The Estrogen Paradox

The hormone that protects women's hearts also turns their immune systems against them. Biology doesn't pick sides.

I was talking to a group of medical students about this last year and they all had the same reaction. First there was confusion, and then there was this very specific kind of discomfort that you get when someone is rearranging a mental model that you are still in the middle of using.

The hormone that masculinizes the developing mammalian brain is not testosterone.

It is estrogen.

The one we all think of as the female hormone. The one on the pink team, if you are still thinking in those terms. And yet here it is doing the heavy lifting in male brain development. What happens is that testosterone circulates through the male fetus and it crosses into the brain just fine. But once it is inside those neurons, there is an enzyme called aromatase that grabs it and converts it into estradiol, which is a form of estrogen. And it is that locally brewed estrogen, not the testosterone, that binds to the estrogen receptors and does all of the actual construction work on the male brain.

If you block aromatase, then brain masculinization just stalls. The testosterone is sitting right there. There is plenty of it. It does nothing. Because it was never the active ingredient in the first place. It was just the packaging for the thing that actually does the job.

Naftolin and his colleagues worked all of this out in the 1970s. It has been standard neurobiology for about fifty years now. People keep forgetting about it because it makes their heads hurt.

Where the enzyme concentrates

So aromatase shows up unevenly across the brain, and that turns out to matter more than you would think.