.

The Intervention

The study ran for 24 weeks, and women who were 65 years or older and within 22 weeks of surgery for a hip fracture were randomized to one of three groups:

1. Supervised exercise plus testosterone gel

2. Supervised exercise plus placebo gel

3. Enhanced usual care.

The supervised exercise program included functional movements, flexibility, and balance, as well as progressive resistance training, two nonconsecutive days per week for 24 weeks at a dedicated exercise facility, home exercises, and a progressive walking program.

The enhanced usual care group served as a placebo for the supervised exercise component of the intervention. The women were prescribed a low-intensity home-based exercise program to perform independently. They received an in-person instructional session, written instructions, and descriptive photos, and they met with an exercise specialist monthly.

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First, It was NOT a Female Dose

The reference range for testosterone for women in the lab used for the study was 12-78 ng/dL, and the target testosterone levels were 110-160 ng/dL. It is incorrect to refer to this as a “female dose.” My guess is the investigators were pushing the testosterone levels higher than we would when treating for low libido because studies don’t show any benefit for testosterone on muscle mass until levels approach the reference range for men, which is around 300 ng/dL (it depends on the lab, but so you have an idea for reference). You can read more about the benefit or testosterone on muscle here in a previous post.

Here are the average testosterone levels from the study:

The average levels exceeded the target range several times and were clearly NOT in the female range.

What Did the Study Show?

I’m a big believer in starting with the conclusions drawn by the investigators:

“Our findings do not support the hypothesis that supervised exercise plus testosterone gel improves endurance or long-distance mobility in older women after a hip fracture.”

This seems a little (add a note of sarcasm) different from what was presented to the FDA—also, there is no mention of a decreased need for canes. But don’t worry, we’ll get to that part in a minute.

Here is the visual abstract that sums up the study rather nicely and shows that testosterone level rose, but that did not help:

There were also some secondary outcome measures, which are generally findings of lesser importance, but may well be meaningful. Just like the primary outcome measure, these secondary outcome measures were part of the overall study plan. There were 10 secondary outcome measures; only one was statistically different, and no, it was not about using a cane.

The only statistically significant difference was with a measurement called the Short Physical Performance Battery (SPBB). It’s true that at 24 weeks, the exercise plus testosterone group showed a statistically significant difference compared with the exercise plus placebo gel groups; however, the testosterone group performed no better than the usual care/exercise placebo group. I think the graph below from the supplemental material is a great visual example of the lack of difference between enhanced care and exercise plus testosterone.

And so we can say there was no benefit for testosterone in the primary or secondary outcome measures.

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Where Does this Claim about Cane-free Walking Come From?

Cherry-picking can mean choosing a single piece of data from a study that isn’t the primary outcome and focusing on that one result while ignoring everything else that may contradict that data. Cherry picking can also be using one, usually lower quality, study to claim a point when there are other, usually high quality, studies that say otherwise. Cherry-picking is like tracking the rain all day while it was pouring for 23 hours and 45 minutes, and using the 15-minute window of sun to claim it was a sunny day.

Cherry-picking is even worse when it comes from a post hoc analysis, which is conducted after all the data are collected, in which investigators sift through the results looking for signals. Findings from a post hoc analysis are guesstimates at best, because the study was not designed to measure or control for the variables that might have mattered. Post hoc findings could represent a signal, and they could also be the result of bias or a fluke.

Here’s what the investigators wrote: “In a post hoc analysis of assistive device use among participants who required a walker or cane at baseline to perform the 6MWD, 15 of 38 (39.5%) in the exercise plus topical testosterone gel group did not require an assistive device at 24 weeks compared with 7 of 41 (17.1%) in the exercise plus placebo gel group and 3 of 17 (17.7%) in the enhanced usual care group.” This is the 50% reduction in cane use among women who used a cane at baseline.

This information about canes or walker use was not part of the original study design, so women were not randomized based on their baseline use these devices. This post hoc analysis is not adjusted for variables such as age, other illnesses, or anything else, so we cannot draw any conclusions. Is this a spurious finding? Is it real? Who knows. The only thing we can say is, “Hmmm, that is interesting. If we decide to do any further studies, maybe we should look at this more formally.” That is how research works.

Using the post hoc analysis from this study as evidence of testosterone’s effectiveness, while the investigators concluded that their findings do not support the hypothesis, is, to me, a classic example of cherry-picking. In my opinion, it’s a tragedy that it was presented at the meeting.

Conclusion

A study that looked at higher-than-normal doses of testosterone showed no improvement in recovery from surgery for hip fracture.

Is this worth further study? Possibly, but based on what we know today, I think it would be unethical to recommend this as therapy.

We know that misrepresenting data can cause harm. Look at how the WHI study has been misrepresented? We don’t correct that error by misrepresenting other studies about the effectiveness of hormones. If we are going to base medical decision-making on post hoc analyses, it’s a pretty short hop to saying women don’t really need studies at all.

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If the FDA announcement on Monday happens in the morning EST, I will do a live to discuss. And of course, will post a longer take.

