We still have guys that feel like crap with E2=~40 who feel a lot better, mentally and physically, nearer E2=22 pg/ml.
Defy Medical states: "Another concerning fact is that many clinics may be using the wrong estradiol test that may be over-estimating the levels of this hormone in men. An ultrasensitive estradiol test more accurately measures estradiol in men instead of the regular test that costs less. "
So we have to also keep there ratio suggestions in that context. Defy Medical states that very little data exists, but they in turn are making some very definite statements. It appears that they are making recommendations engineered to not treat E2 levels unless above normal lab ranges. We know from many many guys here that that is a recipe for disaster.
The bottom line is how an individual feels VS his E2 lab results and not all lab results are the same. We know what works well for most guys here. There are always exceptions, like guys who are anastrozole over-responders and testosterone hyper metabolizers, guys who have bad reactions to clomid. The best course of action is doing what works well most of the time, then refining doses to suit individuals. We can't let the few who need E2 levels higher be making assertions that would be horrible for most guys.
So what is it about estrogens in males that affects mental health? During puberty, increased testosterone changes brain function and patterns. This is very disruptive and been a teenager can be a difficult transitionary process. Many brain circuits are pruned out and others inhibited. For many male, estrogen dominance leads to mood, intolerance, sexual and energy problems, with confusion as the brains adult configuration struggles when estrogens alter brain function. Just how ones brain circuits evolved to a male brain state and how the brain copes when supporting T and E states change is as individual as the the person. But larger patterns are obvious and easy to recognized.
I have read a two good books, not recalling the titles at this moment, that explore the differences of and between male and female brains and how these change and differentiate over ones life time. Women typically have more caring and nurturing circuits that develop under the domination of estrogens. Men have those circuits largely pruned out under the influence of testosterone and are better equipped to butt heads with other males and excel as warriors and hunters [not driven by empathy and caring]. When women loose estrogen levels they can become less caring. When men have lower T or some estrogen dominance they can become weepy, emotional and typically have a very difficult time of that.
Guys who are really doing better with high normal E2 levels on TRT, do not have the same brain characteristics of guys who would feel like crap with those lab numbers. There is not way to determine these things in advance and they need to struggle to find out what works for them.
SHBG: SHBG is created in the liver to scavenge hormones in blood circulation for return to the liver to be metabolized. The female blueprint controls this and greater estrogen levels cause the liver to produce more SHBG. If E2 is high, not only is E2 blocking E2 benefits, SHBG increases and more T becomes T+SHBG and FT levels decrease. So with more E2 and less FT, there is a double hit on E2:bio-T. And T often blocks estrogens at estrogen receptors and that may be why increased T levels tend to drive down SHBG, leading to more bio-T as there is less T-->SHBG+T. There are some medical conditions that increase/decrease SHBG levels. And a few here seem to have quite low SHBG levels with reasons unexplained.