Latest / The Sirona Health Podcast: PMDD, Hormones & Mental Health / PMDD treatment: GnRH analogues

Transcript

PMDD treatment: GnRH analogues · The Sirona Health Podcast: PMDD, Hormones & Mental Health

• 0:04
  Speaker: Hormones don't just run your cycle.
• 0:06
  Speaker: They run your mood, your mind, your whole sense of self.
• 0:10
  Speaker: I'm Dr.
• 0:12
  Speaker: 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.
• 0:25
  Speaker: Last time, I mentioned I wanted to move into a treatment that works completely differently from anything we've covered so far.
• 0:33
  Speaker: Medication that switches off ovulation entirely, rather than just stabilizing hormones around it.
• 0:39
  Speaker: That's what today is, GnRH agonists and antagonists.
• 0:44
  Speaker: I want to explain what they actually are, why they're central to how we understand PMDD in the first place, not just how we treat it, and why the research on long-term ovarian suppression from other conditions entirely tells us so much about how to use them safely.
• 1:01
  Speaker: So GnRH stands for gonadotropin-releasing hormone.
• 1:06
  Speaker: It's produced by a small structure in your brain called the hypothalamus, and it's really the top of a chain of command.
• 1:14
  Speaker: It signals down to your pituitary gland, which in turn signals to your ovaries, and that whole chain is what drives your natural monthly cycle, the rise and fall of estrogen and progesterone we've talked about right through this series.
• 1:29
  Speaker: A GnRH agonist works in a slightly counterintuitive way.
• 1:34
  Speaker: It actually starts by strongly stimulating that pathway, which can cause a brief flare of hormone activity in the first week or two.
• 1:43
  Speaker: But with continued use, it ends up doing the opposite.
• 1:46
  Speaker: It desensitizes the receptors so thoroughly that the whole signaling chain essentially switches off.
• 1:53
  Speaker: A GnRH antagonist gets to the same destination by a more direct route.
• 2:00
  Speaker: It blocks the receptor immediately.
• 2:02
  Speaker: No flare, faster onset of suppression.
• 2:05
  Speaker: Either way, the end result is the same.
• 2:08
  Speaker: Your natural hormone production drops right down, close to the level you'd see after menopause, and ovulation stops completely I've actually referenced this exact tool a few times earlier in the series without fully explaining it, so let me properly join the dots now.
• 2:25
  Speaker: This is the medication behind that landmark study I described a few episodes back, where researchers suppressed women's ovaries down to near zero using a GnRH agonist, and then, in a blinded way, added estrogen and progesterone back in.
• 2:44
  Speaker: Only the women with PMDD developed symptoms when the hormones returned.
• 2:49
  Speaker: The women without PMDD, given exactly the same doses, felt nothing.
• 2:54
  Speaker: I think it's worth pausing on what that actually means practically, beyond being a clever piece of research.
• 3:00
  Speaker: It means GnRH agonists aren't just a treatment option, they're one of the best tools we have for confirming with confidence that someone's symptoms are hormonally driven in the first place.
• 3:13
  Speaker: Some clinicians use a time-limited trial of ovarian suppression specifically as a way of answering the question, "If I take your cycle away completely, do your symptoms actually go away too?" If they do, that's powerful evidence you're dealing with genuine PMDD, and it's also sometimes used this way before a woman considers a permanent step, like surgical removal of the ovaries, essentially a reversible rehearsal for an irreversible decision.
• 3:45
  Speaker: In terms of how well it actually works when used as ongoing treatment, a review pulling together the evidence found that upwards of 70% of women with treatment-resistant PMDD responded well to a GnRH agonist with hormone add back.
• 4:02
  Speaker: I think it's just as important to be honest about the other side of that number.
• 4:07
  Speaker: Roughly 30% of women don't respond adequately, even to this, which reinforces something I've said throughout this series, "PMDD isn't one single thing with one single fix, and even our most powerful tool doesn't work for everyone." In practice, the most studied injectable GnRH agonist for PMDD is leuprolide, typically given as a monthly injection, usually starting at a dose of 3.75 milligrams, and once someone's had at least a month of improvement on the combination of the agonist plus add back, some clinicians move to a higher dose given every three months instead, purely for convenience.
• 4:52
  Speaker: Other agonists like goserelin are used too.
• 4:56
  Speaker: The underlying principle is the same across all of them.
• 4:59
  Speaker: More recently, GnRH antagonists have come onto the scene, and some of these are useful for PMDD specifically because they're oral.
• 5:10
  Speaker: They act faster since there's no flare to wait out, and a couple of the newer combination formulations actually build a low dose of hormone replacement directly into the same pill.
• 5:22
  Speaker: I want to be honest about where the evidence base for these newer antagonists actually comes from, because it's relevant to how confidently I can talk about them.
• 5:32
  Speaker: The large, well-designed trials for Relugolix have been done in endometriosis and fibroids, not PMDD specifically, simply because those conditions, they're more common, and the trials are bigger and better funded.
• 5:47
  Speaker: What that research tells us is genuinely useful, how well these medications are tolerated, how effectively they suppress ovarian production, and crucially, what happens to bone density over one and two years of use, since that's tracked closely in these trials, with a bone scan built into the monitoring schedule after the first year of treatment.
• 6:10
  Speaker: We then apply a lot of that knowledge to how we use these same medications for PMDD it's a reasonable extrapolation, since the mechanism suppressing ovarian hormone production is identical, but I think it's honest to say the PMDD-specific evidence is thinner than the endometriosis and fibroid evidence is borrowing confidence from.
• 6:33
  Speaker: This is the part I really want you to take away from today because I think it's the single most important safety point in the whole episode.
• 6:40
