Why Do Some Women Get PMDD and Others Don't? The Genetics Behind It

If two women have identical hormone levels but completely different experiences of their cycle, what's actually different between them? In this episode, Dr Georgina Standen goes back a step further than hormones themselves, into the genetics and cell biology behind why some brains are wired to be more hormone-sensitive than others.

In this episode:

• The classic hormone-suppression study that proved PMDD isn't about hormone levels at all
• What twin studies tell us about how much of PMDD is inherited
• The specific genes researchers keep finding — ESR1, a serotonin receptor gene, and GABRB2
• The cellular research showing PMDD cells respond differently to hormones at a genetic level, right down to a mismatch between gene instructions and the protein actually produced
• Why understanding the mechanism explains why treatment isn't one-size-fits-all

Sirona Health Podcast is hosted by Dr Georgina Standen, GP and founder of Sirona Health (sironahealth.co.uk), a specialist women's health practice covering menopause, PMS/PMDD and teen health. Book a consultation at sironahealth.co.uk.

This podcast is for general information only and doesn't replace individual medical advice — please speak to your GP or a specialist about your own symptoms. If you're struggling, please reach out for support.

Transcript

0:04

Hormones don't just run your cycle. They run your mood, your mind, your whole sense of self. I'm Dr. Georgina Standen, GP and founder of Sirona Health, and this is the Sirona Health Podcast, where we talk about the relationship between female hormones and mental health properly, without the mystique and without the dismissal. It's a question that comes up when I'm working through this with patients, and it's one I find myself thinking about too. Two women, similar lives, similar cycles, similar hormone levels on a blood test, and one of them is fine every month, and the other is basically not herself for a week or two before her period. Same hormones, wildly different experience. So what's actually going on there? That's what I want to get into today. We're going back a step further than we have so far in this series and asking why some brains end up hormone sensitive in the first place So let's start with the foundation because everything else today builds on it. This is something we've established earlier in the series, so I'll go through it quickly rather than treat it as new. If you measure estrogen and progesterone in the blood of a woman with PMDD and compare it to a woman without PMDD, the numbers usually come back the same. There's a particularly elegant study that really nails this down using a similar experimental setup to the brain scan research I talked about last episode. Ovaries switched off with medication, then hormones added back in a controlled way. But this one tracked actual symptoms rather than brain activity. In that suppressed state, neither group had symptoms. Then, researchers added back estrogen and progesterone in a blinded way so nobody knew what they were getting, and it was only the women with PMDD who actually developed mood symptoms when the hormones came back. The women without PMDD, given exactly the same doses, felt nothing at all. So the conclusion from that work, and it's held up well since, is that PMDD isn't a hormone problem in the sense of too much or too little. It's a difference in how the brain, and possibly the whole body, responds to completely normal hormone signals. Something about the response is different, not the signal itself. Today I want to push one step further and ask, where does that difference in response actually come from? So if it's about sensitivity rather than hormone amount, the obvious next question is, where does that sensitivity come from? Is this something you're born with? Twin studies are usually how researchers try to answer that question, because comparing identical twins who share all their genes to non-identical twins who share about half lets you estimate how much of a trait is coming from genetics versus environment. For premenstrual symptoms, several twin studies have found that identical twins are more likely to share the trait than non-identical twins. And heritability estimates across different studies have landed somewhere between roughly a third and a bit over a half. So there's a real genetic contribution there, though it's clearly not the whole story. Environment and life experience matter, too, and I'll come back to that later. I'd flag one honest caveat: most of these older twin and family studies relied on women remembering their symptoms after the fact rather than tracking them day by day in real time, which is the more rigorous way to diagnose PMDD properly, as we talked about in the diagnosis episode. So the heritability numbers are probably in the right ballpark but not perfectly precise. Before I get into specific genes, let me quickly explain what I actually mean when I say that, since it matters for understanding what comes later. A gene is essentially an instruction, a stretch of DNA that tells your cells how to build a particular protein, and proteins are the actual working parts of your body. They're what receptors are made of, what enzymes are made of, what most of the machinery inside a cell actually is. Having a gene doesn't automatically mean it's being used, though. Genes can be switched on or off, or turned up and down, a bit like a dimmer switch, and that's called gene expression. So when I talk about a gene being more or less active, I mean the instruction is being read out more or less often, which usually, but not always, as we'll see, translates into more or less of that protein actually being made. Given that PMDD runs in families to some degree, researchers have gone looking for specific genes. And this bit is honestly a bit humbling because most candidate gene studies have come back negative, or the results haven't replicated well from one study to the next. That said, a few genes keep coming up. One is the estrogen receptor gene called ESR1, which codes for the docking site estrogen attaches to inside cells. A variant in this gene has been associated with PMDD risk in more than one study. There's a related gene, ESR2, the other estrogen receptor, with some more limited evidence too. Another one is a variant in the gene for a particular serotonin receptor. Serotonin is heavily involved in mood regulation generally, so a change in how sensitive that receptor is could plausibly shift how someone's brain handles the emotional load of hormonal change. And then there's a gene called which is one of the building blocks of the GABA receptor, the same system I talked about a few episodes ago. Your brain's main calming inhibitory chemical, essentially the brake pedal for the nervous system. There's some striking work in mice bred without a working copy of this gene, showing a mixed picture. Some things that look like an exaggerated PMDD type profile, other things that go the opposite direction, alongside clear disruption of several other brain chemical systems, not just GABA. It's animal data, so we have to be careful about how directly it maps onto women, but it does support the idea that the wiring of the GABA