[SPEAKER_00]: Hello and welcome to the Aquaman podcast.
[SPEAKER_00]: This is an exploration of woman kind.
[SPEAKER_00]: Here we discuss what it is to be a woman in the modern world while utilizing ancient and modern modalities in tandem to create a bounty of health for the body, mind and spirit.
[SPEAKER_01]: Good day everyone and welcome back to the pod.
[SPEAKER_01]: Hopefully having a nice day, hopefully you're having a nice week.
[SPEAKER_01]: I'm trying to record this so I can get to the airport in time to pick up my best friend.
[SPEAKER_01]: She's coming here to visit me for a few days.
[SPEAKER_01]: I'm so excited about it.
[SPEAKER_01]: But I just felt that it was my due diligence to do my weekly podcast.
[SPEAKER_01]: And before we get into it, I'd like to pay my respects to the elders past, present, and future in literary the Tasmania where I am recording this podcast today.
[SPEAKER_01]: baby.
[SPEAKER_01]: Let's talk about GLP ones.
[SPEAKER_01]: It is a huge thing online.
[SPEAKER_01]: I'm not going to go too hard call into their application.
[SPEAKER_01]: I'm just going to be covering it at the outset if you haven't heard about them.
[SPEAKER_01]: Wow, amazing for you.
[SPEAKER_01]: You must be living under a rock.
[SPEAKER_01]: I know I'm super late to this party, but I just I like to wait for the dust to settle for the height to kind of settle down.
[SPEAKER_01]: And then I look at the research and see what is actually being stated in the research, what we actually looking at in the research, what the research actually suggests versus what the hype is saying.
[SPEAKER_01]: And I can't really say that much about GOP 1's and that broad application to lots of different women's health.
[SPEAKER_01]: But I can speak to PCOS because I've looked into a lot of the research here.
[SPEAKER_01]: And I will say at the outset, there is a huge mismatch between
[SPEAKER_01]: What people are saying online and how we can apply PCOS and what it actually does and what the research has shown.
[SPEAKER_01]: And I've found some clinicians, I've found like health professionals online who are taking pilot randomized control studies with 28 women and saying,
[SPEAKER_01]: application for IVF, girl, we cannot say that yet.
[SPEAKER_01]: Anyway, I'm going to get into it.
[SPEAKER_01]: Let's talk about GOP ones and what they are, so you actually understand what they are and how they work in the body and how we're kind of hijacking a system.
[SPEAKER_01]: So GOP ones stand for glucagon, like peptide 1, GOP 1.
[SPEAKER_01]: That refers to the naturally occurring increase in hormone made by our body.
[SPEAKER_01]: So yes, our body makes GLP ones, not just synthetic GLP ones.
[SPEAKER_01]: We actually make them in the body.
[SPEAKER_01]: They produce primarily by the endocrine L cells in the disto small ilium.
[SPEAKER_01]: So in our small intestine, and in our colon in response to food intake, specifically carbohydrates of fats, and specifically a bowlless of carbohydrates of fats.
[SPEAKER_01]: So you sit down and have a fat pasta covered in olive oil.
[SPEAKER_01]: your small intestine is going to release your P1s in response to that.
[SPEAKER_01]: We also see GLP1s being released in the brain stem.
[SPEAKER_01]: So we have a brain kind of extends down into the upper part of our neck and we're also seeing GLP1s being released from the alpha cells in our pancreas as well.
[SPEAKER_01]: And this acts as a local neurotransmit and more gelator for insulin as well because the pancreas is where insulin is being made and released.
[SPEAKER_01]: So basically, what happens naturally?
[SPEAKER_01]: We eat a bowl of pasta covered in olive oil.
[SPEAKER_01]: Lots of fat, lots of carbohydrates, awesome macronutrients, we need them.
[SPEAKER_01]: That troubles through our small intestine when it reaches our small intestine of small intestine goes, wow, that's a lot of fat in carbohydrates.
[SPEAKER_01]: What I do in this situation is, I release gulping once, and that basically will enhance glucose dependent insulin secretion from the pancreatic beta cells.
[SPEAKER_01]: So our pancreas has beta cells, those beta cells release insulin.
[SPEAKER_01]: Insulin's job is to go over to the cell, attach to the cell receptor side that basically says there's keeps of glucose around my guy.
[SPEAKER_01]: You need to open up your glucose channel so you can use this as energy to power your mitochondrial function and all of the enzymatic reactions inside of the cell or we can store it as
[SPEAKER_01]: We're storing that as fat in our muscle tissue, in our liver, and in our outer post tissue, which is our fat tissue.
[SPEAKER_01]: Right?
[SPEAKER_01]: So GLP ones are basically the messenger between we see carbohydrates and fats, and oh, we're releasing insulin.
[SPEAKER_01]: It is a peptide that connects these two.
[SPEAKER_01]: physiological things that happen every day in our body.
[SPEAKER_01]: It will also at the same time, GLP's I'm talking about will also suppress glucogone release from the pancreatic alpha cells and that reduces hepatic glucose production.
[SPEAKER_01]: So our body will take other constituents in the body, it will take stored glucose and it will make glucose and put it into the blood system.
[SPEAKER_01]: GLP ones basically say we don't need to do that because we've got heaps of glucose in the blood system already because we've just had a bowl of pasta.
[SPEAKER_01]: You get and also on top of this GLP ones
[SPEAKER_01]: in the brainstem.
[SPEAKER_01]: So that's where some of your appetite centers are, and you have a thalamus in the brainstem, and GLP ones tend to tell those parts of our brain hey, we don't need any more, we're pretty full.
[SPEAKER_01]: The interesting thing about endogenous, so naturally occurring, we produce our own GLP ones, they are rapidly degraded within minutes by an enzyme called DPP4,
[SPEAKER_01]: which limits the duration of the action.
[SPEAKER_01]: So remember, this is a peptide, so it's made of amino acids that have been fully formed into a protein just yet.
