Estrogen (E2) in Men: The Narrow Window

Something really interesting with the men I work with across the world is how much of their TRT or cycle protocol can be influenced by their estrogen levels. So in this post, I want to outline a strategic approach to ensuring that the ‘other’ often overlooked hormone, estrogen, is accounted for if you are on TRT, or struggling with dialling in your replacement therapy. I often have emails from clients months later saying how much better they feel on the same dose, simply by cleaning up their estrogen levels.

And that’s the whole goal right? Feeling better. So I hope this post gives you some help if you are struggling with E2 either through confirmed bloodwork or some symptoms that may be along the same lines of those I delve into below. As always, thank you for reading!

Estrogen’s Function in Male Sex Drive

Estrogen has a critical role in male sexual desire. Actually studying what areas of the human brain control behaviour can be a daunting task, especially because there are often a number of incredibly complex intertwining neural processes at work. However, studies from as the early 1970 and 1980s have time and time again shown that the male preoptic area (POA) and anterior hypothalamus are key regions of the brain (hypothalamus) implicated in sexual desire and libido. In rodents, damage to the POA pretty much abolished sex drive. But why does this matter?

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Well, both of these regions have a very high concentration of estrogen receptors (ERs). And mice mutant for the aromatase enzyme (and thus who cannot produce any estrogen at all), show a profound decrease in sexual behaviour and aggression.

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But, what is interesting is that in ARKO (androgen receptor knockout mice), who don’t possess androgen receptors, treatment with estrogen rescued their sexual behaviour and libido. So estrogen turned them back into horny little mice again. Administration of DHT (which doesn’t aromatise to estrogen and is thus a good choice of hormone as a pure androgen receptor agonist rather than having two vectors like testosterone, which can be aromatised into estrogen and thus bind to both the androgen and estrogen receptor subtypes) had no effect on rescuing these ARKO mice from their diminished sex drive.

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So really, the research backs up that estrogen seems to have a criticial role in sex drive at a brain level, and I believe this is why so many of my clients struggle on TRT with serum estrogen (estradiol) levels outside their optimal ‘window’.

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Estrogen: The Window

The research really shows a dual effect. And I tend to find two rough camps of people who start TRT.

1. The anti-AI group. The group that under no circumstances will ever touch an AI and will let estrogen float to wherever and whatever level it wants to, on their TRT protocol.
2. The AI group. This group will try and keep estrogen under a predetermined level at all times by utilising an aromatase inhibitor.

And yet, both approaches seem to neglect the fact that the research time and time again backs up that estrogen levels either too high or too low cause significant issues.

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Estrogen induces VEGF, which is a potent vasodilatory (relaxing) signal protein. Usually, when we get erect, the veins responsible for blood leaving the penis are constricted to ensure blood stays in the penis and hard for our poke in the whiskers. However, estrogen through VEGF has been shown to increase venous ‘leakage’, meaning that it gets very difficult to maintain an erection, as blood is physically not remaining where we want it - in our Johnson.

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In fact, in this study, the ONLY difference in men with and without erectile dysfunction was that the men who had ED had vastly increased estrogen levels. Estrogen receptors (ERs) are also found extensively in the corpus cavernosum vasculature of our penis - the sponge-like structures that contain most of our blood during erection. And so, it seems key that ensuring these receptors are stimulated to the optimal degree (not too much, not too little) through modulation of estrogen is going to be the key to getting the most out of TRT from a sexual standpoint.

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Not only this, but estrogen has profound impacts on the HPT axis. Some people think it’s just testosterone that has a negative feedback loop to inhibit gonadotropin release and production (LH/FSH) in the hypothalamus/pituitary. However, estrogen also has a strong negative feedback effect, and increased estrogen levels can absolutely reduce circulating LH/FSH and thereby testosterone levels.

