Could GLP-1s Help Endometriosis? The Progesterone Resistance Theory

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0:43So, order more pizza. The math demands it. Get the Venmo debit card. Venmo Stash bundle terms and exclusions apply. See terms at Venmo.me slash stash terms. Venmo checkout not available at all merchants. Venmo MasterCard is issued by the Bancorp Bank NA. Your girl has been working 12 to 15 hour days and I just submitted my book. I jumped on my bike. I did some cardio kickboxing. I lifted some weights so that my brain could actually function to talk to you about progesterone resistance, GLP-1 therapies, and some promising research that we may be able to apply to endometriosis, certainly starting to get looked at for PCOS and then endometrial cancer as well.

1:24And I think this is exciting and I want to talk about it, but I also have to tell you that like all of this research is really preliminary. And I know sometimes some people love to hear what I say and then be like, yes, this is fact. This is the way it's being done now. And we're just not there yet. This is like the honest truth. We're just not there yet, but we're going to get into latest research updates that I think you should be on the know about because this is really exciting in women's medicine, especially when you consider like the treatments for endometriosis are absolutely just shit sometimes.

1:58Like I'm gonna say what I'm gonna say because they really are. Like taking away women's hormones, giving them GNRH agonists, like what a freaking joke. Like you can't even be on those more than six months. And that's because of the significant bone loss. Yes, I know there are some practitioners out there being like, you could stay on it for two years. Bro, no, you can't. No, you cannot. And the reason why you cannot is because the pharmaceutical company that makes does not want to get sued because they know how detrimental it is to your bone mass and they know how early expiration comes with having a hip fracture.

2:33Or to make it more doctor speak, what I'm saying is that if you have osteoporosis, your mortality risk is so much higher and we want to avoid that. So I'm not going to keep going off about endometriosis treatments that I hate so much and that I wish we had better options for, I'm going to talk about what could potentially be an option. Now, listen, I already did an episode breaking down all these other components in ways that GLP-1s may help endometriosis. I know you guys have been asking for that. I came across this research. Actually, as I was working on my book, and I'm like, I wonder if GLP-1s could actually help with progesterone resistance.

3:13And so let's talk about this mechanism in endometriosis, why it matters, and then like how I arrived here. So first things first, in endometriosis, there are people who have progesterone resistance. That means the lesions are not going to be receptive to your own progesterone, progesterone that you take, or even progestins. Now in this conversation, what I'm talking about here, progesterone versus progestins, it matters. So progesterone is what you make or you take a bioidentical form of it. Progestins do not have the same benefits as progesterone for like brain health, bone health, definitely not breast health as new research is coming out.

3:56I'm like, yeah, it's not looking so sweet for progestins. But the advantage that progestins do have in endometriosis is that the reason why they cause such big side effects in some of us, raise your hand in the comments if you also experience mood symptoms with progestins, I know it's not just me, they bind very tightly to the progesterone receptor. So in doing that, when we have progesterone resistance, some clinicians will opt for progestins because they're going to bind tighter. But there's a problem that if you're having side effects, like you shouldn't have to like trade period pain for like wanting to unalive yourself once a month.

4:35Like that's not cool to be like, yeah, just trade that. Or to be like, you know, you have endometriosis. What do you expect me to do? Like, just freaking deal with it. Like, suck it up. Like, I can just suck it up medicine. I'm not down with that. Like, that's like, you know what? You bring the matches. I'll bring the kerosene. We burn this down together. So here's the deal. Progestins can be effective, but they can also cause side effects. So it's very individualized. And it's not necessarily that like one is always better than the other in terms of endometriosis treatment. It's about what works for you.

5:06When it comes to when we're talking about like brain health, absolutely progesterone wins, like hands down progesterone wins with that. So we've got the progesterone, the progestin going on. Let's talk about the resistance. Now, some people say the endometriosis lesions are directly down regulating the progesterone receptors. Okay, so like here's my theory of things is that these lesions are highly inflammatory. This is one reason why GLP-1s can be helpful because they are anti-inflammatory, as are things like Boswellia, turmeric, omega-3 fatty acids. So GLP-1s, I just want you to know, they're not the only way, and I'm not trying to push anyone on GLP-1s.