References:

Binder EF, Bartley JM, Berry SD, Doré PM, Fisher SR, Fortinsky RH, Guild C, Kiel DP, Kuchel GA, Marcus RL, McDonough CM, Monroe KM, Orwig DL, Paluch RA, Reeds D, Stevens-Lapsley J, Volpi E, Schechtman KB, Magaziner JS. Combining Exercise Training and Testosterone Therapy in Older Women After Hip Fracture: The STEP-HI Randomized Clinical Trial. JAMA Netw Open. 2025 May 1;8(5):e2510512. doi: 10.1001/jamanetworkopen.2025.10512.

The Menopause Society meeting officially started on Wednesday afternoon, but I attended the Sexual Health course the day before. I’d like to share some updates from the lecture on testosterone for low desire/libido given by Dr. Sue Davis, as there is ongoing interest in this topic, and I had the opportunity to learn from a (probably the) world expert. Also, as a bonus, I interviewed Dr. Davis (you will find the video in the post and also over on my Instagram), so you can listen to her explain some of the complexities of measuring testosterone and why levels don’t tell us very much. She gave such a great explanation in the course that I wanted to record it to share!

There is No Such Thing as a Low Level of Testosterone

There is no level below which we would say a testosterone level is too low, and there is no established androgen deficiency syndrome in women. This means that there are no health conditions that we can link to low levels of testosterone, there is no medical concern with lower levels, and :low levels” do not need replacement.

It is not appropriate to measure testosterone when women have symptoms, such as fatigue or depression, because a “low” level just doesn’t tell us anything.

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Testosterone Levels Do Not Tell The Whole Story

The testosterone we measure in the blood is spill-over from the cells, meaning it’s excess from the cells that has spilled out (if you will) and made its way into the blood. Moreover, the levels in the blood do not indicate what is happening in the cells, and

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There is a new study that is hot off the press about testosterone levels and menopause. It’s well done and from a group that regularly produces good data, so I am eager to share it.

This is an important study because there is a lot of misinformation about testosterone and menopause, and social media plays an oversized role. There are menoinfluencers who, unfortunately, spread the message that testosterone levels drop in the menopause transition, and hence it should be replaced. “After all,” they say, “We’re just giving women what they’ve lost” and women “shouldn’t be afraid of their natural hormones.”

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The data that we have had until now has not supported the idea that testosterone levels change in any relation to the menopause transition; instead, they follow an age-related decline, with an increase again around age 70. I’ve written about that previously here. The primary limitation of these studies is that most have employed immunoassays, which lack precision at the lower levels typically found in women. There is a study using liquid chromatography tandem mass spectrometry (LC-MS/MS), the gold standard for measuring testosterone in women, which found that from ages 18 to 39, levels dropped by 25% in an age-related decline, but that doesn’t help us understand the menopause transition.

Enter the new study, which uses LC-MS/MS to measure testosterone levels in a large cohort of women aged 40-69 from The Australian Women’s Midlife Years (AMY) Study. Some aspects of the study that make it strong include:

• The investigators measured testosterone along with androstenedione and DHEA, which are hormones that the body converts into testosterone. They also measured sex hormone binding globulin (SHBG).

• They excluded women taking hormones and those with medical conditions that might affect hormone levels.

• They had data from 1,104 women.

• Menopausal stage was determined using specific criteria. They classified women as:

  • Premenopausal

  • Perimenopausal

  • Menopausal and < 55 years

  • Menopausal and ≥ 55 years.

What Did the Researchers Find?

Testosterone levels declined from age 40 until age 58-59, when they hit their lowest. Over this time frame, testosterone levels dropped by about 25%. There was no relation between menopause status and testosterone, and the researchers were able to conclude this because they controlled for reproductive aging. After age 58-59, there was a gradual increase in testosterone, but not back to the levels at age 40.

Here are the median values by age group in both nmol/L and ng/dL from the study:

There was also an age-related decline in DHEA. In contrast, androstenedione levels decreased in relation to menopause. The authors felt this fit with what we know about steroid production (see chart below).

It makes sense that androstenedione levels drop in relation to menopause, as 50% is produced by the ovaries. On the other hand, no decrease in DHEA related to menopause was observed, which fits with what we know about steroid hormones, as the ovaries only produce about 20% of DHEA.

Why don’t testosterone levels drop in menopause if 25% of it comes from the ovary and the other 25% from androstenedione made by the ovary? The ovaries continue to produce some testosterone after menopause. In one study, the amount of testosterone coming from the ovaries after menopause was 24-fold higher than the testosterone in the general circulation (the researchers took blood from the ovarian veins during surgery, right before hysterectomy, and compared that with the testosterone in the general circulation). Granted, it’s a small study, and they used radioimmunoassays, so it needs to be replicated with more accurate tests. But we also know that women who have their ovaries removed typically have lower levels of testosterone. In addition to testosterone from ovaries after menopause, DHEA is still being produced and is converted into testosterone.

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Some Interesting Thoughts from the Authors

They note that in early perimenopause, there is a higher incidence of disorders of desire and arousal than in premenopause. Yet, there is no meaningful change in testosterone levels between these two groups. As a result, these findings do not support the use of testosterone for libido or arousal-related concerns in the menopause transition.