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In fact, because we know that adipose (fat) tissue has a high expression of aromatase enzyme, I have dealt with many of my clients who have been significantly overweight or carrying excessive body fat that also have low testosterone levels. I’ll never forget the case study of John* (*not his real name), who came to me with circulating total testosterone levels of 97 ng/dL, taken at 8am in the morning. Terrible by any means, and it was severely affecting his cognition, energy, sex and life. John was carrying excessive body fat, and had estrogen (estradiol) levels at 2.5x reference range. Through an extensive dietary intervention we reduced his bodyfat % from around 38% to roughly 18%, give or take. His latest blood test just a few months ago? Almost 650 ng/dL, naturally. His estrogen was also well within reference range. No other intervention except losing weight, and decreasing his aromatase enzyme activity locally in his adipose tissue.

So my point here is: letting your estrogen float as high as it wants on 200mg/week of testosterone (which isn’t really TRT, by the way) will almost always lead to an E2 level higher than optimal, causing the issues mentioned above.

Estrogen also has a complex interplay with 5-HT (serotonin) receptors in the brain, affecting mood and libido. I won’t go into the science too much here, but there are positive correlations between estrogen and serotonin binding (the more estrogen, the more binding). And studies have shown that high levels of serotonin in the cortex, limbic system, hypothalamus, and midbrain, mean sexual desire is inhibited with subsequent induction of refractoriness and sexual satiety. High levels of serotonin in the brain (like what SSRIs achieve) typically lead to lower levels of sexual desire, and, according to the research, estrogen at high levels can do this. This study showed that administration of estrogen desensitised serotonin receptors and increased serotonin concentrations in the synaptic cleft, again, leading to reduced sexual desire. So estrogen at high levels can absolutely reduce sexual desire, and I know for myself when I’ve left my E2 float ridiculously high, my morning wood has all but disappeared and I’ve barely been able to get hard.

And then of course, you have the AI group who try and crush their estrogen levels. In men with low testosterone (and therefore low conversion to E2), administration of exogenous E2 has been shown to increase libido. In this study, eliminating estrogen and increasing the T/E ratio too much reduced sexual drive significantly. The fact is, that important sexual regions of the human brain rely on E2 to drive masculinisation and sexual drive, so completely crushing E2 is going to lead to issues. And I see it with the people I work with (clients), whereby they have crushed their E2 and for the life of them cannot get hard or have significantly low libido.

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What range is best for estrogen in men? What to do?

So of course, with all that out of the way - what can we do?

If you are on TRT, I would say the best option is to keep your E2 levels in a ‘window’. Studies have shown estradiol levels <5 ng/dL (50 pg/mL) to be correlated to a decrease in libido. However, through experience I find this can be too aggressive, so I would suggest anywhere from 40-65 pg/mL to be a rough guide to the optimal window. If you want a calculator because you are in a country that reports E2 lab values in different units, see here.

However, a huge caveat here: all of this is incredibly individualised. One man at 65 pg/mL may feel vastly different from someone else at the same level. And so part of this is an experimental process with your doctor to see where you feel best. And of course, all of this is my opinion. You should always speak to your doctor about your protocol and managing your health.

How to get there? In my opinion only, a well-structured TRT protocol will require either no, or a very minimal approach to aromatase inhibition (E2 suppression). I have recommended to some people natural aromatase inhibitors if their E2 is only slightly high and they have symptoms of high E2. Compounds like resveratrol, grape seed extract, curcumin and some other flavonoids are candidates here. If that fails, literally like 1/8th of an AI per week can be subtle enough to move the needle just enough to get some people feeling better, and within the E2 ‘window’ that is best for them.

In terms of low estrogen, this would be remedied by a proper TRT protocol in any case. If not, I would look at both the dose volume and dose frequency. Apart from those, if I had someone who still wasn’t responding, they could have a mutation in the CYP19A1 gene leading to aromatase deficiency. However, this is so exceedingly rare in most cases it isn’t worth mentioning in my opinion.

And of course, the TL;DR: estrogen seems to be a hormone best kept within a therapeutic window, that will be individual to you. Too high or too low in my experience and anecdotally working with men across the world can lead to significant sexual, mood and cognition issues that may then lead to the blame being shifted to TRT; “my TRT protocol is wrong, I must up my dose!” I hope this post gives you something to think about as part of this whole TRT puzzle.

Thanks as always for reading.

-The Fitness Doc.