Could Ozempic Help Solve PCOS?

I don't have ovaries. Surprise! Or maybe not. What I'm trying to say is I'm in the privileged position to not have to worry about polycystic ovarian syndrome, or PCOS, a burdensome condition that is defined by at least 2 of the following 3 criteria: irregular periods, elevated androgens like testosterone, and polycystic ovaries. And PCOS is further associated with cardiovascular disease, high blood pressure, and insulin resistance-related disorders like diabetes.. But as you learn in medical school, the etiology, the cause, the pathophysiological cause of PCOS is pretty poorly understood. It's something to do with insulin resistance, but the specific causes are still being worked out. And a paper recently published in Nature Metabolisms, quickly becoming one of my favorite journals, entitled "The microbial metabolite Agmantine Acts as an FXR Agonist to Promote Polycystic Ovarian Syndrome in Female Mice," although they have a lot of human data, which we'll get to, provides new answers and highlights avenues for further solutions. So let's dig into the, some of the data and hopefully learn something valuable. Welcome to my channel, stay curious. First, for a bit of background, it's known that patients with PCOS tend to have insulin resistance and microbiome dysbiosis, an altered gut microbiome. Now, these are rather nonspecific signs associated with metabolic diseases, so what we really need is mechanistic links between PCOS and the microbiome and insulin resistance. It's like taking a biological puzzle box, flipping out the pieces, and then you have to flip the pieces over and puzzle them together to get a better pathophysiological picture, a clearer picture of the puzzle. So that's what we're doing here in this paper. So let's start to puzzle some of the pieces together, starting with data from human subjects. In this paper, they looked at patients with PCOS and healthy controls. The patients with PCOS had much lower level of the hormone GLP-1. You might have heard of this hormone's name before because it's the hormone that blockbuster weight loss drugs like Ozempic and Wegovy try to mimic, which is why they're called GLP-1 receptor agonists. They bind to and activate the GLP-1 receptor. This is also why you can call GLP-1 nature's Ozempic, because it's the natural form of the hormone that these drugs try to mimic. So they looked at patients with PCOS and saw they had much lower levels of GLP-1, as you can see in this graph, and also that lower levels of GLP-1 associated with higher androgens, as you can see in this graph, and more insulin resistance. So what you're really seeing here is that GLP-1 levels are lower in PCOS and that that associates with the profile, the metabolic profile of PCOS, higher androgens, more insulin resistance. Now let's change to talk about a little bit of mouse data. Okay, now let's turn to a little bit of the mouse data. From prior research, the researchers knew that mice with PCOS tended to have higher levels of a particular gut bug, B. vulgatus, and that they thought this may have roles in PCOS. So they looked at these mice and found they had a very, very similar profile to humans with PCOS, including lower GLP-1 levels and of course ovarian cysts. And you can see that here. Look here, this is the control and this is the B. vulgatus BV PCOS mice. And you can see these large cysts represented by the clear cysts and the hashtag over them in the PCOS mice. But here's the interesting thing. What if you take these mice with the B. vulgatus and you treat them with the GLP-1 receptor agonist? If GLP-1 deficiency is driving PCOS, that should improve the PCOS and the cysts should go away. Do we see that indeed? What should we do? So these are the PCOS mice now treated with the GLP-1 receptor agonist liraglutide, and you can see the cysts go away, which is really cool. Okay, now pause and see what I've done here. I've intentionally filled in some of the puzzle, started to put the corners together, but left out conspicuous pieces. We have the observation that a particular bacteria, B. vulgatus, might be elevated in PCOS and the GLP-1 levels are reduced. But let's link these together. What is the metabolite produced by the bacteria, and to what receptor does it bind to potentially decrease GLP-1 production? What we really want is a microbe-metabolite-receptor-hormone axis to help explain PCOS. So let's work backward along this pathway, starting by talking about the receptor. If there's a receptor activation of which depletes GLP-1 levels and drives PCOS, then if you break that receptor so you can't activate it, you should restore GLP-1 levels and improve PCOS. So that's what they did in one experiment. Because you can genetically manipulate mice, they broke a receptor they identified as key in depleting GLP-1 levels, the FXR receptor. So the FXR is activated, and when it's activated, it depletes GLP-1. When they took mice and broke FXR, what you can clearly see is that GLP-1 levels are