5:47I just think this research is fascinating. I want to talk about it with you. Okay, so we've got all this inflammation, cytokines being produced by these endometriosis lesions. Those are your chemical messengers of the immune system. Then we've got histamine. We've got tons of mast cells hanging out in there, dumping histamine. And then there are also prostaglandins being produced, which we know from period flu, period poop, and period pain. That's what prostaglandins are bringing down on us. Now, because of all that inflammation, just like any other cell in the body, when we have inflammation, we can get resistance.

6:20See also insulin resistance. That's one of the best studied conditions where we can see that when there's inflammation, there is receptor resistance. to that insulin. Now, I think this is the same thing going on with progesterone there, because the lesions are just so dependent on estrogen. There is a whole connection here where they're prioritizing estrogen, so the estrogen docs, because that is the way that they survive. So when I started thinking about all of this, and I was doing all this research on GLP-1s and inflammation, all that, and I had the thought of like, could GLP-1s actually make progesterone receptors work better.

6:59So let's get into it. By the way, this is like the longest introduction ever before I welcome you to the Dr. Brighton show. And if you're new here, I'm Dr. Jolene Brighton. I usually wear makeup and do my hair for you. But today I'm wearing blue light blocking glasses because I can't even handle the light in the studios. And I just don't feel like doing one more dang thing in my day. If you feel me in the comments on that, like drop it because I'd love to hear it. But I have just like reached capacity of like, we'd be teetering on burnout. So one more thing that pulls on my executive function.

7:25That's just not going to happen today. But what needed to happen today is a podcast. Okay, so here's the deal. This podcast only works because you're here and supporting it. If you can subscribe, leave a comment, share this with someone else. That helps so much. But I don't like to spend a lot of time there asking you for support. I do appreciate your support. I want to get into what the core of this conversation is today. Okay, so as we've been talking about, inflammation may be driving or amplifying what's going on with estrogen receptors and progesterone receptors within those endometriosis lesions.

7:58We know that estrogen does not cause endometriosis, but that endometriosis is highly responsive to estrogen. Estrogen can help fuel the fire of endo. So endometriosis lesions, anytime you look in the research, they are commonly described as having estrogen dominant signaling together with reduced progesterone responsiveness. So this is a localized estrogen dominant state. And we know endometriosis, while being estrogen dependent, it is a systemic inflammatory disease. That is why we will see executive dysfunction. We see ADHD gets worse. We see autism, sensory sensitivities get heightened. We see a correlation between PMDD and endometriosis, but spoiler, they don't study us.

8:45So they don't study and they don't fund endometriosis. And if you thought that was bad, PMDD, which is premenstrual dysphoric disorder, gets even less funding. It's just like bottom of the barrel. So when you're reporting that there is endometriosis and PMDD co-occurring in your life, and then a doctor says, well, there's no research to support this, let's not hold our breath on that. Let's just believe the woman that is sitting in front of us. Now, I've come across some really cool studies. I will link them in the show notes. They'll be at drbrayton.com, D-R-B-R-I-G-H-T-E-N.com. So the first study that I want to talk about is one that was done on semaglutide, which most people know is ozempic.

9:21And what that study was looking at was the use of progestin with it. And they found that semaglutide may make progestin therapy work better in early endometrial cancers. We're talking cancer here. So in lab models, combining semaglutide with progestins reduced cancer cell viability more than either treatment alone. So that's like really cool to think about like, okay, endometrial cancer, this may be a promising treatment being brought in. Now, what's especially interesting is that the combination seemed to boost progesterone signaling. So progesterone receptor signaling, we are talking about a progestin here.

10:01The researchers found that semaglutide increased the progesterone-related receptor activity. And that may explain why hormone therapy worked better, even in some tumors with lower progesterone receptor expression. So this is like one of the reasons that like endometriosis is sometimes parallel to cancers because there are some shared mechanisms. Endometriosis is not a cancer. And I will link an episode of the Endometriosis Expert series where we talk about why it's not a cancer. But I think that's really interesting when we look at this study with endometrial cancer that has down-regulated progesterone receptors and semaglutide actually helped the progestin therapy work better.

