Dr. Betty Murray explains how allopregnanolone, a progesterone metabolite, affects mood in an inverted U-shape: too low causes anxiety, but mid-range levels during the luteal phase can paradoxically trigger PMS and PMDD in some women. Individual differences in how the liver metabolizes these hormones dramatically change the experience.
So here's the biological puzzle at the center of all this. Allopregnenolone, the metabolite your body makes from progesterone, follows an inverted U-shape, right? We love to talk about this. So what it means at low levels, it can increase anxiety and irritability. At the middle range, it's specifically around where you get to kind of that second half of your cycle called the luteal cycle. At that middle range, that can cause a paradoxical negative effect in susceptible women. So let me help kind of clarify this for you. So some women feel awesome until they ovulate and they hit the second half of their cycle, and then they are moody as hell, right? That's where PMS comes from. Premenstrual syndrome is the variation of progesterone in the second half of your cycle. Then you have PMDD, premenstrual dysphoric disorder, which is even worse, right? This is that U-shaped curve. We're probably okay until we get to here, and then as it starts to come up, we get this paradoxical effect in some women. This is not a small quirk. Some women feel amazing on progesterone— calm, sleep better, less anxious— and some women feel like they're coming out of their skin. And that's not where the research is wrong. It's the individual metabolism, where I spent my research and my PhD. Of how our body takes that stuff through the liver and processes it that is enormously impactful here. And this is what's the conversation that's missing from prescribing, absolutely, and never talked about in the nuance of social media.
