What is High Estradiol?: Predicted Blood Levels in Young and Older Men on TRT

This is a Video Transcript:

Hello, guys. Nelson Vergel here from DiscountedLabs.com. I decided to do a video on what the highest levels of estradiol should be for men on testosterone replacement therapy (TRT). There's a lot of confusion on the subject since LabCorp and Quest have very narrow sensitive estradiol test ranges. Those estradiol test ranges were derived mostly from men not on testosterone replacement therapy.  Men on TRT usually tend to have higher testosterone levels than men that are not on testosterone replacement. So, believe it or not, there is actually a paper that was published many years ago that predicts estradiol and DHT levels in men given different doses of testosterone.  This study looked at what happens to blood levels of testosterone, estradiol and DHT when you inject different doses of testosterone in young and older men. This study was very nicely done at the Boston University School of Medicine by well-known testosterone researchers. Dr. Bassin is one of them who has done excellent work for the last 30 years.


Testosterone is the precursor hormone for estradiol. Estradiol is a hormone more abundant in women than men that is produced by the aromatization of testosterone in the liver, fat, and other cells. Nature created it for a reason. It has been shown to be responsible for healthy bone density and cholesterol but its role in men's sex drive, body composition, and other variables is a source of great debate.


Many anti-aging or men's health clinics prescribe aromatase inhibitors (AIs) to men who start testosterone replacement (TRT). Higher estradiol blood levels in the presence of low testosterone can potentially cause breast tissue growth in some men and possibly other issues. Some people speculate that high estradiol can also lead to erectile dysfunction but no scientific papers have been published on this subject. Since higher testosterone blood levels can originate higher estradiol levels, the belief is that using an AI will prevent breast tissue growth and erectile dysfunction by lowering any potential increase in estradiol. However, we have no data on how high is too high when it comes to this hormone in men using testosterone therapy. Emerging data shows that low testosterone-to-estradiol ratios may be more closely correlated to infertility, gynecomastia and erectile problems than high estradiol levels alone.

The truth about these speculations is starting to emerge but we still do not have enough data to say what the upper value of the optimal range of estradiol really is. We have a lot of evidence about the lower side of the optimal range since it has been found that estradiol blood levels below 10-20 pg/ml can increase bone loss in men. A recently published study also nicely demonstrated that low estradiol can be associated with higher fat mass and lower sexual function in men. So, be careful when a clinic wants to put you on this drug without first justifying its use.


Estradiol After Different Testosterone Doses: Study Details


This study’s findings were published in the Journal of Clinical Endocrinology and Metabolism in 2010.  The amazing thing is that nobody has really reviewed it, even though it's probably the most important paper on the subject of what happens to estradiol and DHT in men on TRT. The study enrolled 51 young men 19 to 35 years of age, and 52 older men 59 to 75 years of age. These men were given a gonadotropin-releasing hormone agonist to shut down all their gonadotropins, their LH and FHS, and to shut down their testosterone, their estradiol, and DHT.


So, these were really brave volunteers that were willing to have their hormones completely shut down. So, why did they do this? Basically, they did it because they, that researcher wanted to start from zero when it comes to hormones. So, those men were given injections of different doses of testosterone enanthate 25, 50, 125, 300 up to 600 milligrams a week for five months. And the researchers measured the testosterone, estradiol and DHT blood levels. Unfortunately, they used the old test estradiol test based on immunoassay. This estradiol test may not be as accurate as the new test that we're using now, the ultra-sensitive estradiol test that has no interference from CRP and inflammatory markers. Usually, the sensitive estradiol is 20% lower than estradiol levels measured by the old test.


Let's just assume that most of these men did not have inflammation. Here are their baseline characteristics. It is interesting that they were even exposed to such high doses of testosterone. So, after a four-week controlled period, they were given the leuprolide depo which is the gonadotropin-releasing hormone agonist that shuts down gonadotropins. This drug is actually used for prostate cancer. Anyway, so then they were randomized to receive the weekly injections of testosterone enanthate for 20 weeks. The researchers found an issue with the higher testosterone dose in older men who had a few more side effects. They stopped a few of those men from continuing with the 600 milligrams of testosterone weekly. And the randomization was limited after that to 25, 50, 125 and 300 milligrams weekly.


 I've been warning people not to use very high testosterone doses, especially if you're older and have comorbidities and heart problems. Or even not so much heart problems, blood pressure or tachycardia which are usually the main side effects as are listed in the study paper. Anyways, not going to go through the different discussions here.


So basically, what you see here, these are serum estradiol E2:T ratios. We talk about ratios on ExcelMale.com. I usually talk about T divided by E2 (T/E2 ratio), here is the opposite DHT and T ratios.  And the black bars are younger men and the white bars are older men. So, this is total estradiol, free estradiol, total DHT, free DHT. And when we talk about free, what does that mean? It basically is the unbound estradiol and unbound DHT that isn’t bound by sex hormone-binding globulin.


