The Back Story of the Brain Injury Progesterone Study

Dr. David Wright explains how Dr. Donald Stein first started studying progesterone as a way to prevent swelling in the brain after a brain injury.

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The story behind progesterone actually is rather fascinating. It started literally 27 years ago today, and it's when a gentleman by the name of Dr. Donald Stein-- who's a brilliant scientist--was doing work in his lab on brain development and something we call neuroplasticity, where you look to see if the brain can repair itself. Back when he was doing this work, people didn't believe that the brain could repair itself, so it was rather novel work, at the time, anyway. What he found, or kept finding, was that his female rats were recovering better than the male rats in his studies. And, unlike many scientists who would have said, this is causing my experiment a problem-- I'm going to ignore and only do one gender, he basically said, no, this is something very important--I'm going to pursue it. And then--over a period of 17 years, doing a variety of very elegant experiments-- he realized that it was actually the hormonal state of the animal that conferred the neuro-protection. And so, basically what he found was that when the animal was high in progesterone-- which is a hormone that goes up and down in the menstrual cycle-- that the animal had almost no brain swelling after an injury compared to the male cohorts or compared to females that didn't have the progesterone high in the animals. He then did another experiment where he made the animals think they were pregnant. It's called pseudopregnancy, and there's a way to do this. Essentially, the female animal thinks it's pregnant, and so it's hormones change dramatically. One of those changes is that progesterone goes 10- to 100-fold higher than what it would normally be in the menstrual cycle. Indeed, when the progesterone was really, really high, the amount of swelling in the brain after the injury was equal essentially to as if the animal had no injury. And this was his epiphany. This is where he realized, I'm on to something. After many years of thinking whether it's structural-- what is the reason for the difference in the female rats and the male rats? And it turned out to be hormonal-- which is good, because that's something that we can modulate. So, from that point on, he began to aggressively try to figure out-- Okay, endogenous hormones make a difference. What about if we give progesterone? So, he did an experiment in the animals and was able to show that-- in both female and male rats--that there was equal protection. This actually, again, was a very pivotal question. Remember, at the time, we were thinking that progesterone-- or everybody thought--that progesterone was a female hormone. No one even realized or knew whether males would respond to it at all. And indeed they did, just as well as females. We now know that progesterone is not a female hormone actually. It's a neuro-steroid. It's produced in the brain, by the brain, for the brain. Probably the reason--at least the fundamental thinking behind-- why progesterone is even in the menstrual cycle is because it is there for the neuronal development of the fetus. It begins to get very high in the first, second, third trimesters of development, and it's critical that it be there for neuronal development. That's what the thinking is behind what progesterone is doing in the female menstrual cycle and pregnancy. So, technically it's not a female hormone. Technically it's a neuro-steroid, neuro-development, brain development steroid. It's very highly conserved if you look back evolutionarily. It's in very, very early animals. In very early organisms, progesterone and the receptors for progesterone are present, so you know there's something critically important about it. Much of this discovery has really been more recent than when Don first started his work. So, when he gave it to the male animals and realized that it was working, he began to look at the amount, the dose, the window, and all of the things that you need to get prepared for human testing.
Posted on BrainLine October 25, 2012. Reviewed July 25, 2018.

Produced by Victoria Tilney McDonough, Ashley Gilleland, Justin Rhodes, and Erica Queen, BrainLine.