10:44And it worked better because the progesterone receptor expression was improved. So more receptors available and the receptors being more receptive, what they should be. Now, reality check. This was a preclinical trial. It was not a human trial. It's promising. Mechanistically, it's super interesting, but it doesn't prove that patients with endometrial cancer should yet be treated with semaglutide plus progestin outside of just the clinical research. And it doesn't prove that like this is going to be a treatment for endometriosis. Now, in another study, they found that women with endometrial hyperplasia, very common in PCOS, very common to find in barium menopause sometimes as well.

11:26What is endometrial hyperplasia? That is when the endometrial lining, the lining of your uterus gets big and thick. And we don't like that because that's putting you at risk for endometrial cancer. So this is the upstream of the development of endometrial cancer for some women. And it can result in really heavy, really awful periods. Now, why does it happen in PCOS and perimenopause? Because of unopposed estrogen. There is a relative estrogen dominance. What does that mean? That means relative to progesterone, estrogen is being left unchecked. It's in a higher state than it should be. Now, that doesn't mean it like is automatically super high, but relative to how much progesterone is around, it's not blocking it enough.

12:11So it stimulates the endometrium to grow, grow, grow, and then we get endometrial hyperplasia. Okay, so what this study found, endometrial hyperplasia, other benign uterine conditions, when these women used GLP-1 medications along with progestin, they had a much lower risk of developing endometrial cancer than women who were using progestin alone. And the benefits of this seemed to still be there when they looked at age, BMI, the risk group, whether the progestin was an oral progestin or just an IUD. And the combo was associated with fewer hysterectomies, which women in the endometriosis community, PCOS community, adenomyosis community, fibroid community, like all just perked up, right?

12:51Because, you know, it should be always your choice to have a hysterectomy. We know there is too large of a portion of hysterectomies that are found to be medically unnecessary. Now, whether it was your choice or not, that's a different conversation. But I hate to say this, but sometimes doctors are financially incentivized to take your uterus out rather than actually do a full excision surgery because a hysterectomy might take an hour, but a full excision surgery might take six hours depending on the endometriosis. And so hysterectomy is going to pay well. It's going to compensate you for your time.

13:23And that is a insurance model problem in the United States. And listen, if you're in the government and you're listening now, could we fix that? Could we like maybe fix that? Because that's the upstream issue that so many women with endometriosis are running up against. Okay, but back to the study. Okay, so this study showed GLP-1s plus progestin more effective at lowering endometrial cancer risk than if we just use progestin alone or when there was a combination with metformin, which is really important for the PCOS community to understand that as well. And that doesn't mean you don't need metformin.

13:57It's just in this particular study. Now, important caveat here, this is more observational. It does not support proof that GLP-1s should be used as a standard for endometrial cancer prevention therapy. I think that's just important to understand. It's just promising. And it's showing us that like there is something here to these progestins being able to work better when GLP-1s are around. What's interesting is that I've done another podcast episode talking about how HRT and GLP-1s work better together when we're talking about perimenopause menopause. I'll link to that in the show notes as well if you want to check that out.

14:34Okay, so like what does all this mean for endometriosis? Well, we didn't study endometriosis. As I've said before, we have no human clinical trials on GLP-1s and endometriosis. What we have are a lot of clinicians talking about their patients' experiences and a lot of patients talking about how, yes, I use GLP-1s and the endometriosis pain got better. Things were improving. Now, we know that progestins don't stop the progression of endometriosis. Birth control pills do not stop the progression of endometriosis, with the caveat being one particular type of endometriosis may see a slowing of growth, and that is an endometrioma.

15:18That is specifically in the ovary. When we see lesions, though, on the peritoneum, lesions on the ureters, when we see lesions, you know, on the bowels, when we see lesions on the ligaments, When we see lesions on the diaphragm, like I could keep going. Those do not stop growing just because you're on birth control. What birth control may do is stop. So it's going to stop your period and stop the cyclical hormones happening. It may help with pain management. That's not the same as being a treatment. So with progestins, those are one of the most common go-to with adenomyosis and endometriosis. Now, when we think about research and it's looking at endometrial hyperplasia, that's the buildup of the endometrium due to estrogen.