And those two free estradiol and free DHT lab tests are rarely tested in clinics. DiscountedLabs.com does provide a free estradiol test for those that are interested. But since there are no studies about free estradiol blood levels in men, it's hard to say what's a good free estradiol level.


Why Are Men on TRT Concerned About High Estradiol?


Most men on TRT are initially afraid about high estradiol since they fear it causes water retention and gynecomastia. They feel puffy, they may have more sensitive nipples. Which I'm going to discuss in another video because those symptoms are usually not connected to high estradiol per se when men have moderate to high levels of testosterone. Edema, the holding of water weight problem is usually caused by the slowdown of sodium metabolism in the kidneys caused by testosterone and androgens in general. Sodium retention, salt retention that happens in the first few weeks, especially with higher TRT doses in older men. The sensitive nipple issue usually does not lead to gynecomastia and may be caused by stimulation effects of testosterone.


So, as you can tell, that total E2, free E estradiol, and DHT increase with increasing testosterone dose, and this increase is much more pronounced in older men. It’s good to mention that these volunteers were not fat men. Increased fat mass has been linked to increased estradiol levels. These are men with a BMI of around 26 which is not a high number. But anyways, so we do see an increase. And obviously the older men, in white, tend to have higher increase of estradiol. DHT is the same thing. Although the differences were not as noted between young and old, you can tell here the free DHT. When you divide estradiol to testosterone, and that's when you see decreases. Obviously, estradiol increases in a higher degree than testosterone, so you see the ratio of E2 divided by T decreases. The total DHT to T ratio the same, it decreases as we increase the testosterone dose, but not as fast as the estradiol.


It is important to mention that 0.4% of testosterone is aromatized to estradiol. That's a very tiny amount, that's 0.4%. The conversion of testosterone to DHT by 5 alpha reductase is around 10%. That's why you see the scales a little bigger on the DHT side.


How Can This Study Help to Predict Normal Estradiol and DHT Test Levels?


Most men on TRT don't have to be so concerned about the LabCorp or the Quest estradiol ranges that usually scare people because they're always high.


And there is a statistical significance in the baseline values of both young men and older men. DHT increases were higher in older men. In younger men, usually that's also connected to the total testosterone and is also connected to higher libido. Older men had lower DHT, also linked to their lower testosterone. Sex hormone-binding globulin (SHBG) is also higher in older men.


The researchers in this study they came up with a model with factors to predict the estradiol and DHT response curves. They provided two equations for young men (Estradiol and DHT) and two for older men.  Using those equations, you can roughly estimate what the predicted estradiol and DHT levels should be for different testosterone blood levels.  These equations enable us to see what is considered a “normal” estradiol level instead of using estradiol lab ranges that are ill fitted for men on TRT. As previously mentioned, the estradiol ranges of LabCorp and Quest were not derived from a dataset of men on TRT who usually have total testosterone blood levels over 600 ng/dL (many are having T levels of 1000 ng/dL or more!).


The Importance of Preserving Proper Estradiol Levels in Men


Our bodies transform 0.4% of testosterone into estradiol on purpose to balance the potentially negative effects of testosterone alone on lipids and other variables. If you have “high” testosterone, your estradiol should really be “high”. Treating that estradiol with aromatase inhibitor may not be needed and can potentially crash your estradiol level.


Estradiol has important roles in men. Estradiol comes in to protect us from the higher testosterone. It actually improves lipids, improves HDL, improve endothelial function. That's why women tend to live longer than men, because they have had higher estradiol along their lives to protect them against the cardiovascular risks that we all exposed to. So, don't freak out when you see 60s, even in 70s, depending obviously on how high is your testosterone. And they only problem we're having in this fields, that we have not done a study that actually goes after symptomology depending on estradiol blood levels when we control for testosterone. We know that estradiol levels under 15 picograms per milliliter cause problems with bone density and even fat gain.  Anecdotally, many members of ExcelMale.com say that their penile sensitivity decreases when they have low estradiol.


Well, when it comes to high estradiol, we really do not know what high value can cause issues in men on TRT with relatively high testosterone blood levels. If somebody that is, let's say, at 1,275 ng/dL of testosterone and 64 pg/mL of estradiol, are there any consequence to that? We really don't know. And the problem I'm seeing is that most of you guys are assuming too much, you're assuming that because you're holding water or you're having sensitive nipples, you have high estradiol. And you start treating with an AI without even testing your blood levels of estradiol, especially using the sensitive assay. That concerns me because once you start treating with an AI, you can crash your estradiol. “Crashed estradiol” has become one of the biggest traffic source keywords for ExcelMale, because people are experiencing that more and more.


I hope you enjoyed the presentation. I also want to let you guys know that I've put together a free testosterone book (over 400 pages) that I use when I train physicians. Please do not forget to subscribe to the ExcelMale forum and the ExcelMale YouTube channel, and make sure that you click on that little bell that will tell you when I upload new videos. Thanks a lot and stay safe.