The Truth About Estradiol Levels and Menopause Hormone Therapy

Chasing “perfect numbers” can lead to confusion, misdiagnosis, and mistreatment

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There is a growing chorus of medical professionals and health coaches who are promoting estradiol levels as a magic tool for managing menopause hormone therapy (MHT). The claim is that there is a specific level women need to achieve for health, and that this is necessary to investigate various symptoms to see if someone is absorbing enough estrogen, and, if the levels are “subtherapeutic,” then the dose is increased. The idea that levels matter was also unfortunately promoted in that problematic M Factor documentary (my write up is here) and there is even a recent article in the journal Menopause, from Newson Health clinic n the U.K., making bold claims that, “almost a third of women (32%) using licensed doses of estradiol had subtherapeutic serum estradiol levels,” which they defined as < 60 pg/mL (<200 pmol/L). It behooves me to point out that the idea of this specific level being “subtherapeutic” is not evidence-based medical care, it’s an older theory that was never widely accepted and that has been discarded because, quite frankly, we have a lot more data. The article is so problematic in so many ways that it prompted two long letters to the editor detailing the litany of concerns from two different groups that represent a veritable “Who’s Who” of world experts on hormone levels. I’m seriously shocked it was published.

Because of the increased in misinformation about estradiol levels, and because I’ve seen messages on social media from women who are “desperate” to increase their estradiol levels based on this misinformation, and because that article in Menopause has tragically become popular, I want to review the facts about estradiol levels and why they can be misleading, which can easily lead to overdosing or under dosing. We have enough data on estradiol levels that medical professional societies would be recommending them, if they were indicated. Really. We are not shy about orering indicated tests. No one is gatekeeping estradiol levels; the truth is that checking an estradiol level is not the same as checking the level of thyroid hormone in the blood.

Let’s review some essential points about estradiol testing and discuss how it can be both misleading and harmful.

Is the Specific Test Even Accurate?

One test for estradiol is a direct radioimmunoassay, which was used in the Newson Health study. It can overestimate estradiol because it can cross-react with estradiol metabolites. It also performs poorly at the lower end of the hormone range, including the estradiol levels we might expect with a 12.5, 25, or 37.5 mcg patch (or oral equivalent). Clearly, you can see how it might lead someone getting a lower dose to think they are not receiving any hormone at all.

The authors from the Newson Clinic study defended the direct immunoassay because that is what they use in the “real world.” Look, if your speedometer is broken in the real world, you don’t rely on it. We should not encourage practitioners and mislead patients into thinking that direct radioimmunoassays should be used this way. Mass spectrometry-based assays are the gold standard for measuring estradiol levels at the lower end, which is required for the levels seen in menopause hormone therapy.

Timing Matters. A lot.

Estradiol levels vary based on when the sample is taken. For example, in one study, one hour after a 100 mcg patch was first applied, estradiol levels were an average of

152 pg/ml, but at 72 hours, they were an average of 46 pg/ml. If people are tested on day three, it might look like they are not absorbing estradiol well, when it was just the expected downward drift of the level. When levels are ordered in the office or for a study, timing must be tightly controlled, or the data will be useless.

The recently published study in Menopause from Newson Health did not control for timing, so any conclusions based on this point alone should be dismissed out of hand.

Cross Contamination

Estrogen gels, creams, and lotions can cause contamination at the blood draw site, resulting in a falsely elevated result. To reduce cross-contamination with estrogen products, a specific protocol is needed when drawing estradiol levels for people using these products.

And you guessed it, the study in the journal Menopause did not report a protocol to mitigate this.

BMI Affects Estradiol Levels

As BMI goes up, so do estradiol levels. The theory is that fatty tissue produces estrone, which is then converted into estradiol. Someone might see higher levels on a blood test and worry they are taking too much hormone, when it's a BMI-related phenomenon. Consequently, they might be told to reduce their dose and then have symptoms reemerge.

The study in the journal Menopause did not control for BMI. At this point, do you sense a trend toward significant concerns about the article?

Alcohol Affects Estradiol Levels

More than two drinks a day will raise levels, so alcohol use must be strictly controlled for in any study (and yes, you guessed it, that also did not happen in the study we’ve been referencing).

Estradiol Levels are Useless for MHT in Perimenopause

Estradiol production continues during perimenopause (the menopause transition) as women continue to ovulate. There are cycles when estradiol levels can even be higher than typical due to the phenomenon known as LOOP ovulation. I’ll do a short write-up on LOOP ovulation in another post, as it’s an interesting biological phenomenon.

And yes, once again, 22.35 % of women in the Newson study were in perimenopause! I can’t wrap my head around the fact that her group is charging women for estradiol levels to monitor menopause hormone therapy in perimenopause. I think you are getting the drift as to why I might wonder how this article made it through peer review in the first place.

Estradiol Levels Fluctuate, Even Throughout the Day

Even if we used mass spectrometry and controlled for every other variable I’ve mentioned, estradiol levels fluctuate throughout the day. Again, for someone stuck on a mythical level of 60 pg/mL, what if the estradiol is 80 pg/mL at 8 am and 50 pg/mL at 6 pm? Then what? This scenario can absolutely happen.