They note that the lowest levels of testosterone are seen at ages 58-59, which corresponds with “the peak prevalence of low sexual desire, arousal, and sexual self-image.” This does support the use of testosterone to treat disorders of sexual desire and arousal for women who are postmenopausal and who are distressed by these changes and desire treatment.

They offer caution that the lowest levels of testosterone at ages 59-59, “should not be interpreted as justification for testosterone treatment of females of this age” for other reasons outside of libido/desire, as “randomised placebo-controlled trials have not shown testosterone supplementation confers other health benefits, such as prevention of muscle loss, cognitive benefits or improved mood, or increased bone density, with the caveat that many studies reporting these outcomes had major design limitations.” It is important to emphasize that there is no level where testosterone for women is considered too low. This is not like thyroid hormone or iron, where we know the body needs a specific level.

There is a lot of interest in understanding why testosterone levels naturally rise around age 60. Some data show that the women who don’t get that rise are more likely to have reduced grip strength, have more depressive symptoms, and are more likely to have cardiovascular disease. However, correlation does not necessarily mean causation, and we don’t know if this is cause and effect, so people should not jump to conclusions. It’s just as possible that depression or cardiovascular disease result in lower testosterone levels or that physical activity, which reduces cardiovascular disease risk and can treat depression, raises testosterone. Further research is required to elucidate the physiology underlying the later-in-life increase in testosterone.

The Caveat

This is a cross-sectional study, meaning women were not followed over time. We assume that the groups of women are pretty similar based on all of the screening and being matched for the stage of menopause. Still, it’s always possible that in a longitudinal study, there may be different results.

While longitudinal studies are ideal, following a large group of women over approximately thirty years and retaining enough participants to have sufficient data would be a significant undertaking and almost impossible.

Summing It All Up

Understanding what actually happens to testosterone across the menopause transition helps us separate evidence from influencer fantasy and sales pitches. The takeaway? For women, testosterone levels decline gradually with age, not because of menopause, and we should use the data we have to guide testosterone therapy based on science, not social media marketing.

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World Menopause Day

Tomorrow, October 18, is World Menopause Day. In recognition, I will be doing a Substack Live at 9 am Pacific Time/Noon Eastern. I’ll be discussing the International Menopause Society White Paper on Lifestyle Medicine and Menopause, the Consumer Reports story on lead in protein powders, answering some questions from the community, and taking live questions. Hope to see you then!

References

Yuanyuan Wang, Rakibul M. Islam, Molly Bond, Susan R. Davis. Testosterone and pre-androgens by age and menopausal stage at midlife: findings from a cross-sectional study, eBioMedicine, Volume 121, 2025, 105972, ISSN 2352-3964.

Fogle RH, Stanczyk FZ, Zhang X, Paulson RJ. Ovarian androgen production in postmenopausal women. J Clin Endocrinol Metab. 2007 Aug;92(8):3040-3. doi: 10.1210/jc.2007-0581. Epub 2007 May 22. PMID: 17519304.

Combined oral hormonal contraceptive pills (pills with an estrogen and a progestin) can be an excellent choice for perimenopause (the menopause transition). This is because the estrogen in the pill can treat hot flashes and the progestin reduces bleeding. In addition, the suppression of ovulation can stop erratic bleeding as well as treat a variety of symptoms due to ovulatory chaos of perimenopause, including the rather unique LOOP ovulation (click here for a video explainer). For a deep dive on how these pills work and how to convert from pills to standard MHT when the time is right, please see this previous post.

The biggest safety issue with the estrogen-containing birth control pills is the risk of blood clots, which is due to the estrogen. Here are the relative yearly risks of clots for different situations:

Baseline risk: 1-3 per 10,000

An estrogen-containing pill: 5-14 per 10,000

Pregnancy: 5-20 per 20,000

Postpartum: 40-65 per 10,000 (in the first 12 weeks postpartum)

To simplify the math, if the risk of a blood clot with an estrogen-containing pill is an additional 10/10,000 per year, that is an additional 0.1% risk of a blood clot per year, which most people likely consider to be a low risk. And, the medical consensus is that for people who are at low risk for clots, this is a favorable benefit-to-risk ratio. On the other hand, if I told you that 22,000 women a year in Europe alone get a clot from the pill (which is the estimate), you might now think the risk is high, because 22,000 sounds like a lot more than 0.1%, even though the number of people affected is the same – that’s the difference between looking at the absolute risk for an individual and a population-level risk. When several million people take a medication with a 0.1% risk, the numbers add up.

As blood clots are the biggest single risk with an estrogen-containing contraceptive, many have wondered if there is a way to lower the already low risk even further.

In addition, we know the risk of clots increases with age, and there is some observational data to suggest that for women over age 50 who are using hormonal contraception, their risk of a clot is higher with an estrogen-containing pill than with menopause hormone therapy. However, many women between the ages of 50 and 55 are still ovulating, and they may need ovulation suppression, so trying to find the lowest risk pill is a worthy goal. While we think the benefit-to-risk ratio for the estrogen-containing pill is favorable up to age 55, a lower risk pill from a blood-clot perspective would be even better.