[SPEAKER_01]: That will basically signal carbohydrates in system, fats in system as well, and we need to release insulin.
[SPEAKER_01]: It's only around for a short period of time, right?
[SPEAKER_01]: And it's also around in different parts of our brain to signal that we are full, and we don't need to eat that many more carbohydrates.
[SPEAKER_01]: Yeah, pretty interesting.
[SPEAKER_01]: Exogenous GLP ones, these are GLP-1 receptor agnus, so GLP-1 arrays.
[SPEAKER_01]: They are medications designed to mimic and enhance the action of natural GLP-1.
[SPEAKER_01]: But they resist that rapid breakdown by DPP4, which means it can stay around for a lot longer, it allows longer biological activity.
[SPEAKER_01]: GLP ones have been used for ever, for type 2 diabetes, weight management, obesity and overweight treatments.
[SPEAKER_01]: And they also have cardiovascular risk reduction indications as well, which makes total sense.
[SPEAKER_01]: Because if you are obese or overweight, you have too much out of post tissue that's going to put pressure on your cardiovascular system.
[SPEAKER_01]: If you lose the weight, it puts less pressure on the cardiovascular system.
[SPEAKER_01]: So those two things very often go hand in hand.
[SPEAKER_01]: Most GOP ones are administered by a subcutaneous injection using a pre-filled pen, so you can't really, unless you are talking to your doctor about doing different dosages, control the dosage, you can control it by if you're using it once a day, twice a day, once weekly, etc.
[SPEAKER_01]: There is oral formulation, so semi-oglutide, those are tablets and they're taking on anti-stomach and it's really, really strict how we take these, you have to make sure you're doing it on an anti-stomach to ensure absorption in your eating a specific food within a period of time after that.
[SPEAKER_01]: And that depends on your dosage, that depends on your doctor, et cetera.
[SPEAKER_01]: But mostly we're seeing gel p1s are administered via an injection.
[SPEAKER_01]: And so they include dual gluteide, exanotide, lower gluteide, and semi-gluteide.
[SPEAKER_01]: So semi-gluteide is ozampic.
[SPEAKER_01]: That's the most popular one when we've heard about animal jar as well.
[SPEAKER_01]: So again, once we, when we inject a GLP1, whatever one I just said, it will go into the blood system.
[SPEAKER_01]: Blood system goes throughout the entire body.
[SPEAKER_01]: And that will bind two receptors in the pancreas, brain and gastrointestinal tract, and your cardiovascular system as well.
[SPEAKER_01]: They're GLP1 receptors everywhere throughout the body.
[SPEAKER_01]: I don't have that much time to talk about it today.
[SPEAKER_01]: It's not really the primary purpose of this podcast, but I just want you to understand that we have GLP1 receptors all over the body, but usually they're not very activated because we don't have GLP1 circulating for that long, but this exogenous medication stays around for longer, which means it can attach to receptor sites longer.
[SPEAKER_01]: stay attached to those receptor sites and they exhibit their response for longer periods of time.
[SPEAKER_01]: Then we would see endogenous naturally occurring GOP ones from our brainstem and our small intestine.
[SPEAKER_01]: So when we use exogenous GOP ones, they suppress glucose integration, they reduce hepatic glucose output.
[SPEAKER_01]: They slow gastric emptying, so you feel fuller for longer.
[SPEAKER_01]: And that also means that you aren't as hungry.
[SPEAKER_01]: Because European ones are also acting on those appetite centers in your brain.
[SPEAKER_01]: We were just talking about in your hypothalamus in your brain stem.
[SPEAKER_01]: It attaches to this receptor site and says, we don't need to eat, we are full.
[SPEAKER_01]: And so therefore, people don't eat that much in their lose weight.
[SPEAKER_01]: We see that European ones improve blood pressure, lipid profiles, cepatic stereosis markers, and secondary metabolic markers.
[SPEAKER_01]: And we can put that all down,
[SPEAKER_01]: to the fact that we're losing weight.
[SPEAKER_01]: Yeah.
[SPEAKER_01]: So we see those outcomes even if you're not on a GLP1, we see those outcomes if you lose weight GLP1s just help that process along quite significantly.
[SPEAKER_01]: So there are a whole lot of different benefits associated with GLP1s because of this reason.
[SPEAKER_01]: Right?
[SPEAKER_01]: So we're seeing lower cardiovascular risk and we're seeing better cardiovascular outcomes.
[SPEAKER_01]: We're seeing a lower sister like blood pressure.
[SPEAKER_01]: We're seeing better acetylid endophilial function, we're seeing improved lipoprophiles, we're seeing decreased triglycerides.
[SPEAKER_01]: We're seeing a reduction in the liver fat storage, which is great because that decrease is liver disease, and that also decreases geo-fewants also enhance insulin sensitivity.
[SPEAKER_01]: So basically our cells have receptors for insulin and they actually start listening to insulin.
[SPEAKER_01]: So a lot of the time when we're talking about insulin, we're talking about the sensitivity that our cells have to insulin.
[SPEAKER_01]: So insulin comes over, attaches to a receptor site that opens up a glucose channel.
[SPEAKER_01]: But in individuals who have had high insulin for a long time, who have had high glucose for a long time,
[SPEAKER_01]: This is very often when those PCOS.
[SPEAKER_01]: What can happen is our cells go we're not listening to you anymore There's always insulin around a bit of a you know, it's a bit of a situation where these cells are like Okay insulin I hear you.
[SPEAKER_01]: I know that you're telling me that there's glucose in the blood system
[SPEAKER_01]: and that I need to open my glucose channel, but I'm actually good.
[SPEAKER_01]: I don't need any more glucose.
[SPEAKER_01]: I've had enough stored.
[SPEAKER_01]: We've got like all of our enzymatic reactions happening.
[SPEAKER_01]: We don't need any more glucose here.
