Latest / The Sirona Health Podcast: PMDD, Hormones & Mental Health / What Brain Scans Actually Show: From PMDD to Menopause

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What Brain Scans Actually Show: From PMDD to Menopause · The Sirona Health Podcast: PMDD, Hormones & Mental Health

• 0:04
  Hormones don't just run your cycle.
• 0:07
  They run your mood, your mind, your whole sense of self.
• 0:11
  I'm Dr.
• 0:12
  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.
• 0:27
  over the last couple of episodes, I've talked about hormone sensitivity, dash MC, and then reproductive depression, this idea that one underlying trait keeps showing up across a woman's whole reproductive life.
• 0:41
  And I said at the end of that last episode that I wanted to come back to the evidence properly, because by this point you might reasonably be asking,"Okay, but how do we actually know any of this?" So that's what today is.
• 0:57
  We're looking directly at brain scans, what actually happens inside a PMDD brain in real time, and how that compares to a brain without PMDD.
• 1:08
  I think before we could get to PMDD specifically, researchers first had to answer a much more basic question: do gonadal hormones actually affect brain function at all in any measurable way?
• 1:23
  Before I get into that, let me just quickly explain what the prefrontal cortex actually is, since I'm going to keep coming back to it today.
• 1:33
  It's the part of your brain sitting right at the front behind your forehead, and it's really your brain's control center.
• 1:41
  It's what handles concentration, planning, decision-making, holding information in mind while you work with it, And importantly, for everything we talk about on this podcast, it's heavily involved in regulating your emotions, putting the brakes on an impulse, or talking yourself down from a reaction before it takes over.
• 2:04
  So when I say a study found changes in the prefrontal cortex, I don't mean some obscure corner of the brain, I mean the exact region responsible for concentration, self-control, and keeping your emotional reactions in check.
• 2:21
  That's why it keeps showing up in this research again and again.
• 2:26
  There's a particularly good example of this where researchers used a brain imaging technique to measure blood flow while women performed a demanding cognitive task, one that reliably activates the prefrontal cortex under three different hormonal conditions.
• 2:45
  First, with their ovaries essentially switched off using medication, then with estrogen added back, then with progesterone added back instead.
• 2:56
  The result was properly striking.
• 2:58
  With hormones removed from the picture entirely, there was almost no activation in the prefrontal cortex during the task, even though the women performed it just as accurately as ever.
• 3:12
  As soon as either estrogen or progesterone was added back, normal prefrontal activation returned.
• 3:19
  So the prefrontal cortex doesn't just tolerate having these hormones around, it actually seems to need them to engage properly during demanding mental work.
• 3:30
  I think that finding reframes this whole conversation.
• 3:34
  If the frontal lobes need hormonal input to function normally, it starts to make complete sense that fluctuating hormones across a cycle would have real measurable effects on mood and cognition, not as some vague hand wave about being hormonal, but as an actual specific mechanism you can watch happening Once that groundwork was established, research turned to the parts of the brain most relevant to mood, particularly the amygdala, which is central to processing threat and negative emotion.
• 4:10
  One study scanned naturally cycling women twice, once early in their cycle when both hormones were at their lowest, and once in the mid luteal phase.
• 4:21
  While viewing negative images, both the amygdala and the hippocampus showed significantly greater activity during the luteal phase This fits a much broader pattern across the research generally.
• 4:36
  A large review looking at methodologically sound cycle studies found that cognitive differences across the cycle, things like mental rotation or verbal memory, tend to be small and inconsistent, but emotional changes are far more reliably observed, and they track much more closely with progesterone than with estrogen.
• 5:00
  High progesterone has consistently been linked to increased amygdala reactivity and stronger emotional memory formation.
• 5:10
  There's a related study I find fascinating looking specifically at the orbitofrontal cortex, which sits right next to the amygdala and helps regulate emotional responses.
• 5:22
  It found a real split across the cycle.
• 5:26
  The medial part became more active in response to negative words premenstrually, while the lateral part, that's the bit on the outside, became less active during the same window, even in women with no premenstrual symptoms at all.
• 5:43
  The interpretation is that this reflects increased top-down regulatory demand premenstrually.
• 5:51
  The emotional brain becomes more reactive, and the regulating regions have to work harder to keep on top of it I think this next bit is worth flagging because it surprised me when I first read it properly.
• 6:07
  A structural MRI study looked at actual gray matter volume across the cycle, rather than just how active different regions were.
• 6:15
  It found that gray matter in part of the hippocampus was relatively increased after menstruation compared to the premenstrual phase, with the opposite pattern showing up in part of the basal ganglia.
• 6:30
  Verbal memory performance improved after menstruation too, so this isn't just about which regions light up moment to moment.
• 6:38
  There are actually detectable structural differences in brain tissue across a single month.