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Enter the Newer Estrogen Contraceptive Pills

Traditionally, estrogen-containing oral contraceptives have been ethinyl estradiol and a progestin. Ethinyl estradiol is a synthetic estrogen, meaning it is not found in nature. It’s very useful from a contraceptive standpoint as it’s easily absorbed and is potent, but it also has a significant effect on several proteins made by the liver, which contributes to its clot-forming propensity. Modern-dose birth control pills have ethinyl estradiol in doses of 10 mcg, 20 mcg, 30 mcg, and 35 mcg. Higher dose pills are 50 mcg and up and are generally not recommended as they have a higher risk of clots. Some experts have proposed that the 10 or 20 mcg pills may have a lower risk of clots. This is an intuitive assumption; after all, one would think a lower dose would have less of an adverse effect. The problem is that the data is all over the place. It’s possible that the effect of ethinyl estradiol on clotting factors is just so significant that even a low dose has a negative effect, and it’s equally possible that a lower dose is actually lower risk; we just don’t have the data to say.

There are now some oral contraceptives with naturally occurring estrogens: estradiol, estradiol valerate (which is essentially a prodrug of estradiol, it is quickly broken down into estradiol and valeric acid), and estetrol (made by the fetal liver). Many have wondered if oral contraceptive pills with these estrogens pose a lower risk for blood clots.

There is some interesting basic science that looks at how these naturally occurring estrogens stimulate clotting factors, and they appear to have less of an effect on proteins produced by the liver than ethinyl estradiol, which is promising.

There are also several reviews and meta-analyses, one of which was an article that we had to read in our annual certification to be board-certified as an OB/GYN in the United States (and which prompted me to write this post). According to these papers, the risk of blood clots may be 33% lower with these newer pills than with the older ethinyl estradiol pills.

The issue here is that we lack sufficiently large head-to-head studies comparing the risk of clots between an ethinyl estradiol pill and an estradiol or estetrol pill. Given the relatively low rate of blood clots, it would likely take tens of thousands, if not hundreds of thousands of people in a study to get an answer, and that just isn’t feasible for many reasons. Until we get those studies, I think we can say that the data is encouraging that these newer estradiol or estetrol pills are lower risk clot-wise.

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What About the Choice of Progestin?

Progestins by themselves appear to have no impact on the clotting system. However, ethinyl estradiol-containing contraceptives with the “low-testosterone” progestins such as desogestrel and drospirenone may be associated with a higher rate of blood clots compared to ethinyl-estradiol pills with “older” progestins like levonorgestrel and norgestrel. The theory is that because these newer progestins are less testosterone-like, they don’t counteract the effect of estrogen on the clotting system as well as the older progestins. The studies here are not all in agreement, with some showing the increased risk of blood clots and others not showing it.

For someone over age 45 who doesn’t have a pill preference and who is going to use an ethinyl estradiol-containing pill, I recommend a pill with one of the older progestins.

The Drospirenone Pill

This pill has 4 mg of drospirenone, but not estrogen (trade name Slynd), so it is not associated with blood clots. It won’t help with hot flashes, but because it’s very effective at suppressing ovulation, it can prevent erratic ovulation-related mood swings and control bleeding while also providing contraception if needed.

We can prescribe estrogen from MHT along with the drospirenone pill. Meaning, someone could start the pill it for bleeding and/or symptom control and then add in estrogen if needed. The 4 mg of drospirenone should be more than enough progestin to protect the endometrium if traditional doses of menopause hormone therapy are needed (100 mg estradiol patch or 2 mg oral estradiol or less). I say “should” because while this is unstudied, Angeliq is a combination menopause hormone therapy that contains 0.5 mg of drospirenone and 1 mg of oral estradiol.

Putting it All Together

There is an increasing amount of data suggesting that estradiol and estetrol contraceptive pills are a lower risk option for blood clots, although this is based on surrogate lab markers, retrospective reviews, and post-marketing surveillance.

In addition, it’s a little easier to switch from an estradiol pills to standard MHT, because while we don’t have a good formula for converting from the ethinyl estradiol in the pill to oral or transdermal estradiol, in the estradiol-based pills, the dose is known (about 1.5 mg of oral estradiol a day). We have less data on how to switch from an estetrol pill to traditional MHT, but that may not even be needed, as studies are looking at it specifically for menopause hormone therapy, and we may see an approval for that indication in the next year or two. (I say “we may” because one never knows).

While traditional ethinyl estradiol pills are very safe, it may be even safer to try an estradiol or estetrol contraceptive pill if one is needed in perimenopause, especially when the plan is to use the pill until age 55. And, of course, the drospirenone pill doesn’t raise the risk of clots at all.

And finally, you will hear many people dismiss the birth control pill as an option for perimenopause. In my opinion, anyone who does that is not educated sufficiently on menopause and doesn’t understand LOOP ovulation, or they have a political agenda. It’s also possible that social media content on birth control pills gets less attention, because people don’t view it as menopause hormone therapy, so some influencers are incentivized not to to discuss it. All I know is that oral contraception is an invaluable therapy for many women in perimenopause.