[SPEAKER_01]: So I'm actually, I'm not going to respond to your message.
[SPEAKER_01]: I'm kind of going to ignore it.
[SPEAKER_01]: It's like when your mum calls you and you don't want to answer, yeah, that's what it's kind of like in a way to modernize it and to help you understand insulin sensitivity.
[SPEAKER_01]: But when people take
[SPEAKER_01]: They go, okay, yeah, cool.
[SPEAKER_01]: We can take in more glucose news worries and that stabilizes the blood system and that has lots of positive outcomes on cardiovascular metabolic and also like our weight management as well, which all positively impacts PCOS.
[SPEAKER_01]: We'll get there eventually.
[SPEAKER_01]: We're also seeing because there is a slower transit time.
[SPEAKER_01]: We're seeing altered bile acid signaling.
[SPEAKER_01]: We're seeing an improved metabolic environment.
[SPEAKER_01]: So lower blood glucose, lower insulin.
[SPEAKER_01]: So lower inflammation, generally.
[SPEAKER_01]: We're seeing that that indirectly positively influences the microbiome, which is awesome because a lot of women with PCOS generally have a non-diverse
[SPEAKER_01]: pretty sterilized and inflamed gut.
[SPEAKER_01]: But if we take a GOP one, what we do generally see because have how it impacts our gastric emptying and our blood glucose and blood insulin levels, we're generally seeing the gut microbiome becomes more diverse.
[SPEAKER_01]: and can heal a little bit.
[SPEAKER_01]: So we're seeing less intestinal hyper permeability and less inflammation, which generally is really, really great.
[SPEAKER_01]: Alongside this, GLP ones are so interesting.
[SPEAKER_01]: They impact our hyper thomas and our petuitary gland and how it responds to dopamine and the dopamine
[SPEAKER_01]: And a lot of things that I've heard about food and food addiction and binging, which a lot of women with PCOS struggle with, is that they don't feel like they need to do that anymore because your P1s can impact the diphenergic circuits in our brain.
[SPEAKER_01]: And so we're not addicted to things anymore.
[SPEAKER_01]: So I've heard stories of women who are shopaholics.
[SPEAKER_01]: who just don't necessarily feel like they need to do that anymore, people who are addicted to smoking addicted to alcohol, both incredibly addictive substances, don't really feel the need to drink or smoke anymore.
[SPEAKER_01]: And we also see that with food.
[SPEAKER_01]: So that's another way we're seeing weight reduction is because people aren't drinking that much, people aren't smoking that much, which is both associated with weight increase, and they're also not binge eating and not craving sugary salty, high fat, high carb hydrate, low protein processed foods,
[SPEAKER_01]: how dopamine is released and circulating in your brain, which is think is really fascinating as well.
[SPEAKER_01]: It's not all good though.
[SPEAKER_01]: There is a massive lawsuit happening at the moment with OZMPIC.
[SPEAKER_01]: So OZMPIC is the brand name for SEMMAglutide.
[SPEAKER_01]: So...
[SPEAKER_01]: This is a related GLP one drug and the target manufacturer is no good not stick and the focus is on serious adverse events that have happened 2000s of people.
[SPEAKER_01]: So litigation started in 2023 in February 2024, the US judicial panel in Pennsylvania put forward a case.
[SPEAKER_01]: So the case number.
[SPEAKER_01]: is MDL number 3094 if you want to look it up.
[SPEAKER_01]: Case numbers are expanding really quickly.
[SPEAKER_01]: It originally started with 1,500 and now we're up to beyond 4,000 cases, 1,000 plaintiffs involved in this lawsuit.
[SPEAKER_01]: So it is
[SPEAKER_01]: Absolutely, huge.
[SPEAKER_01]: It's absolutely massive.
[SPEAKER_01]: In December of 2025, there was a multi-district litigation that established focusing on vision loss claims.
[SPEAKER_01]: Originally, this lawsuit only included gastrointestinal problems and adverse reactions, but now we're also seeing that people who have
[SPEAKER_01]: and went blind and have now had vision problems as well.
[SPEAKER_01]: So the primary injuries that we saw originally in the original lawsuit in 2023 was stomach paralysis,liest bowel obstruction, system vomiting, via digestive dysfunction.
[SPEAKER_01]: And now we're seeing vision loss and creatitis, gallbladder disease, dehydrated, related kidney injury and thrombotic events.
[SPEAKER_01]: Oh, big yikes, that's not very fun.
[SPEAKER_01]: So what the plaintiffs are basically arguing in this lawsuit is they're saying that nausea and GI upset were disclosed and they were told to them in there.
[SPEAKER_01]: The doctor's appointments in the packet insert of OZMPIC, but the long term gastric paralysis and severe intestinal injury were not clearly communicated, which is a bit concerning because maybe OZMPIC didn't know about that.
[SPEAKER_01]: maybe they released this drug without actually doing proper testing, big yikes.
[SPEAKER_01]: So basically, this lawsuit is for $2 billion and the plaintiffs are seeking compensation for medical costs lost income, long-term disability pain and suffering.
[SPEAKER_01]: You really cannot put a press tag on health to be owned dollars is got Ganschewin.
[SPEAKER_01]: I feel like OZMP probably has that money, they're probably trying to deal with this quite quietly, but it's not going that way.
[SPEAKER_01]: And I just want to point that out that there is serious risk associated with the overuse of certain peptides.
[SPEAKER_01]: Peptides are a massive conversation happening and they help sphere at the moment.
[SPEAKER_01]: GLP ones are like the oldest one that we know about.
[SPEAKER_01]: GLP ones, we've known about GLP ones, we've been using GLP ones for type 2 diabetes, and obesity in a way, individuals forever.
[SPEAKER_01]: But because they are popular, I believe, that they have been overused, they've been dosed to high, and we actually haven't seen individuals eating enough.
[SPEAKER_01]: So the problem is associated with weight loss at that rate.