16:09If your periods knock you out, if sex is painful, if you're told your scans are normal but your pain isn't, listen up. That's not something you have to just live with. Endometriosis is often missed, misdiagnosed, or managed without a full evaluation of what's actually happening. Endo Global specializes in advanced endometriosis review, including imaging assessment, multidisciplinary evaluation, and excision-focused surgical planning. They offer affordable options and a complimentary consultation to review your case and determine whether surgery is even right for you. If you're tired of guessing or gaslighting, start with answers.

16:56Go to drbrighton.com slash endoglobal to schedule your complimentary consultation. That's d-r-b-r-i-g-h-t-e-n dot com slash e-n-d-o-g-l-o-b-a-l. Endometriosis doesn't always show up the way people expect it to. And too many women are left managing symptoms without a full evaluation of what is actually happening. Endoglobal specializes in complex endometriosis care, including advanced imaging review, multidisciplinary evaluation, and excision-focused surgical planning. You deserve a team trained to recognize the full scope of this disease. To learn more or schedule a consultation, visit drbrighton.com slash endoglobal.

17:50That's D-R-B-R-I-G-H-T-E-N dot com slash E-N-D-O-G-L-O-B-A-L. And we know that the tissue within the muscle wall that makes adenomyosis is similar to the endometrial lining. it's like just like it just like wants to be endometriosis but it also still wants to be the endometrial lining and it's also understudied so we don't have like a full understanding of adenomyosis but we see it behaves like endometriosis in some ways but it does have components it's not it's not in newer studies it's not being explained as endometriosis is just the endometrial lining in the muscle body it's being more described as the components of what the endometrial lining is being found in the muscle body because similar, but it's behaving a little bit differently.

18:40However, it may be possible. Let's say you're offered a progestin IUD and your providers like use the progestin IUD because that could slow the growth of adenomyosis. And maybe it will. I think you need to be monitored for it. You have a higher risk of expulsion. But you know, if you're like 21, 22, you're like one of the baby, but like, listen, I'm in college right now. I got like things to do and like I got to find that person that like I want to have a family with. Like this might be a good tool to use. And if you are someone who is also, you know, overweight, you have metabolic dysfunction, maybe you have high inflammation and you've got insulin resistance going and you fit the picture of a GLP-1, using a GLP-1 with progestins may in the future prove to be a more efficacious therapy than just using progestin alone.

19:29Now, when it comes to endometriosis, those progestins may help with managing symptoms. Now, imagine if you couple that with something that's actually anti-inflammatory because the progestins are not. Progesterone is. That's why I often like to use progesterone more. Progesterone is also great at helping with gut integrity, which is a big problem in the endometriosis community. I need to do a whole episode on that. And what we may see is that using the GLP-1s, drop inflammation, help with metabolic health help. If you take away the inflammation, your HPA axis starts responding better. And then having the progesterone or progestins on board may actually improve the response of the endometriosis lesions, perhaps.

20:14This is a theory that I'm putting out there. But I think this is how we start to build information when the people holding the purse strings just do not care about opening it up and like giving us some funding on things. But what is interesting about research is that it pays attention now more to social media than it ever has before. So the more we talk about things, the more likely we are to spark the interest and intrigue of people who have the power to actually study these things. I am in a position to do different kinds of studies, but clinical trials, I'm not in a position to do that. So people who are, I would love for us to start putting pressure on the per-string holders so that we can get this kind of research.

20:59Now, why is progestin always being studied and not progesterone? I think this is important to understand because so often clinicians will say, well, no, like the studies only show progestin. So why would you use progesterone? Oh, okay. Because progesterone is a bioidentical hormone and something that is bioidentical cannot be patented. What can be patented is a progestin and what can then make money is a progestin and what you can then go out and market. And like, you know, if, if like, here's the thing, if they find that GLP-1s work with progestins and it becomes this treatment and it's a lifelong treatment for something like endometriosis or PCOS, like these chronic conditions, they're going to try to find the right progestin for that.