I think back to the 1990s, when I trained and when I first started practicing, and I don’t remember seeing as many women with concerns in perimenopause as I do now. A greater awareness is clearly playing a big part of this, and that’s a great thing, and my own recall bias or bad memory may be part of it as well. However, before 2000 we had fewer contraceptive options and fewer tools to manage the erratic and heavy bleeding of perimenopause, so it feels to me like many more women were taking an estrogen-containing birth control pill until their early 50s. I wonder if changes in prescribing hormonal contraception has impacted the cultural and even the medical experience of perimenopause? And because of the insistence by some on social media that an estrogen-containing pill isn’t “real MHT,” I wonder if there are many women in perimenopause who are struggling today because they haven’t been offered hormonal contraception? I don’t have any answers, these are just ideas rattling around in my brain.

Regardless of the past, it’s good to know we have even more oral contraceptive options today, and while the drospirenone pill is definitely the lowest risk, it seems the newer estradiol and estetrol based pills may be lower risk than their ethinyl estradiol counterparts. More options are always better for women.

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References

ASRM Practice Committee: Combined Hormonal Contraception and the Risk of Thrombosis https://www.asrm.org/practice-guidance/practice-committee-documents/combined-hormonal-contraception-and-the-risk-of-venous-thromboembolism-a-guideline-2016/

Reed S, Koro C, DiBello J, Becker K, Bauerfeind A, Franke C, et al. Prospective controlled cohort study on the safety of a monophasic oral contraceptive containing nomegestrol acetate (2.5mg) and 17beta-oestradiol (1.5mg) (PRO-E2 study): risk of venous and arterial thromboembolism. Eur J Contracept Reprod Health Care. (2021)26:439–46. doi: 10.1080/13625187.2021.1987410

Douxfils J, Raskin L, Didembourg M, Donis N, Dogné JM, Morimont L, Beaudart C. Are natural estrogens used in contraception at lower risk of venous thromboembolism than synthetic ones? A systematic literature review and meta-analysis. Front Endocrinol (Lausanne). 2024 Aug 16;15:1428597. doi: 10.3389/fendo.2024.1428597. PMID: 39220361; PMCID: PMC11362054.

Gaussem P, Alhenc-Gelas M, Thomas JL, Bachelot-Loza C, Remones V, Ali FD, Aiach M, Scarabin PY. Haemostatic effects of a new combined oral contraceptive, nomegestrol acetate/17β-estradiol, compared with those of levonorgestrel/ethinyl estradiol. A double-blind, randomised study. Thromb Haemost. 2011 Mar;105(3):560-7. doi: 10.1160/TH10-05-0327. Epub 2011 Jan 12. PMID: 21225090.

von Stockum S, Becker K, Bauerfeind A, Franke C, Fruzzetti F, Calaf J, Keck C, Heinemann K. NOMAC-E2 compares to LNG combined oral contraceptives in women over forty: real-world PRO-E2 study. Gynecol Endocrinol. 2023 Dec;39(1):2166032. doi: 10.1080/09513590.2023.2166032. Epub 2023 Jan 23. PMID: 36690019.

Bauerfeind A, von Stockum S, Boehnke T, Heinemann K. Venous Thromboembolic Risk of Estradiol Valerate-Dienogest Compared with Ethinyl Estradiol-Levonorgestrel Combined Oral Contraceptives. Obstet Gynecol. 2024 Mar 1;143(3):431-434. doi: 10.1097/AOG.0000000000005509. Epub 2024 Jan 16. PMID: 38227942.

Klipping C, Duijkers I, Parke S, Mellinger U, Serrani M, Junge W. Hemostatic effects of a novel estradiol-based oral contraceptive: an open-label, randomized, crossover study of estradiol valerate/dienogest versus ethinylestradiol/levonorgestrel. Drugs R D. 2011;11(2):159-70. doi: 10.2165/11591200-000000000-00000. PMID: 21679006; PMCID: PMC3585947.

Endrikat J, Parke S, Trummer D, et al. Ovulation inhibition with four variations of a four-phasic estradiol valerate/dienogest combined oral contraceptive: Results of two prospective, randomized, open-label studies. Contraception. 2008;78(3):218–225. doi: 10.1016/j.contraception.2008.05.00

Porterfield, Laura MD, MPH1,2; Davis, John W. BA3; Weller, Susan C. PhD3; Chen, Lu MS3; Wilkinson, Gregg PhD3. Does hormone therapy exacerbate other venous thromboembolism risk factors?. Menopause 31(2):p 123-129, February 2024

Stanczyk, Frank Z. et al. Comparison of estrogenic components used for hormonal contraception Contraception, 2024;130, 110310

How does one convert between different estrogens in menopause hormone therapy (MHT)?

This is not an uncommon question. For example, someone might be using an estradiol patch and is happy with it, but is getting a rash from the adhesive and wants to switch to a topical gel. Or, when there is a hormone shortage, which has happened before and you can read about why those can happen in a previous post.