One reason for fluctuations in levels with transdermal therapy, like patches and gels, is absorption varies through the day according to skin warmth and activity. This means that checking estradiol levels before or after exercise, or even running to catch the bus, might result in different results.

Estradiol is one estrogen, but we also have estrone, estrone sulfate, and many other estrogen metabolites. We’ll just focus on estrone for simplicity. Estrone is a much weaker estrogen than estradiol and primarily functions as a reserve. When a cell needs more estradiol, it can converts estrone into estradiol, like drawing on a reserve tank.

When estradiol is taken orally, estrone levels are higher than typical because estradiol is converted into estrone in the bowel and the liver, so more enters the blood. With transdermal estradiol, the liver converts estradiol to estrone, but it’s far less than oral. Estradiol levels don’t consider this estrone reserve tank, and even though estrone is relatively weak, it still reflects what has been absorbed. The ratio of estrone to estradiol can fluctuate significantly throughout the day as estradiol is converted into estrone and back again, which is one explanation for how estradiol levels can vary so much.

Are Low Estradiol Levels Even A Sign of Poor Absorption?

Even if we knew how much estradiol was being converted back and forth to estrone, if someone used a 75 mcg patch and their estradiol level was 25 pg/mL, that doesn’t necessarily mean they have not absorbed much estradiol. Remember, the estradiol in the blood isn’t the worker bee; it’s the estradiol inside the cell. Low estradiol levels may reflect rapid clearance from the blood and into the tissues, meaning the cells are getting plenty of estrogen, it’s just not hanging around in the blood.

At this point, you are probably thinking, “Wow! That’s a very different estradiol level story from the one I've been sold!” And you would be right. Consider all this, and the fact that no menopause society recommends a specific estradiol level, and it’s pretty clear why no society recommends estradiol levels to “monitor” MHT.

Side note: This information on hormone levels also reinforces one of the key reasons pellets are so concerning: the folks selling this stuff guide the dosing of the pellets based on hormone levels.

Why Do People Order Estradiol Levels When They Aren’t Helpful?

Some practitioners probably don’t know, as the inner workings of lab tests aren’t typically well taught. It’s complicated and that is why we have experts in laboratory medicine. That’s not a good excuse, but it is just the reality. I also believe that some people order them so they can charge for interpretation. And my theory is others order them to support the illusion that they are doing something different and special for their patients. Hormone levels tend to be pushed much more by people who only take and who charge a fair bit. It’s likely harder to charge $1,500 USD or £600 to prescribe a patch when you can see me or any other doctor that takes insurance (or in many more civilized parts of the world, can see you at no cost) and get the very same patch. Unnecessary tests that evidence-based doctors like me will not order provides an illusion of extra care and attention.

I was curious, so I looked up what the Newson clinic charges for hormone levels to supposedly “monitor” hormone therapy. I am not clear what that covers, just the test or the test and counseling, but it’s not cheap, especially if it’s to be done repeatedly.

How do We Manage MHT Without Levels?

By listening to patients, drawing on experience, and being honest about what hormone therapy has been shown to do, what it might be able to do, and what we don't have evidence to support. It bears repeating: if estradiol levels were useful in clinical situations, this would be in the guidelines.

While it is true that there are some women who do not absorb estradiol well across their skin, the answer is not to use a misleading test to guide increasing the dose of something that isn’t working. I mean, that’s absurd. The next step is to evaluate the situation and decide if the persistent symptoms are likely something that should be well-treated with estrogen or not. For example, if someone is using a 100 mcg patch or other transdermal equivalent and is still having hot flashes, the next step is to make sure there isn't another cause, for example, starting an antidepressant, and then, if no, switch to oral estradiol or oral Premarin. Switching to a different transdermal therapy makes less sense, but it’s not wrong. The Femring (vaginal delivery) could also be considered; while it’s transdermal, it delivers estradiol across the mucosa, so there may be different absorption kinetics. However, if someone is using a 100 mcg patch and they still have joint pain, something where the studies we have show that the effect of estrogen is at best marginal, it’s more likely that the estrogen just isn’t the right therapy. Although it’s honestly never wrong to switch from a transdermal to oral, it’s just important to be honest about expectations.

What about protection against osteoporosis? Is there an estradiol level we should aim for? The idea of a mythical number has long been discarded. We know a 25 mcg estradiol patch and up (0.5 mg estradiol by mouth, Premarin 0.45 mg) is an effective prevention for osteoporosis. Even a 14 mcg patch or Premarin 0.3 mg offers protection for bone, albeit less. Bone is exquisitely sensitive to estrogen.

In the end, the science is clear: estradiol blood levels are an unreliable and misleading tool for titrating doses in menopause hormone therapy. Even assuming the correct testing platform, when you consider multiple variables like timing, BMI, exercise, and alcohol use, along with the biological complexity of estrogen metabolism and cellular absorption, the picture is far too nuanced for the technology that we have for estradiol levels to dictate care in any meaningful way. The recent surge in enthusiasm for using estradiol levels as a guide is not supported by high-quality evidence, and worse, it risks harming patients through unnecessary dose adjustments and misplaced trust in bad data, and for some, it will also be expensive. Instead, clinicians should return to the fundamentals—listening to patients, using clinical judgment, and understanding the real evidence behind hormone therapy. Menopause management deserves better than oversimplified metrics and lab-driven gimmicks.

References

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