• 6:45
  And a couple of further studies widened this picture even more.
• 6:48
  One compared men and women scanned during different cycle phases while viewing stressful images, looking at the brain's stress response circuitry as a whole.
• 6:59
  Women scanned when estrogen was high and unopposed by progesterone showed markedly reduced activation in this circuitry compared to men, particularly in the prefrontal regulatory areas.
• 7:13
  So estrogen, when it's not being opposed by progesterone, seems to have a real protective, calming effect on the brain's stress response.
• 7:23
  Another study looked at reward circuitry specifically and found the amygdala, orbital frontal cortex, and striatum were all more reactive during the follicular phase than the luteal phase, both anticipating a reward and receiving one, which is a useful reminder that these hormone-brain interactions aren't only about negative emotion, they touch reward and motivation too, and that might have relevance well beyond PMDD Everything I've described so far is normal hormonal modulation of the brain in women without significant symptoms.
• 8:05
  I think the important question is what's different in the brains of women who do have PMDD?
• 8:11
  And this is where the evidence gets a lot more specific and a lot more compelling.
• 8:16
  One study directly compared women with PMDD to women without it, scanned in both the premenstrual and post-menstrual phases while doing an emotional word task.
• 8:29
  In the premenstrual phase specifically, the PMDD group showed an increased amygdala response to negative words compared to controls, alongside a decreased response in the ventral striatum to positive words.
• 8:44
  That's a meaningfully different pattern from ordinary cycle fluctuation.
• 8:50
  It means the PMDD brain isn't just more reactive premenstrually in the way any sensitive brain might be, it's reactive in a way that's measurably abnormal compared to women without the condition.
• 9:04
  A further study went even further, using two different brain imaging methods in the same patients, scanning women with PMDD during a working memory task under three tightly controlled hormonal conditions deliberately designed so any differences found couldn't be explained by different hormone levels between groups because those levels were kept identical.
• 9:29
  Across both imaging methods, the PMDD group showed abnormally increased activation in a specific part of the prefrontal cortex I mentioned earlier, called the dorsolateral prefrontal cortex, essentially the part most involved in concentration and working memory compared to controls.
• 9:49
  And here's a bit I think is remarkable.
• 9:51
  The degree of that overactivation correlated with real clinical measures, functional disability scores, the age at symptom onset, and how severely mood symptoms had changed between the premenstrual and postmenstrual weeks measured before the study even began.
• 10:10
  Earlier onset and greater disability were both linked to more pronounced overactivation.
• 10:16
  I think that's strong evidence this abnormal brain response isn't just a side effect of someone's mood on the day of the scan.
• 10:24
  It looks like a stable trait-level marker of vulnerability to PMDD itself.
• 10:30
  I want to mention another piece of research, a wider review that pulled together findings from 18 separate PMDD neuroimaging studies, covering over 360 women in total.
• 10:44
  On one level, it's actually reassuring because pooling across that much data, the same core pattern holds up.
• 10:51
  Enhanced amygdala reactivity alongside reduced frontal cortical reactivity compared to women without PMDD.
• 11:00
  A single study finding something is interesting.
• 11:03
  18 independent studies converging on the same pattern is much harder to write off as coincidence.
• 11:10
  But it also surfaced two unexpected things.
• 11:14
  First, several studies found greater gray matter volume and altered metabolism in the cerebellum in women with PMDD, a region traditionally associated with movement and coordination, but increasingly understood to play a role in emotional processing too.
• 11:32
  Second, several studies found altered serotonin and GABA signaling in the PMDD brain specifically, not just which regions activate, but how the underlying chemical systems function.
• 11:46
  And I think that's a really important finding because those two systems are actually what our two most established PMDD treatments actually target.
• 11:56
  SSRIs act on serotonin, and allopregnanolone, which we've talked about before, acts directly on the GABA system Everything I've talked about so far concerns hormones fluctuating across a monthly cycle or across the menopause transition itself, but there's an obvious question that follows on from all of this, which is what actually happens once those hormones settle at a permanently lower level after menopause?
• 12:25
  If the brain needs gonadal hormones to function normally, what happens when they largely stop being produced at all?
• 12:33
  There's a really substantive piece of research on this published only recently that I think is worth taking seriously because of its sheer scale.
• 12:42
  The researchers analyzed data from almost 125,000 women, and around 11,000 of those actually had detailed brain scans.
• 12:53
  They split women into three groups: premenopausal, postmenopausal and never used HRT, and postmenopausal and using HRT.
• 13:05
  Postmenopausal women in both groups showed measurable reductions in gray matter volume compared to premenopausal women, and this wasn't spread randomly across the brain.