  Speaker: We actually know an enormous amount about what happens to a woman's body when estrogen is taken away for a prolonged period, and we know it from research into something called primary ovarian insufficiency, where a woman's ovaries stop working properly well before the natural age of menopause, sometimes in her twenties or thirties, whether that's spontaneous or caused by treatment.
• 7:05
  Speaker: That research is sobering and is exactly why this matters here.
• 7:10
  Speaker: Sustained estrogen deficiency at a young age is linked to meaningfully reduced bone density and a real increase in fracture risk down the line because estrogen plays a direct role in maintaining bone.
• 7:25
  Speaker: It's also linked to an increased risk of cardiovascular disease because estrogen has a protective effect on blood vessels and cholesterol that you lose when levels drop and stay low.
• 7:37
  Speaker: If you've been listening to the series from the start, you'll remember the episode on brain scans where I talked about estrogen's role in memory and brain structure, and premature prolonged estrogen deficiency is a concern in that same territory too.
• 7:53
  Speaker: And overall, women with untreated primary ovarian insufficiency have been shown to have a shorter life expectancy on average than women who go through menopause at the typical age, largely explained by these downstream cardiovascular and bone effects.
• 8:11
  Speaker: So when we use a GnRH agonist or antagonist for PMDD, we are deliberately creating a temporary version of exactly that state, medically induced ovarian insufficiency, and I don't think that should be said lightly.
• 8:27
  Speaker: Here's the genuinely reassuring part though, and I think it's important to say this clearly because it can sound frightening otherwise.
• 8:35
  Speaker: The research shows that when a GnRH agonist is given alongside proper add back of an estrogenic hormone, bone density essentially stays unchanged compared to a real measurable drop when the agonist is used alone, even with calcium supplements.
• 8:53
  Speaker: So add back isn't just risk reduction, it appears to prevent the bone loss almost entirely for as long as ten years of use in some of the data we have.
• 9:04
  Speaker: Monitoring still matters.
• 9:07
  Speaker: A baseline bone scan is generally recommended if someone has other risk factors for low bone density and a follow-up scan every one to two years thereafter but this isn't a treatment where harm is inevitable and add back merely softens it.
• 9:22
  Speaker: Properly implemented add back is genuinely protective, not just damage limitation.
• 9:28
  Speaker: Current guidance is clear that these medications generally shouldn't be used for more than about six months without that add back in place.
• 9:37
  Speaker: And I want to be clear, going without it isn't a slower, gentler option.
• 9:42
  Speaker: It's simply not considered safe practice beyond that window.
• 9:46
  Speaker: Beyond the bone picture, add back also appears to meaningfully reduce cardiovascular risk compared to suppression without it, and the same logic applies to the brain health concerns.
• 9:57
  Speaker: One thing that might surprise you, for women who also get hormone-related migraines, add back doesn't tend to make things worse, And some women actually find their migraines improve on a stable, non-fluctuating regimen like this, rather than the unstable natural cycle they're used to.
• 10:15
  Speaker: Given everything I've just said, I want to be clear about where this treatment fits.
• 10:21
  Speaker: It's not a first-line option, and I don't think it should be, given everything we've covered today.
• 10:26
  Speaker: It tends to be reserved for women with severe, disabling PMDD who haven't responded adequately to the approaches I've covered in earlier episodes, the combined pill, transdermal oestrogen with a progestogen, or Slynd.
• 10:39
  Speaker: It's specialist-led, it needs proper baseline and follow-up monitoring, as I've described, and it's not something I'd expect a GP to initiate alone without input from a specialist with a specific interest in this area.
• 10:55
  Speaker: One thing worth knowing before you start, if this is ever right for you, is that the first month can genuinely be rough hormones are shifting into a new, stable pattern, and it's not unusual to feel worse before you feel better.
• 11:10
  Speaker: The advice from clinicians experienced in this area is consistent.
• 11:15
  Speaker: Don't stop or adjust the dose based on that first month alone, because symptoms very often settle once things have properly stabilized.
• 11:24
  Speaker: But for the right woman, someone whose life has been on hold because of monthly symptoms that haven't responded to anything else, it can be transformative, and knowing with real confidence through that suppression and add-back process that her symptoms are truly hormonally driven can be enormously validating in itself, even before you get to the treatment benefit.
• 11:47
  Speaker: So to bring today together, GnRH agonists and antagonists switch off the hormonally signaling chain that drives your cycle almost entirely.
• 11:59
  Speaker: And that same tool that treats severe PMDD is also the tool that first proved scientifically that PMDD is a real hormonally triggered brain condition rather than a psychological one.
• 12:12
  Speaker: We understand the long-term risks of that suppression really well, not from PMDD research directly, but from the sobering data on primary ovarian insufficiency.
• 12:25
  Speaker: And that's exactly why add back hormone therapy alongside it isn't optional.
• 12:29
  Speaker: It's what makes this a safe, reversible tool rather than something that trades one set of problems for another.
• 12:36
  Speaker: Next time, I want to move away from hormonal treatment altogether for an episode and talk properly about SSRIs and why they can work so much faster for PMDD than they typically do for standard mood problems.
• 12:51
  Speaker: That's it for today.
• 12:53
  Speaker: I'm Georgina.
• 12:55
  Speaker: Thanks for listening.
• 12:56
  Speaker: A quick note before you go.
• 12:58
  Speaker: This podcast is for general information, not individual medical advice.
• 13:02
  Speaker: 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.
• 13:18
  Speaker: You can find Sirona Health and book your appointment at sironahealth.co.uk.
• 13:23
  Speaker: See you next time