[SPEAKER_01]: are all of these other issues that these plaintiffs have experienced as well.
[SPEAKER_01]: So I don't want anyone like taking a GLP ones after they see an Instagram post because someone you know said that it helped them with their PMDD.
[SPEAKER_01]: And I'm not going to discredit the use of GLP ones for things like that, but I'm just saying that
[SPEAKER_01]: There is serious risk associated with this.
[SPEAKER_01]: When you look in the packet inserts, they will say it's rare that you'll get pancreatitis and it's rare that you'll get blood, that you'll get blindness and things like this.
[SPEAKER_01]: But you have to understand there is a dose-dependent risk associated with the use of GLP ones.
[SPEAKER_01]: And you need to be so bloody careful with who is consulting you on the use of GLP ones, how much of a dose they're giving you.
[SPEAKER_01]: Like you just need to go really, really slow with this peptide.
[SPEAKER_01]: Because our body is not actually built to have so much of this in the system.
[SPEAKER_01]: If we really understand that we only release it under a very certain condition for a short period of time, then we have an enzyme to break it apart really quickly.
[SPEAKER_01]: There's a reason why there is an enzyme to break it apart really really quickly.
[SPEAKER_01]: I think overuse of this medication.
[SPEAKER_01]: is going to have negative health outcomes and there is risk associated with it.
[SPEAKER_01]: So that's why I'm going to sound this podcast.
[SPEAKER_01]: This is not a consulting.
[SPEAKER_01]: I'm not consulting you on the use of GLP ones.
[SPEAKER_01]: I'm not encouraging the use of GLP ones.
[SPEAKER_01]: I'm also not saying don't use them.
[SPEAKER_01]: I'm just saying here is the information that we know about.
[SPEAKER_01]: Please take this to your health practitioner and your health provider.
[SPEAKER_01]: So you can make an informed choice.
[SPEAKER_01]: That's what this whole thing.
[SPEAKER_01]: That's what all of my work to do with our Corbin is.
[SPEAKER_01]: So I can give you the research and say, hey, this is what we know.
[SPEAKER_01]: So you know, so you can make informed decisions about your body.
[SPEAKER_01]: I'm not telling you what to do.
[SPEAKER_01]: I'm not telling you not what to do.
[SPEAKER_01]: I'm just saying, hey, this is what we know, and this is what we don't know.
[SPEAKER_01]: That, okay, okay, so let's look at the research on GLP1 specific to PCOS.
[SPEAKER_01]: So I've switched it through quite a lot of the research.
[SPEAKER_01]: Their PCOS focus randomised control trials, their prospective cohorts, their matter analysis, reporting, reproductive and endocrine outcomes, apart from weight loss, which includes menstrual secrecy, so how regular your periods are, ovulation, whether people are
[SPEAKER_01]: Androgen profile, so DHAs, free testosterone, six hormone binding, globulin, ovarian morphology, inflammation markers, CRP, being one of them.
[SPEAKER_01]: Incelin sensitivity and facility outcomes, including IVF and also people spontaneously conceiving as well.
[SPEAKER_01]: We're also going to be looking at the mechanistic literature on ovarian and central reproductive axes, so you'll happen to have the Lymec pituitary genatotrophin, so that's a HPG axis or HPO axis in women that's relevant to PCOS.
[SPEAKER_01]: So all the research I'm going to be looking at now is on PCOS, so if you have endometriosis, if you're menopausal, none of those research is really going to apply to you.
[SPEAKER_01]: I have to just say this at the outset, 80 to 90% of the research that we have on GLP ones and the application to PCOS is in overweight no-be's individuals.
[SPEAKER_01]: If you have PCOS and you're at-weight, maybe you have a little bit of extra weight, but you're not classified as obese or overweight, we don't know about you.
[SPEAKER_01]: We really don't.
[SPEAKER_01]: We don't have that much research and the reason why is because when we reduce weight, we improve insulin markers when we improve insulin markers, we improve ovarian and
[SPEAKER_01]: and inflammatory markers.
[SPEAKER_01]: That's kind of how it works.
[SPEAKER_01]: So if you are at way, if you are under way, if you are fit and healthy and you're considering a GLP1 because you've heard they're good for PCOS, we simply do not have the research on you.
[SPEAKER_01]: Almost all of the research is on women with PCOS who are overweight or obese.
[SPEAKER_01]: And alongside this as well, literally every study I looked at, the max it ran for was 26 weeks.
[SPEAKER_01]: So very few track what happens beyond that.
[SPEAKER_01]: They're a really small open label, low participant studies that might look beyond that, but those studies are really inconclusive as well.
[SPEAKER_01]: So when people are making broad overarching statements about PCOS and their application for things beyond white management, I just read your phone there.
[SPEAKER_01]: I didn't see that.
[SPEAKER_01]: I don't know where that is.
[SPEAKER_01]: research papers, please put them in a comment section and make me aware of them because I am seeing them.
[SPEAKER_01]: Okay, okay, let's get into the research.
[SPEAKER_01]: Shall we?
[SPEAKER_01]: Do you have one in PCOS research?
[SPEAKER_01]: I looked at a large prospective randomized open label trial of metformin plus semi-glutide.
[SPEAKER_01]: So that's metformin plus OZMPIC basically versus metformin alone.
[SPEAKER_01]: And so the treatment was for 16 weeks.
[SPEAKER_01]: They had 40 women for reproductive follow-up.
[SPEAKER_01]: They reported higher rates of menstrual cycle recovery, which basically means they had periods more regularly.
[SPEAKER_01]: So the group that had met form and endosampic, they had regular cycles, 72.5% of the time, versus the met form and group alone, which is 42.3.
[SPEAKER_01]: So that's pretty cool.
[SPEAKER_01]: And the higher pregnancy rates as well.
[SPEAKER_01]: So the ozempic and metformin group, they feel pregnant at a rate of 35% versus the metformin group feel pregnant at a 15% rate.