system is one of the places worth looking. I'll be upfront, none of these individual gene findings are settled science. For every positive study, there's usually a companion study that didn't find the same link. What that tells us, I think, is that PMDD probably isn't caused by one single faulty gene in the way something like cystic fibrosis is. It's more likely to be lots of genes, each contributing a small amount of risk, stacking up together, plus environment on top Now, this part I find interesting, and it comes from some clever lab work that gets at the mechanism directly rather than just the genetics. I mentioned this study briefly a few episodes back when I first introduced the idea of hormone sensitivity, so I want to properly unpack it now. Researchers took blood from women with confirmed PMDD and from women without it, and grew them in the lab as cell lines, so they could study them outside the body entirely, and with no hormones added at all, and then again after exposing the cells to estrogen or progesterone in a dish. What they found was a group of genes, 13 of them, that work together as a kind of team. Scientists call it the ESE/EZ complex, but the name doesn't really matter. What matters is what it does. This team of genes acts like a dimmer switch for other genes. It doesn't turn genes fully on or off, it adjusts how loudly or quietly they're expressed, and it's known to be controlled by ovarian hormones In cells from women with PMDD, this dimmer switch system was already behaving differently before any hormone was even added. Most of these thirteen genes were more active at the level of the genetic instructions being copied out in the PMDD cells compared to the control cells. But, and this is the part that really stands out, when they measured the actual protein being made from those instructions, it was the opposite pattern. Lower protein despite higher instructions. So there's a mismatch somewhere between the instructions being issued and the instruction being carried out, which the researchers themselves say they don't yet fully understand. Then when they added estrogen or progesterone to the cells, the two groups responded completely differently. In the control cells, several of these genes increase their activity in response to progesterone. In the PMDD cells, that same response didn't happen, and for one gene, activity actually dropped in response to estrogen. So it's not just a static difference sitting there in the background, it's a difference in how the cells react in real time when hormones actually arrive. Here's the plain English version of why this matters. Imagine the hormone is a key, and this gene complex is part of the lock mechanism deeper inside the cell that decides what actually happens once the key turns. In most women, that lock mechanism responds in a fairly steady, predictable way each cycle. In women with PMDD, it looks like the lock mechanism itself is built slightly differently, already primed differently before the key ever arrives. And it turns in an atypical way once the key does arrive. The hormone, the key, is completely normal. It's the lock that's different. And this lock and key system isn't confined to reproductive tissue, by the way. The gene complex sits inside a family of proteins that also modifies how DNA is packaged, a form of epigenetic control that shows up in brain regions involved in mood, in stress response, in GABA signaling, in how neurons grow and adapt. So a cellular difference like this, found in blood cells in the lab, plausibly reflects something similar happening in the brain, even though nobody's claiming blood cells are a perfect stand-in for neurons. So if I try to draw this together in one picture, you've got a genetic predisposition probably built from many small genetic variations rather than one big one. Some of them affecting hormone receptors for estrogen, some affecting hormone receptors for the breakdown of progesterone, allopregnanolone, and some affecting this deeper gene regulation machinery. And underneath all of that, genetics probably isn't acting entirely alone. Things like early life stress or trauma seem to interact with this biological vulnerability too, which is a reminder that biology and life experience aren't separate boxes. They influence each other. I think that's important enough that I'm going to give it a whole episode of its own properly once we get into how PMDD overlaps with other conditions later in the series, so I won't do it justice by rushing it here today. I think it's worth pausing on why any of this actually matters beyond what's interesting. A few reasons. First, it takes away the idea that PMDD is a woman not coping with normal hormones or being overly sensitive in some vague, dismissable way. There's a measurable biological difference in how cells and receptors respond. That's real physiology, not a character issue. Second, it explains something that's confusing in clinic, why treatments that work brilliantly for one woman do nothing for another. If PMDD isn't one single condition with one single mechanism, but rather a handful of different biological pathways that can all produce a similar symptom pattern, which is exactly what the DASHMC framework I talked about earlier in this series is getting at, then it makes complete sense that an SSRI works wonderfully for some women, a GnRH agonist works for others, and neither does much for a third group. Third, and this is more forward-looking, understanding the mechanism opens the door to more targeted treatments down the line, medications that work directly on GABA receptor sensitivity, for instance, rather than just adjusting hormone levels or serotonin generally So to bring it back to the question I opened with, why do some women get PMDD and others don't? The honest answer is it looks like an inherited vulnerability spread across quite a few genes that changes how sensitively the brain's chemistry and certain gene regulation systems respond to entirely normal monthly hormone changes. It's not about having too much hormone, it's about the response. If any of this sounds like it's describing your own cycle, it's worth tracking your symptoms properly against your cycle dates rather than just going on how you feel in the moment, because that's really the first step towards a proper diagnosis and towards figuring out which treatment pathway might actually fit your biology. Next time, I want to take everything we've built across hormone sensitivity, dash MC, and now genetics, and apply it somewhere very specific. What happens to a hormone-sensitive brain as it moves through perimenopause and menopause, and why so many women feel like their mental health suddenly changes in their 40s and 50s without understanding why? That's it for today. I'm Georgina. Thanks for listening. A quick note before you go. This podcast is for general information, not individual medical advice. It doesn't replace seeing your own GP or a specialist. So if anything you've heard today feels relevant to you, please do talk to someone. And if you're struggling, please reach out to your GP, to someone you trust, or to a crisis line if you need one right now. You can find Sirona Health and book your appointment at sironahealth.co.uk. See you next time