Unfortunately, calculating estrogen-equivalents isn’t as easy as it sounds. These products are rarely studied head to head, and the metabolism of oral estrogens is different from transdermal. In general, dose conversions are more guesstimates based on what doses in clinical trials provided equivalent results for vasomotor symptoms and some data on hormone levels. Given this, it isn’t surprising that there isn’t a precise app-based calculator that can readily complete a quick conversion.

The Canadian Menopause Society has just released a conversion table for menopause hormone therapy, including the recommended doses of progestogens (you can find it here). I thought this presented a great opportunity to compare the different estrogen conversions from the various menopause societies (Canada, U.K., Australia) and ACOG (American College of Obstetrics and Gynecology) and also compare them with one that I devised a while back and see how they all line up. (There is no right or wrong here, this is a “lay of the land” kind of exercise). Because comparing all the doses would have been five tables with multiple products each, for simplicity here I am just going to focus on what is typically referred to as a “standard” or “medium” dose of estrogen, as this is likely a common starting dose for many people.

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Estrogen Dose Equivalents for a Medium or Standard Dose of Menopause Hormone Therapy

N/A means either not available in the country or simply not listed in the documents I used as references.

ACOG: American College of Obstetrics and Gynecology

CMS: Canadian Menopause Society

AMS: Australasian Menopause Society, Australian regimens. Did not list a once a week patch.

BMS: British Menopause Society

Even though vaginal therapy is also transdermal, I felt using a different color (green) to distinguish it from the other transdermal therapies (blue) was a good idea. The oral therapies are in yellow.

The biggest difference is North America uses a different transdermal to oral estradiol conversion than the Australian and British Menopause Societies. Everyone seems to be in agreement (or close enough) for the transdermal products and Premarin (oral conjugated equine estrogens).

This chart is far from gospel–we’d need head-to-head studies of these products and only a few of those exist. For example, KEEPS randomized women to 0.45 mg of Premarin, a 50 mcg estradiol patch, or placebo, and the outcomes for hot flashes, night sweats, irritability, and insomnia were essentially the same, so I feel comfortable considering these doses to be equivalent. The reality is that it takes combing through multiple studies, looking at the relief of symptoms and the pharmacokinetics (that is if they were done), and creating a rather complex document to see how they all compare. When I first did it about a year ago, it was really this meme come to life. And of course there can be individual variation in absorption and metabolism, and climate (heat and humidity) may impact absorption of transdermal preparations. And so on.

I’ve included links to all the mains source documents below, for anyone interested in looking at other dosing and how they compare.

There have been some questions about progestogen doses, so I will work on a post. And if enough people want me to put together a similar chart for low or higher dose regimens, let me know.

At the end of the day, estrogen dose equivalents are best thought of as reference points, not absolutes. These tables can guide discussions and decisions, but they can’t replace clinical judgment, patient response, or the realities of product availability. If you’re switching formulations, think of it more as an informed starting place and less as a precise dosing recommendation—then adjust as needed in shared decision making with your health care professional.

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References

Management of menopausal symptoms. Practice Bulletin No. 141. American College of Obstetricians and Gynecologists. Obstet Gynecol 2014;123:202–16. Reaffirmed 2024 https://www.acog.org/clinical/clinical-guidance/practice-bulletin/articles/2014/01/management-of-menopausal-symptoms

Canadian Menopause Society Systemic Menopause Hormone Therapy (MHT) Equivalency Table https://www.canadianmenopausesociety.org/files/publications/%20CMS%20Equivalency%20Table%20-%20English%20final.pdf

Australasian Menopause Society GUide to MHT/HRT Doses Australia Only https://www.menopause.org.au/images/stories/infosheets/docs/AMS_Guide_to_MHT-HRT_Doses_Aus_0325_V2.pdf

British Menopause Society Practice Prescribing https://thebms.org.uk/wp-content/uploads/2022/12/03-BMS-TfC-HRT-Practical-Prescribing-NOV2022-A.pdf

Manley K, Hillard T, Clark J, et al. Management of unscheduled bleeding on HRT: A joint guideline on behalf of the British Menopause Society, Royal College Obstetricians and Gynaecologists, British Gynaecological Cancer Society, British Society for Gynaecological Endoscopy, Faculty of Sexual and Reproductive Health, Royal College of General Practitioners and Getting it Right First Time. Post Reproductive Health. 2024;30(2):95-116. doi:10.1177/20533691241254413 https://journals.sagepub.com/doi/10.1177/20533691241254413?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

British Menopause Society HRT Preparations and Equivalent Alternatives https://thebms.org.uk/wp-content/uploads/2024/02/15-BMS-TfC-HRT-preparations-and-equivalent-alternatives-JAN2024-B.pdf

Drugs for Menopausal Symptoms Med Lett Drugs Ther. 2024 Mar 4;66(1697):33-8 doi:10.58347/tml.2024.1697a https://secure.medicalletter.org/TML-article-1697a