[SPEAKER_01]: So that's really cool.
[SPEAKER_01]: Alongside this as well in this study, it's not entirely clear whether all of these women were trying to for pregnant.
[SPEAKER_01]: Um, so I think that's interesting, but even if we took that into mind, 35% versus 15% is pretty cool, as well as larger improvement improvements in sex hormone binding lovelin.
[SPEAKER_01]: So we want, we want higher sex hormone binding lovelin in women with PCOS because it binds up all of those at the excess testosterone, so that free testosterone.
[SPEAKER_01]: We're seeing lower free androgen index,
[SPEAKER_01]: So the between group differences in Homer IR change were not significant, despite within group improvements.
[SPEAKER_01]: So these absolute differences did appear pretty notable.
[SPEAKER_01]: So that's that first study.
[SPEAKER_01]: And this is a trend that we generally see.
[SPEAKER_01]: In research involving GLP ones and PCOS is very often it's in combination with a different
[SPEAKER_01]: medication that improves insulin sensitivity.
[SPEAKER_01]: And what we're generally seeing is that GLP1's placement format or some other insulin medication is going to work better than metformin on its own.
[SPEAKER_01]: Which I think a lot of people just adhering that at the outset are going to go dull because we have two different medications working on different aspects of insulin sensitivity.
[SPEAKER_01]: of course it's going to do better.
[SPEAKER_01]: So, you know, first study in is GOP1 a miracle cure for PCOS.
[SPEAKER_01]: This study doesn't suggest that.
[SPEAKER_01]: As we're talking about pregnancy, let's talk a little bit about IVF because a lot of women with PCOS will go down the IVF and IUI road.
[SPEAKER_01]: So the evidence for IVF outcomes is really sparse with a small pilot study.
[SPEAKER_01]: So it was a randomized control study that used a
[SPEAKER_01]: and metformin versus metformin on its own, in obese infertile PCR patients, and that reported markedly higher pregnancy rate per embryo transfer.
[SPEAKER_01]: So the group that used metformin and a GLP1, their embryo transfer rate was really high.
[SPEAKER_01]: It was 85.7%.
[SPEAKER_01]: That's really cool.
[SPEAKER_01]: That's super significant.
[SPEAKER_01]: And that is really cool in comparison to the metformin group.
[SPEAKER_01]: So the metformin group, their pregnancy the rate per embryo transfer was only 28.6.
[SPEAKER_01]: So that's really cool.
[SPEAKER_01]: And that's after a drug washout period as well.
[SPEAKER_01]: I have to really say that that we can't really use JRP1s in close contact with pregnancy.
[SPEAKER_01]: So we're using JRP1s in metformin.
[SPEAKER_01]: And then we're stopping the GOP1 and then we're waiting a few months for that drug to wash out that's called a drug wash out period and then those women are falling pregnant with IVF and we're seeing even though there was a drug wash out period and the GOP1 wasn't present at pregnancy we're seeing the IVF pregnancy transfer rate was really high at 85.7% in comparison to 28.6.
[SPEAKER_01]: So that's really interesting.
[SPEAKER_01]: The problematic thing about this study is that I've seen this study doing the rounds quite a lot.
[SPEAKER_01]: I'm not going to name names but some pretty reputable Instagram accounts and you know clinicians and things like that, citing this study and saying, this is amazing, going get a GLP1 prescription and get more format at the same time and then do IVF.
[SPEAKER_01]: Okay, this is a small pilot study.
[SPEAKER_01]: When we see a study like this with such amazing outcomes, I'm so hopeful about that.
[SPEAKER_01]: I think that's amazing.
[SPEAKER_01]: But in this case, it doesn't mean let's treat women with this information.
[SPEAKER_01]: No, it means wow, this is really interesting.
[SPEAKER_01]: We need to do more studies.
[SPEAKER_01]: We need to replicate this study with more participants and we need to do it over a longer period of time.
[SPEAKER_01]: and then we can make conclusions.
[SPEAKER_01]: We cannot make conclusions from this study is that it is a small pilot study which is, it means it is the first of its kind, we cannot make conclusions from this study, right?
[SPEAKER_01]: So from a guideline perspective, the international evidence-based guideline for the assessment and management of policies to go very in syndrome advises that GLP-1 receptor agonists, like a zampic, may be considered for weight management in women with PCOS, but it emphasises that we cannot use GLP-1s for the treatment of infertility.
[SPEAKER_01]: Because we cannot use anti-obesity agents close to pregnancy.
[SPEAKER_01]: So that basically means the international evidence-based guideline has spoken on PCOS and it's used to GOP ones for contraception and said we cannot market this.
[SPEAKER_01]: We cannot use this as a contraceptive improver.
[SPEAKER_01]: We cannot do that.
[SPEAKER_01]: It's basically saying it is unsafe, cannot treat women who were in fertile with PCOS with GOP once.
[SPEAKER_01]: Okay, and that was in 2023, and they still stand by that statement.
[SPEAKER_01]: So it's really concerning when I'm seeing people online, saying, you know, GOP once in proof fertility outcomes going get you GOP once.
[SPEAKER_01]: Okay, the position statement from this organization is vehemally against that, and they've stood by that statement for three years now.
[SPEAKER_01]: They haven't updated it.
[SPEAKER_01]: There's that.
[SPEAKER_01]: Okay, so those are outcomes for pregnancy.
[SPEAKER_01]: Let's look at geography ones and menstrual regularities.
[SPEAKER_01]: So how regular your cycle is?
[SPEAKER_01]: This is a common thing with PCOS.
[SPEAKER_01]: Your cycle might be every 42 days.
[SPEAKER_01]: It might be every 28 days.
[SPEAKER_01]: It's not regular and that is one of the diagnostic criteria underneath the Rotterdam criteria that we use to diagnose women with PCOS.