21:43They're going to patent it and the FDA is going to approve one progestin. That's usually what happens. And this is not a conspiracy theory, okay? And this is not anti-pharma. I mean, I take thyroid medication every day. I'm pretty dependent on pharma to keep me alive in that sense. So I'm not an anti-pharmaceutical individual, but it is a business. And when we look at the history of women's medicine, let's take PMDD as an example, PMDD, the pharmaceutical industry put a lot of energy into making the meeting happen and putting together like how it's going to be diagnosed. And like they did all of that because the outcome was is that the FDA approved one pharmaceutical for the treatment of PMDD.

22:28Now that pharmaceutical, this is what's so ridiculous, was actually just Prozac, but they made it pretty and feminine by making it purple and named it something new and that's all the FDA approved and then they could charge us so much more money for it. So that's what I want you to understand about progesterone and progestin. I choose to start with progesterone in most people first because it's a conversation we have and I talk through all the benefits of progesterone and it's a choice that they make. If they choose progestin, then we go with progestin. If they, you know, try progesterone and it doesn't work, we try progestin.

23:04If they've tried progesterone in the past and they're like, I don't want to mess around. I ain't got time for this. Like, I just need to try to feel better. We can go with a progestin. If they start having adverse mood issues, which tends to be, especially for younger people within the first three months of using it, then we find a different progestin. We go a different route with things. So what I'm saying to you is that there is no one size here, okay? You have a unique experience and we have to figure out what works for you. But we will continue to see the research studying progestins. And progestins, like I said, may dock on the receptors really strong.

23:39And so when you've got significant progesterone resistance, that may be what we need to use. But we have to still monitor someone's mental health. So I think it's really interesting when I couple this information about progesterone receptors and their response improving to progestins with the idea that GLP-1s, we tend to have lower GLP levels in our peritoneum, us with endometriosis, because I'm one of those people. And we know that it's anti-inflammatory. And then I went through some immune mechanisms as well in the other episode that I'm going to link to. So when we start looking at all of this, it starts to make a lot more sense why women with endometriosis are feeling a lot better.

24:20But what if you feel worse with the GLP-1? Absolutely possible. Do you want to know the most common reason why? It's because one of the most common side effects of GLP-1s is that it's going to slow down intestinal motility. So in endometriosis patients, there is some evidence, not enough for me to say absolute, but there is some evidence that our migrating motor complex can be altered. Okay, the migrating motor complex, I like to call it the street sweeper of your gut because you go to bed at night and then the street sweeper, that's going out in your neighborhood, right? Get your car off the street because it's about to clean this whole town.

24:52Now, that's the same of what's happening in your body. You go to sleep at night, you better get that food off the street, right? Because street sweeper's coming through. So that's why we close the kitchen after dinner. We don't eat again until breakfast so that the street sweeper can do its four cycles at night. Now, women with endometriosis, we have a long history of medical interventions for endometriosis that can harm how the gut functions. We also see a lot of women who have small intestinal bacterial overgrowth. We also see women who have adhesions on their intestines, and that's affecting how they function.

25:25Now, you introduce a medication that may slow down gut motility, especially if they start you at a higher dose with some of these. With this, you use the GLP-1, slows down your gut motility. Small intestinal bacterial overgrowth might get worse. Migrating motor complex may not work as well. You are feeling bloated and you are feeling like gassy, but you don't actually pass gas. That could be intestinal inflammation. It could also be that, you know, things are moving through slower. You've got lesions. You've got adhesions that are happening on the bowels. That becomes uncomfortable. It is very hard to distinguish this pain that's happening down in the nether region.

26:04Is it endometriosis? Is it my bowels? Is it that I like pulled a muscle because I was working out? Like there's a lot going on in there. But often what I have found is that if there are symptoms, usually it's what's going on with the gut. And that can absolutely, it can feel a lot like endobelly, endometriosis, but there's no reason why it can't also aggravate. endometriosis because many of us, you know, we experience pelvic floor dysfunction as well. So part of having endometriosis, pelvic floor dysfunction, it's why we have surgery and pain can persist. And so difficulty emptying your bowels, difficulty emptying your bladder.