Santoro N, Allshouse A, Neal-Perry G, Pal L, Lobo RA, Naftolin F, Black DM, Brinton EA, Budoff MJ, Cedars MI, Dowling NM, Dunn M, Gleason CE, Hodis HN, Isaac B, Magnani M, Manson JE, Miller VM, Taylor HS, Wharton W, Wolff E, Zepeda V, Harman SM. Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study. Menopause. 2017 Mar;24(3):238-246. doi: 10.1097/GME.0000000000000756. PMID: 27779568; PMCID: PMC5323337. https://pmc.ncbi.nlm.nih.gov/articles/PMC5323337/

There are three recent publications on brain health and menopause hormone therapy (MHT) that are worth discussing. One because it will likely be misinterpreted (and overhyped) by a lot of folks and the other two because they are long term follow up of KEEPS (Kronos Early Prevention Study). The latter two have received very li…

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I’ve posted recently about the nomenclature of menopause hormone therapy (MHT), and specifically about how the word “bioidentical” is misused (you can find the post here). In my research for that post, I spent some time digging around trying to find the exact origin of the word bioidentical. I fell down quite the rabbit hole in my search, and wanted to share that side quest with you.

Suzanne Somers should be credited with popularizing the term bioidentical hormones.

Above is a Google Trends search for the phrase “bioidentical hormones”, and you can see that there are three early spikes, each one of which correlates with one of Somers’ books about high doses of hormones and longevity and looking hot (which to her were really the same thing). The final massive peak corresponds with Somers’ appearance on Oprah. Interestingly, Oprah’s latest special on menopause earlier this year did not have the same impact, but the media and menopause landscape have both changed significantly since then.

The term “bioidentical” was languishing in the functional medicine/alternative medicine world long before Somers glommed on to it (read more about Somers’ influence here). Dr. Christiane Northrup, noted conspiracy theorist, used the term in her 2001 book, The Wisdom of Menopause.

I conducted a variety of internet searches and came up empty handed. I was so desperate that I even asked ChatGPT about the origin of the term as it relates to hormones! The answer was always the same: it supposedly comes from a 1997 book by Jonathan V. Wright, MD, and John Morgenthaler called Natural Hormone Replacement. The problem? I’ve read that book, and I didn’t remember the term bioidentical hormones. So I re-read all 124 pages (which is now going to require me to take some recovery time, but I was committed!) and still no use of the term bioidentical hormones. I wondered if I might have temporarily blacked out from the medical gibberish and missed a word or two, so I found a PDF version of the original version on the Internet Archive, and searched for the words “bio-identical” and "bioidentical" and turned up nothing. Lots of hits for “identical” though.

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The ideas supporting the concept of bioidentical hormones as a marketing strategy are certainly present in this book. At times, there is an insinuation that Premarin, which ironically is the only natural hormone we prescribe for menopause, is synthetic. Remember, this book is pre-WHI, so this hormone protocol needed to compete with Premarin and Provera, which had the lock on the market, based on what we believed about hormone therapy pre-1997. It appears the answer to Premarin and Provera was medically unsupported ideas about synthetic drugs being evil and that “natural” hormones were the answer, where “natural” meant promoting custom, compounded estrogen concoctions of estradiol, estrone, and estriol managed with blood levels in an attempt to “mimic” (albeit incorrectly) what the ovary made during the ovulatory years. There were, and still are, no quality studies supporting this practice. The book also implies that it is really Premarin associated with endometrial cancer, not “natural estrogens.” No word on how it is natural for a woman in menopause to take estriol, considering the main source is the placenta and typically estriol levels are usually close to undetectable outside of pregnancy!

The false idea that Big Pharma isn’t interested in natural hormones, like estradiol or progesterone, because they can't be patented in the same way that hair can't be patented (!!!), is also discussed in Wright’s book. No, really. “Natural hormone therapy,” according to Wright, “can’t be patented”, so apparently, Pharma doesn’t care. I guess the compounding pharmacies are making the products at cost without profit? But I digress. This claim about Pharma not being interested in hormones like estradiol and progesterone is absurd. For the record:

1. Ayerst first sold estriol (extracted from human placentas) under the brand name Emmenim in 1930 in Canada, several years before it was introduced into the United States in the mid 1930s.

2. Estradiol as we know it today has been a pharmaceutical since the 1970s, introduced as oral Estrace. Estradiol was not commonly used before the 1970s, as the ability to formulate it so it could be absorbed orally wasn’t perfected until the late 1960s.

3. Oral progesterone, as we know it today, has been on the market, again courtesy of Big Pharma, since 1982, when it was introduced by Besins-Iscovesco in France. The ability to make progesterone so it could be absorbed when taken by mouth was not perfected until the early 1980s.

4. It is Big Pharma that took estetrol to market (a pharmaceutical version of an estrogen made in the fetal liver), and it is now in a birth control pill.

5. It is Big Pharma that took a birth control pill with estradiol to market.

6. While hormones cannot be patented, extraction processes and manufacturing processes can be, and that is just as profitable.

The idea that Pharma isn’t making money from pharmaceutical versions of naturally occurring hormones is ludicrous and easily disproven.