[SPEAKER_01]: So the evidence that we have on GOP ones, based therapy improves menstrual regularly.
[SPEAKER_01]: This does exist, but the magnitude and the consistency depend on the comparator and how menstrual outcomes were basically noted in these studies.
[SPEAKER_01]: So bleeding ratio, menstrual frequency, and cycle recovery.
[SPEAKER_01]: So there are a lot of different ways that we can look at the metrics of the regularity of a cycle.
[SPEAKER_01]: And each study is going to be looking at different metrics, basically.
[SPEAKER_01]: So in a study where they use semi-glucide and metformin in the randomized control trial, menstrual cycle recovery was 72.5 versus 42.3 after 16 weeks.
[SPEAKER_01]: So women were on metformin or metformin and ozampic at the same time, and they looked how regular their cycles became.
[SPEAKER_01]: And the group that were on a GLP1, and they were also on metformin.
[SPEAKER_01]: Their cycle recovered and was cyclical and we know when it came and it was more regular, 0.5% of the time, in comparison with 42.3 after 16 weeks.
[SPEAKER_01]: So that's a pretty clinical improvement.
[SPEAKER_01]: And we can put that down again to the fact that insulin is being decreased, blood glucose is been controlled, inflammation is decreasing, we have less endrogens and therefore we are more able to
[SPEAKER_01]: If you want to understand the pathophysiology of PCOS, I have a whole masterclass, I have a book on that, and I also have a whole podcast on it as well.
[SPEAKER_01]: And I post about PCOS pretty much every single day.
[SPEAKER_01]: So if you wanted to learn more about that, there is lots of resources that I've made on PCOS that you can go and find.
[SPEAKER_01]: In another study I found, they used a placebo-controlled Lyrogloup Tide, a trial.
[SPEAKER_01]: They found that both a variant dysfunction and cycle regularity improves in both groups.
[SPEAKER_01]: But between group difference in cycle regularity
[SPEAKER_01]: So that favored the GLP1 over the placebo.
[SPEAKER_01]: When we look at metaanalysis, so a metaanalysis is when we find a lot of different randomized control trials, and we pull them into one, and we look at the data, and we pull apart different data points, and we talk about the data that's found in a group of studies.
[SPEAKER_01]: So metaanalysis are at the top of the evidence hierarchy, so metaanalysis and systematic reviews are really, really amazing when you're looking at anything.
[SPEAKER_01]: So there is a metaanalysis I found that used GLP1's PCOS.
[SPEAKER_01]: And so the results are really, really mixed and the results are really, really mixed because we're using different combinations of bit form and your P1 receptor agonists, we have different obesity and obese classes of women with PCOS, the dosage and length is different.
[SPEAKER_01]: and what they're testing and what they're basically looking at different metrics in the human body and what they're looking for to change is different as well.
[SPEAKER_01]: So when we looked at that pooled evidence in that systematic review metronolysis, we're seeing large standardised improvement in cycle regularities.
[SPEAKER_01]: So overarchingly we are seeing the cycles of becoming more regular with the use of metformin and a GLP1 or a GLP1 on their own.
[SPEAKER_01]: So whenever there is a GLP1
[SPEAKER_01]: which is really, really great.
[SPEAKER_01]: In a different meta-analysis though, so this meta-analysis looked at Exenotide, which is a specific type of GLP1 versus metformin, so in this meta-analysis they looked at lots of different randomized control trials that tested the same thing.
[SPEAKER_01]: They found that psycho-regularity did not clearly differ between the drugs suggesting that suggesting that any
[SPEAKER_01]: when comparing to insulin-sensitizing weight-affecting agents and comparing it to a placebo.
[SPEAKER_01]: So basically an English what that means is, didn't really matter.
[SPEAKER_01]: Like, GOP ones didn't really stand out.
[SPEAKER_01]: When we're looking at outcomes of soccer regularity, in comparison to other insulin-sensitizing drugs that we have on the market, it's full and being one of them.
[SPEAKER_01]: So yeah, basically what I'm trying to say there is cycle regularity pretty mixed, generally looking pretty good, but looking pretty mixed, depending on what research you're looking at.
[SPEAKER_01]: Okay, so let's look at GLP ones and ovulation rates because we move with PCOS, are commonly anovulatory, so they're not ovulating, and that's because the thicker and granular cells are too thick and it can't actually break open and the follicle can't do its job.
[SPEAKER_01]: and break open.
[SPEAKER_01]: That's why LH goes higher, and that's why we get these cascades of hormonal events.
[SPEAKER_01]: So what we see in a metronylysis of randomized control trials with a GLP1 called exenitized that increased ovulation rate in comparison with metformin.
[SPEAKER_01]: So when we looked at metformin on their own and how often women with PCOS were ovulating,
[SPEAKER_01]: versus the GLP-1, the GLP-1 worked a little bit better.
[SPEAKER_01]: I have to rehash this again.
[SPEAKER_01]: If you are listening to this, if you have PCOS and you're considering a GLP-1 for fertility outcomes, you cannot use it close to the time where you're getting pregnant.
[SPEAKER_01]: You need to have a drug out, wash out period.
[SPEAKER_01]: Hopefully your practitioner is really open with you about that.
[SPEAKER_01]: just to go back to the 2023 International PCOS guideline, we're seeing that GOP ones are superior to metformin for most reproductive outcomes and ovulation rate is inclusive in that.
[SPEAKER_01]: So generally we're seeing GOP ones improve ovulation, but we cannot take GOP ones close to pregnancy.
[SPEAKER_01]: I'm going to read from the guideline here.
[SPEAKER_01]: It still recommends using anti-obesity agents so GOP ones
[SPEAKER_01]: undergoing ongoing uncertainty at the guideline level.
[SPEAKER_01]: So risks, we are not sure of the risks.
[SPEAKER_01]: So if you have like an IVF doctor, if you have a health practitioner telling you, oh, you want a full pregnant go on a GLP one, this is awesome.