• 13:16
  It was concentrated in three specific areas: the hippocampus, which forms and stores memories The entorhinal cortex, which acts almost like a gateway, passing information between the hippocampus and the rest of the brain, and the anterior cingulate cortex, which helps you manage emotions, make decisions, and focus your attention.
• 13:39
  Those researchers pointed out something I think is genuinely important.
• 13:43
  These are exactly the regions that tend to be affected early in Alzheimer's disease.
• 13:49
  Their view was that menopause may make women more vulnerable further down the line, and that this could be part of why we see roughly twice as many cases of dementia in women as in men.
• 14:01
  Now, here's the part I really want to get right because it's easy to misrepresent.
• 14:05
  That same large study found that HRT did not appear to reverse or reduce these gray matter changes.
• 14:13
  The one place it seemed to help was reaction times.
• 14:17
  Women not on HRT showed a faster age-related slowing in reaction speed than those on it.
• 14:25
  But on memory tasks specifically, there was no meaningful difference between any of the three groups.
• 14:31
  And interestingly, the same study found that women prescribed HRT actually had somewhat higher anxiety and depression scores than those who weren't, though when the researchers dug into the data properly, those differences were already present before menopause even began.
• 14:49
  So it's likely a case of doctors prescribing HRT for women they anticipated would struggle more rather than HRT itself causing that difference.
• 14:59
  I think it's worth being honest that the wider research on HRT and dementia risk is genuinely conflicting, not just quietly inconclusive.
• 15:09
  One large study of around four hundred thousand women found that HRT was associated with a reduced risk of the conditions that cause dementia.
• 15:18
  Another, following over fifty-five thousand women in Denmark, found the opposite, that HRT was associated with an increased risk.
• 15:28
  Part of why this is so difficult to untangle is that brain fog itself is a common, normal menopausal symptom.
• 15:36
  But it can also be an early symptom of dementia.
• 15:39
  So if early dementia is ever mistaken for ordinary menopausal brain fog and HRT gets prescribed as a result, that alone could distort the numbers in either direction.
• 15:51
  This is very much still an active, unresolved area of research and I think the honest position right now is that we don't have a clear answer either way So where does that leave us?
• 16:02
  I think what this research actually gives us is a plausible biological explanation for the very real brain fog, memory changes, and word-finding difficulties so many women describe around this time, alongside good evidence that HRT isn't a simple fix for it at the level of the brain structure, However much it may help with hot flushes, sleep, or mood for a given individual.
• 16:27
  I want to be careful not to make this sound alarming, though.
• 16:30
  These are average group-level findings, not a prediction for any individual woman, and the overwhelming majority of women who go through menopause never go on to develop dementia.
• 16:41
  I'll go into brain fog itself and what it actually feels like day to day, how to tell it apart from something more serious, and what actually helps properly in its own episode a bit further into the series.
• 16:53
  For today, I just wanted you to have the underlying evidence for why it's real.
• 16:58
  So to bring today together, gonadal hormones don't just exist in the bloodstream and separately affect mood as an afterthought.
• 17:07
  They act directly and specifically on the brain circuits responsible for emotional reactivity, regulation, memory, and stress response, and they do so differently across the cycle in every woman.
• 17:20
  In PMDD, that same system responds abnormally, not just more strongly in the way any sensitive brain might, but in patterns of over and underactivation that are measurably different from women without the condition and that correlate directly with how severe someone's symptoms actually are.
• 17:40
  And once hormone levels settle permanently lower after menopause, we see measurable structural change in some of these same regions too, which helps explain why brain fog and memory changes at that life stage are real, not imagined.
• 17:57
  I think it's worth sitting with why the serotonin and GABA findings matter beyond the lab too.
• 18:03
  They're not just an interesting detail.
• 18:05
  They line up directly with why our two most established treatments actually work.
• 18:11
  The newer imaging isn't just describing PMDD, it's pointing at exactly the systems we're already treating clinically and helping explain why those treatments help.
• 18:22
  This is really the scientific foundation for something I keep coming back to across the series.
• 18:27
  PMDD is not a psychological overreaction to normal hormones.
• 18:32
  It's a specific identifiable difference in how certain brain circuits respond to the same hormonal signals every woman experiences.
• 18:42
  The hormones aren't the problem, the brain's response to them is.
• 18:47
  Next time, I want to go one step further back and ask why some brains are built to respond this way in the first place.
• 18:55
  We're going to look at the genetics That's it for today.
• 18:59
  I'm Georgina.
• 19:01
  Thanks for listening.
• 19:02
  A quick note before you go.
• 19:04
  This podcast is for general information, not individual medical advice.
• 19:08
  It doesn't replace seeing your own GP or a specialist.
• 19:12
  So if anything you've heard today feels relevant to you, please do talk to someone.
• 19:17
  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.
• 19:25
  You can find Sirona Health and book your appointment at sironahealth.co.uk.
• 19:30
  See you next time