restored. So the orange bar is the PCOS mice, and the pink bar is the PCOS mice, but they broke the receptor. So the BV bacteria couldn't produce some mystical metabolite that activated the receptor because there was no functional receptor to activate. And you see when the receptor is broken, GLP-1 levels are restored. Now, what happens to PCOS? Well, let's look at the ovaries. You can see here very clearly, PCOS, cysts, PCOS mice, but when you break the FXR receptor, the cysts go away. So you have here a restoration of GLP-1 levels and a recovery from PCOS showing this FXR receptor is critical in the pathway. And there's reason to believe this is relevant in humans as well. Now, you can't genetically manipulate humans, at least not yet, but you can look at markers, say, of FXR activity, one of which is FGF19. And if in humans FXR activity was elevated, driving down GLP-1 and driving PCOS, PCOS, you'd expect FGF19 levels to be elevated with FXR activity. So do we see that? Yes, patients— human patients with PCOS have elevated FGF19 levels, the marker of FXR activity, and there's an inverse association between FGF19 and GLP-1. So really what this is saying again is in PCOS there's this BV bug that's somehow activating FXR to drop GLP-1 levels, driving PCOS. And the next question again is what is the metabolite the BV bug is making that is the mediator of this axis? So again, microbe metabolite receptor hormone axis. We have B. vulgatus as the bug, FXR as the receptor, GLP-1 as the hormone, and what is the metabolite? So how do you find a metabolite, or where do you look for a metabolite that's produced by gut microbes? You look in the poop. So they look in the feces of human patients with PCOS and the BV-PCOS mice, and what they found in both cases, seen here in the orange bars, is higher levels of a metabolite called agmatine, which is a byproduct of arginine and amino acid metabolism. And again, in both cases, human and mice, agmatine levels were elevated. And they found that agmatine can bind to and activate FXR. So we complete the puzzle. B. vulgatus produces agmatine that activates FXR, drives down GLP-1 levels, and that drives PCOS. So now the obvious next question, using this better physiological understanding, can we intervene on this axis to treat PCOS. In this study, they show that you can indeed intervene at multiple points along the axis to treat PCOS. For example, you can inhibit agmatine production with an enzyme blocker called difluoromethylarginine, or you can block the FXR receptor, or you can just boost GLP-1 levels downstream with a GLP-1 agonist. That's all summarized nicely here in this little diagram. And in humans, this should work too, in theory. The issue is, well, what's really available? There are quite a lot of options, potentially a few family of compounds that could, say, boost GLP-1 levels, including TGR5 agonist, FXR inhibitors, DFMA, and of course GLP-1 receptor agonists. But as far as I'm aware, you can't go pick up any of these classes of compounds at your average drugstore over the counter. Now obviously I can't prescribe you a GLP-1 receptor agonist over YouTube, nor would I or should I, but, um, I can offer you one potential idea, which is related to the sugar allulose, the rare natural sugar allulose, which I've covered in deep dives in prior videos. Now, the interesting thing about allulose, a potential metabolic advantage, is that it boosts GLP-1 levels. It's been shown, at least in animal studies, it can boost GLP-1 levels up to fourfold in the portal vein going to the liver, which is really, really interesting and provides biological plausibility for how allulose could actually treat PCOS. Now, there are no human studies on this. I'd love to see that study, it hasn't been done, but in theory, by boosting GLP-1 levels, it could ameliorate PCOS. So Allulose is something that you could try if you want to, and it's no secret I'm sponsored by a company, RX Sugar, which is an allulose company. Really, I think it's a metabolic wellness company disguised as a food company, but they sponsor the editing for these videos so that you can have engaging, fun edits. Hopefully you learn something here, and if you want to try out their products, you can use my discount code NICK20 for 20% off. I will highlight, I don't really care if you buy anything. I don't get any money from your purchases, but I do think they're a good company doing good things, and it's relevant to the content of this video because allulose does GLP-1 levels. It's not like I can force nature metabolism to produce data on GLP-1 and PCOS. This is just how the data came out. And so I hope you can feel the authenticity of me trying to bring you something that you can try, you can not try. I'm all a little bit gun-shy about the whole sponsor thing, but it's the reality of how my channel is evolving, and it allows me again to produce videos like this for you. And if you don't want to buy it, I hope you enjoyed this free metabolic education. Peace.