Pharmaceutical-grade progesterone was not introduced to the United States until 1998, so this is the gap that was exploited by the “natural hormone” gang, as the only way to get pharmaceutical progesterone in the United States before 1998 was to have it compounded. And this, I believe, was the “in” that was used to make the “natural hormone” movement. There were pharmaceutical versions naturally occurring estradiol in the United States, but the functional medicine types couldn’t push for an exclusive “natural hormone” approach if they had to rely on a progestin, a synthetic drug, to protect the uterus. Once progesterone became commercially available as an active pharmaceutical ingredient (API), it could be compounded, opening the door for MHT that did not rely on any synthetic medications.

While Wright covers the “bioidentical greatest disinformation hits” in his book, he never actually uses the term. My next step was to perform a PubMed search for “bioidentical hormones,” restricting myself to 2001 and earlier. Three results!

Two were in journals that were not retrievable for me, but one was in the journal Menopause, and I could get that. In this article, there were two references for the belief about the superiority of these so-called bioidentical products:

Again, through the magic of the Internet Archive, I was able to read PDFs of these books. I’ve previously written about Dr. Lee and his beliefs about progesterone here. In the book, What your doctor may not tell you about menopause, I could not find the word bioidentical or bio-identical—all the same ideas as the Wright book, but not the actual term.

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I struck gold with Natural woman, natural menopause, by Laux and Conrad. It didn’t even take much searching, as the word “bioidentical” was in the subtitle.

It is the same horse and pony—compounded “natural” hormones “tuned” to the body’s need, managed with the testing of hormone levels. All of this is essentially as unstudied today in 2025 as it was in 1997, so the words “Proven safe” are doing a lot of heavy lifting. Also, shows you how invested the people who promote these protocols are invested in doing the research to prove their theories.

Here is a choice quote from the book:

“Why haven't the makers of standard HRT drugs sought out safer alternatives? In the case of Premarin, 940 million dollars and growing is the answer. Premarin is the number-one best-selling drug in the country. Why haven't American pharmaceutical companies strongly marketed these safer bio-identical plant-derived hormone products? Simple. They can't be patented, which means that no single company can corner the market. And since research money will flow only to those projects that will provide a drug company with so-called protected profit, "natural" will always lose to "synthetic" in the pharmaceutical world.” This is on page 23, and yet on page 66, the authors admit that pharmaceutical estradiol is available in at least four products from Big Pharma.

The Natural Woman plan is, of course, compounded Tri-est (estradiol, estrone, and estriol) because, like I said, nothing says natural for a woman in menopause more than a placental estrogen!

While it’s certainly possible that there is some other reference to bioidentical hormones before 1997, the introduction of the term to our lexicon should probably be attributed to Marcus Laux, ND, and Christine Conrad. It’s important to know that the original use of the term bioidentical was for compounded, “plant-based,” hormones with the same molecular structure as those produced by the body, that would be customized based on a patient’s hormone levels, and dosed in such a way as to create hormone levels that approach what we see during the menstrual cycle. Some still use the term in precisely this way today, while others just use it to describe the hormones themselves, but considering the origin, it’s easy to understand the confusion. This is why it is so important to ask people what they mean by the word bioidentical.

It’s easy to understand why so many people on social media are confused because even today, those who promote compounded hormones and pellets use the term bioidentical hormone replacement therapy to sell their products. And I guess if there is a $9 billion market for “bioidenticals,” it’s easy to see the marketing value in the word.

My theory as to why we saw a proliferation of “natural hormone” providers in the late 1980s and early 1990s is simply because this coincided with the the ability to make oral progesterone, and this now allowed them to offer a compounded version of naturally occurring progesterone along with naturally occurring estrogens and hence come up with a marketing plan for a “natural” product as a marketing strategy to compete with what was at the time, the Wyeth/Ayerst Premarin and Provera steamroller.

It’s also clear that the original concept of bioidentical was about mimicking a “natural cycle.” This wasn’t just about hormones with the same molecular structure actually being better for their patients, or those “natural hormone replacement” advocates would have happily written books about the plant-based pharmaceutical versions of naturally occurring estradiol that were readily available in the late 1970s. The smoke and mirrors here are the addition of estrone and estriol. This approach enables the product to be distinguished from the pharmaceutical versions, and supports expensive visits and testing via unsubstantiated claims about the formulation being “natural.” One can charge significantly more for visits that will end in “custom, bespoke products,” and and there is money to be made in follow-up visits and tests for monitoring hormone levels.

The irony is hard to miss: those that accused Big Pharma of profiteering themselves created products and marketed them with the term bioidentical hormones to create a profitable niche. If nothing else, it proves that in menopause, language may be the most potent drug of all.

In the end, “bioidentical” wasn’t born from science, but from marketing and unproven compounded hormone concoction, and many still use that definition today. Understanding its origins reminds us that words matter just as much as evidence in shaping how medicine is practiced and sold.

If you are going to use the word bioidentical, just be sure you know which definition you are using (pharmaceutical version of a naturally occurring hormones or compounded hormones) and remember:

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