[SPEAKER_01]: No, we are only using GLP to enhance and promote fertility in research.
[SPEAKER_01]: facilities and enabling research if you're involved in a study.
[SPEAKER_01]: It's not yet clinical.
[SPEAKER_01]: We can't use it to clinically improve fertility outcomes in women with PCOS yet.
[SPEAKER_01]: I've said that a few times because I just really want to tell you guys that because that is something that I'm seeing a lot online, that people are like, you know,
[SPEAKER_01]: I feel pregnant on a GLP1 and, you know, it might be safe, it might not also be.
[SPEAKER_01]: I just, yeah, if anyone listened to this and they took this information and made a choice to take a GLP1 and then they felt pregnant, they were risks associated with that.
[SPEAKER_01]: That's, we just don't know the risks, basically.
[SPEAKER_01]: Okay, let's look at GLP1s and Androgens.
[SPEAKER_01]: So basically, Androgens are your male hormones.
[SPEAKER_01]: I don't want to say male hormones because we produce them as well and testosterone is really important for overall women's health.
[SPEAKER_01]: It does a lot of different things in your body.
[SPEAKER_01]: which is quite a lot of women with PCOS have really got high amazing sex drives, but it can also decrease the hair on top of your hair head.
[SPEAKER_01]: So we're seeing male pattern baldness in the middle of our head here.
[SPEAKER_01]: We're also seeing acne in the jawline and around the mouth.
[SPEAKER_01]: We're also seeing more hair in this area, hairy arms, hair your legs as well.
[SPEAKER_01]: So that's what testosterone can do because testosterone just works on the hair follicle and that's what it does basically improves.
[SPEAKER_01]: hair growth in areas and it basically can cause baldness in other areas as well.
[SPEAKER_01]: So there are a few studies here.
[SPEAKER_01]: Number one, Exanotide vs. Vettformin.
[SPEAKER_01]: So the first study we'll see here is Exanotide vs. Metformin.
[SPEAKER_01]: This is a Metronalysis.
[SPEAKER_01]: So we're seeing Exanotide, which is a geography one.
[SPEAKER_01]: That increased sex hormone binding globule in by four nanomoles per liter.
[SPEAKER_01]: That's pretty cool.
[SPEAKER_01]: So we're increasing sexual and binding globally, which means for testosterone decreases and we do see that DHES decreased by 16.47 nanograms per deciliter.
[SPEAKER_01]: So that's pretty cool.
[SPEAKER_01]: We're not seeing total testosterone differ significantly overall, but we are seeing a lower DHES.
[SPEAKER_01]: So that's
[SPEAKER_01]: that will basically mean that someone's skin will be clearer, that they might ovulate more frequently, et cetera.
[SPEAKER_01]: We're seeing in another meta-analysis that it goes in the tide modestly reduced total testosterone and it improved sex hormone binding globulin.
[SPEAKER_01]: So that's cool.
[SPEAKER_01]: In another study, looking at a GLP1 plus metformin versus just metformin on its own.
[SPEAKER_01]: So that used semi-glutide, so that's exemplic.
[SPEAKER_01]: Semi-glutide plus metformin produced larger improvements than a metformin alone.
[SPEAKER_01]: So we saw sex hormone binding globally in Christ.
[SPEAKER_01]: We saw testosterone decreased as well in comparison to the group of women with PCOS who only took metformin.
[SPEAKER_01]: When we look at GLP1 receptor agonist as a monotherapy, so we're not using them in tandem with metformin.
[SPEAKER_01]: We are seeing that ovarian dysfunction increased.
[SPEAKER_01]: We're seeing that sex hormone binding globularin increased by 7.4 nanomoles a leader, and we're seeing that free testosterone decreased as well quite marginally, but it did decrease.
[SPEAKER_01]: So even if you use a GLP1 on its own without metformin, we are seeing improvements specific to antigens, so we're seeing generally in that study.
[SPEAKER_01]: So it's hormone binding globularin increased and free testosterone decreased, which is awesome.
[SPEAKER_01]: Okay, let's move on and talk about GLP ones and inflammatory markers specifically.
[SPEAKER_01]: It's going to be CRP, see reactive protein.
[SPEAKER_01]: So that's a liver inflammatory marker, which generally is pretty elevated in women with PCOS.
[SPEAKER_01]: So we're generally seeing that when women with PCOS use a GLP one that inflammatory markers specifically CRP decreases quite significantly.
[SPEAKER_01]: So in an open label, Exanotide study, we're seeing in four months where there were 30 enrolled and only 20 completed.
[SPEAKER_01]: So there's 10 who dropped out in that study, which is a bit sus.
[SPEAKER_01]: So we're seeing HSCRP decrease from 8.5, 0.8 or 1.4.
[SPEAKER_01]: So that's a pretty significant improvement in CRP.
[SPEAKER_01]: When we looked at another study, so semi-glutide and metformin in a randomized control trial, CRP decreased significantly within the combination arm.
[SPEAKER_01]: a metformin and GLP together, their CRP significantly decreased in comparison to the group that only took metformin.
[SPEAKER_01]: Okay, let's look at GLP ones and insulin sensitivity.
[SPEAKER_01]: I don't know why didn't do this earlier because that's basically what GLP ones are all about.
[SPEAKER_01]: GLP ones are designed and used predominantly for weight management and obesity and type 2 diabetes because of its
[SPEAKER_01]: because that's what it basically does in the body.
[SPEAKER_01]: It is a messenger for insulin in the pancreatic beta cells of our body.
[SPEAKER_01]: So, understandably, because of this, we're seeing improvements in insulin resistance and sensitivity, among the most consistent effects of GLP-1 receptor agonist in PCOS, because that's what it's used for.
[SPEAKER_01]: So, generally, we are seeing improvements in Homer IR, when we're just using GLP-1 on its own versus GLP-1's with metformin.
[SPEAKER_01]: Again, when we see GOP ones and metformin together, we're seeing that the insulin sensitivity improves and insulin resistant decreases and we're seeing generally that insulin works better in the body when we're using a combination of GOP ones and metformin together as opposed to a monotherapy.
[SPEAKER_01]: of GOP ones on their own.
[SPEAKER_01]: So hopefully you understand the research a little bit more.
[SPEAKER_01]: If you wanted the article on this, it's on my Patreon and Substar, next week with all of the references and I'll put all of the references in here as well if you wanted to look at the research.
[SPEAKER_01]: But I just at the end I just want to talk about this research and it's gaps, it's limitations and it's clinical implications.
[SPEAKER_01]: So over actually, this is what I've repeated a lot.
[SPEAKER_01]: is that the biggest problem with these studies that we have on GOP ones is that they are really short.
[SPEAKER_01]: They're really small.
[SPEAKER_01]: They only include women who are overweight and obese and have PCOS.
[SPEAKER_01]: We don't know how GOP ones work in lean PCOS types.
[SPEAKER_01]: We don't know how they work for teenagers if they're even being used for teenagers and any other PCOS type.
[SPEAKER_01]: Most of these studies as well, there's four different types of PCOS.
[SPEAKER_01]: It wasn't really talked about what type of PCOS these women were, what diagnosis they had.
[SPEAKER_01]: So PCOS is going to change that's named at the end of this month, or next month, I believe.
[SPEAKER_01]: There are researchers together now kind of formulating a new name.
[SPEAKER_01]: So PCOS is going to change because
[SPEAKER_01]: So, many different women can have PCOS and have very, very different symptomology.
[SPEAKER_01]: So, you can have PCOS and not have many lists on the ovaries.
[SPEAKER_01]: So, you can have no lists on your ovaries and still be diagnosed with PCOS because your antigen's are high because you're in tillers high and because you're overweight.
[SPEAKER_01]: But, someone can have PCOS and have lists on the ovaries and not be overweight.
[SPEAKER_01]: So, you understand why the research is a little bit messy is because the diagnostic criteria and the name that we have for PCOS doesn't really fit.
[SPEAKER_01]: what women are actually experiencing.
[SPEAKER_01]: So that explains why, partially, why this research is a little bit bitzzy, basically.
[SPEAKER_01]: And the undercurrent of it is GOP ones work predominantly really well when they're used in combination with metformin.
[SPEAKER_01]: Metformin itself is quite affordable.
[SPEAKER_01]: GOP ones are not.
[SPEAKER_01]: And you have to be very, very careful with them.
[SPEAKER_01]: Another problem that I have with these studies is how they measured the outcomes.
[SPEAKER_01]: So, menstrual and ovulation results are not measured the same way in these studies.
[SPEAKER_01]: Also, when we're looking at ovarian structure, when we're looking at ovarian morphology, when we're looking at psycho-regularity, if this study doesn't go beyond 24 to 26 weeks, and we're actually starting to see changes at 30 to 40 weeks.
[SPEAKER_01]: which I think is totally plausible in this group of women with PCOS.
[SPEAKER_01]: We're not actually capturing that result, which I think is really, really sad.
[SPEAKER_01]: Like most of these studies don't even go longer than 16 weeks.
[SPEAKER_01]: So these studies are really short.
[SPEAKER_01]: They only include a certain PCOS type, and we're not actually seeing that they're measuring outcomes in the same way.
[SPEAKER_01]: So again, that's why the research is really, really messy.
[SPEAKER_01]: That's why the research is for the most part, pretty inconclusive as well.
[SPEAKER_01]: I don't want to be all doom and gloom.
[SPEAKER_01]: I just want to end this on a happy note.
[SPEAKER_01]: I am stoked about GOP ones and the application for PCOS.
[SPEAKER_01]: I think there can be really great outcome.
[SPEAKER_01]: I am hopeful.
[SPEAKER_01]: I think the research around GOP ones is really great and I'm genuinely excited about it.
[SPEAKER_01]: It's promising, right?
[SPEAKER_01]: But what I just wanted to make this podcast about is like this is the research we have.
[SPEAKER_01]: This is how it's been conducted.
[SPEAKER_01]: This is how long it's for and this is the type of people that they're testing on and they're researching on.
[SPEAKER_01]: and that doesn't fit every single woman with PCOS.
[SPEAKER_01]: And the studies that we do have that are really, really interesting, like the IVF pregnancy outcome, that was really, really great.
[SPEAKER_01]: You know, 85% of women having successful IVF transfers and pregnancies in comparison to what 30%.
[SPEAKER_01]: That's really significant.
[SPEAKER_01]: But if that's being cited a lot on Instagram, by clinicians that people trust, the risk is that women will go out and use that to full pregnant, they won't know about the risks of using G.O.P.1's close to pregnancy.
[SPEAKER_01]: And they also won't know that it might not work because that study only included 28 women.
[SPEAKER_01]: So that's kind of all I needed to do today.
[SPEAKER_01]: Just wanted to say my piece on PCOS and GLP ones, I think they can be effective.
[SPEAKER_01]: They're mostly effective with metformin.
[SPEAKER_01]: So if you're on metformin already, maybe adding a GLP one might be effective, but it might not be as well.
[SPEAKER_01]: It will be effective if you're overweight no base, but it might not be effective if you're lean.
[SPEAKER_01]: Because you might not have insulin sensitivity problems basically.
[SPEAKER_01]: Thanks for listening to my little mini rant on this and I'll see you on the next one.
[SPEAKER_01]: Thank you so much for taking the time out of your busy day to listen to this episode.
[SPEAKER_01]: If you loved it, please remember to like, subscribe, and send to a loved one.
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[SPEAKER_01]: I hope you have a really beautiful morning, afternoon or evening wherever you are in the world, and I will see you on the next episode.