Progesterone Resistance and GLP-1s in Endometriosis: What the Research Means

[00:00:00] 

Dr. Brighten: 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 one 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. And I think this. Is exciting and I wanna talk about it, but I also have to tell you that like all of this research is really pre 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. That's just like the honest truth. We're just not there yet, but we're gonna 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 [00:01:00] absolutely just shit.

Sometimes, like, 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, but No, you can't.

No, you cannot. And the reason why you cannot is because the pharmaceutical company that makes this does not wanna 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, or 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 wanna avoid that. So I'm not gonna keep going off about endometriosis treatments that I hate so much and that I wish we had better options for. I'm gonna talk about.

What could potentially be an option? Now listen, I already did an episode breaking down all these other [00:02:00] components and ways that which GLP ones 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 ones could actually help with progesterone resistance.

And 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, I'm like, [00:03:00] 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. Um, 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 gonna 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 unlive yourself once a month. Like that's not cool to be like, yeah, just trade, 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 like this, 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 [00:04:00] 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. When 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 downregulating, 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 ones can be helpful, because they are anti-inflammatory, as are things like Boswellia, turmeric, Omega-3 fatty acids. So GLP ones, I just want you to know they're not the only way, and I'm not trying to push anyone on GLP ones.

I just think this research is fascinating. I wanna 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 [00:05:00] immune system.

Then we've got histamine. We've got tons of mast cells hanging on 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.

See also insulin resistance. That's one of like the best studied conditions where we can see that when there's inflammation. There is receptor resistance to that insulin. Now I think this the same thing going on with progesterone therapy 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 like GLP ones and inflammation, all that, and I had the thought of like, could. GLP ones actually make [00:06:00] progesterone receptors work better. So 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 'cause 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 'cause I'd love to hear it, but I have just like reached capacity of like, hmm. We'd be teetering in on burnout. So one more thing that pulls on my executive function, that's just not gonna happen today. But what needed to happen today is a podcast. Okay?

So here's the deal. This podcast only works because you are 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 list, spend a lot of time there asking you for support. I do appreciate your support. I wanna 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 [00:07:00] endometriosis lesions. We 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're commonly described as having estrogen dominant signaling together with reduced progesterone responsiveness. So this is a localized, estrogen dominant state.

And we know endometriosis, wellbeing, estrogen dependent. It is a systemic inflammatory disease. That is why we will see executive dysfunction. We see a DHD gets worse. We see autism. Sensory sensitivities get heightened. We see a correlation between PMDD and endometriosis, but spoiler, they don't. Study us so 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. You're just like bottom of the barrel. So when you're [00:08:00] 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 [email protected], D-R-B-R-I-G-H-T-E n.com.

So the first study that I wanna talk about is one that was done on Semaglutide, which most people know as Ozempic. And 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 cancer. So 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 seems to boost. [00:09:00] Progesterone signaling, so progesterone receptor signaling. We are talking about a progestin here. The 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 downregulated, progesterone receptors and semaglutide actually helped the progestin therapy work better. 

And it worked better because the progesterone receptor expression was in proof. So more receptors available and the receptors being more receptive, what they should be now, reality check. [00:10:00] 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 gonna be a treatment for endometriosis. Now in another study, they found that women with endometrial hyperplasia very common in PCUS, very common to find in perimenopause sometimes as well. What is endometrial hyperplasia? That is when the endometrial lining, the lining of your uterus gets big and thick.

And we don't like that 'cause 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 PCS and perimenopause? Because of unopposed estrogen, there's a relative estrogen dominance.

What does that mean? That [00:11:00] means relative to progesterone, estrogen is being left on check. 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. So it stimulates the endometrium to grow, grow, grow, and then we get endometrial hyperplasia.

Okay? So what they study found. Endometrial hyperplasia, other benign uterine conditions when these women use GLP one medications along with progestin, they had a much lower risk of developing endometrial cancer than women who were using progestin alone.

The benefits of this seem to still be there. When they looked at age BMI, the risk group, whether the, uh, progestin was an oral progestin or just an IUD and the combo was associated with fewer hysterectomies, which women in the endometriosis community, PCUS community, adenomyosis community, fibroid community, like all just perked up, right?

Because, you know, it should be always your choice to have a hysterectomy. We know. There is [00:12:00] 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 gonna pay well, it's gonna compensate you for your time, and that is the 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 this study. Okay, so this study showed GLP ones 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 [00:13:00] don't need metformin, it's just in this particular study.

Now important caveat here, this is more observational. It does not support proof that GLP ones should be used as a standard for endometrial cancer prevention therapy. I think that's just important to understand. Um, 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 ones are around.

What's interesting is that I've done another podcast episode talking about how HRT and GLP ones work better together when we're talking about perimenopause menopause. I'll link to that in the show notes as well, if you wanna check that out.

Okay. 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 ones 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 ones and the endometriosis pain got better, [00:14:00] like 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 that is specifically in the ovary. When we see lesions, though on the peritoneum lesions on the ureters. When we see, uh, 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 gonna 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 [00:15:00] 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. 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's 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 there it's behaving a little bit differently.

However it may be possible. Let's say you're offered a progestin IUD and your providers like use the progestin IUD because that [00:16:00] could slow the growth of adenos. And, 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 a baby.

But like, listen, I'm in college right now. I got like things to do and like, I gotta find that person that like I wanna 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, uh, metabolic dysfunction, maybe you have high inflammation and you've got insulin resistance going, you fit the picture of a GLP one.

Using GLP one with progestins may in the future prove to be a more efficacious therapy than just using progestin alone. Now 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. 'cause the progestins are not progesterone is.

That's why I often like to use progesterone more. Progesterone's also great at helping with. Gut integrity, which is a big problem in the endometriosis community. I need to do a [00:17:00] whole whole episode on that. Um, and you know what, you know, what we may see is that using the GLP ones drop inflammation, help with metabolic health help.

If you take away the inflammation, your HP axis starts responding better, and then, you know, having the progesterone, uh, or progestins on board. May actually improve the response of the endometriosis lesions. Perhaps this is a theory that I'm putting out there, but I think this is how we, we start to build information when the people holding the purse strings just do not care about, like 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 [00:18:00] 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 purse string holders so that we can get this kind of research. Now, 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, so show progestin.

So why would you use progesterone? 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 ones 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 gonna try to find the right progestin for that. They're gonna patent it, and the FDA is gonna approve one progestin.

Um, that's usually what happens. [00:19:00] And this is not a conspiracy theory, okay? And this is not antip pharma. Like, I mean, I take thyroid medication every day. I'm pretty dependent on pharma to like keep me alive in that sense. So I'm not an non-pharmaceutical individual, but it is a business. And you know, 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, uh, energy into making the meeting happen and putting together like how it's gonna be diagnosed. And like they, they did all of that because the outcome was, is that the FDA approved one pharmaceutical for the treatment of PMDD. Now that pharmaceutical. This is what's so ridiculous was actually just Prozac, but they made it, 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 [00:20:00] most people first as, 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 progesterone. If they've tried progesterone in the past and they're like, I don't wanna 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 thir 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? Like 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, and 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 [00:21:00] it's really interesting when I couple this information about progesterone receptors.

And, and their response improving to progestins with the idea that GLP ones, we tend to have lower GLP uh, levels in our peritoneum as with endometriosis, uh, 'cause 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. But what if you feel worse with the GLP one? Absolutely possible. Do you wanna know the most common reason why is because one of the most common side effects of GLP ones is that it's gonna 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. 'cause you go to bed at night and then the street sweeper that's going out in your [00:22:00] neighborhood, right? Get your car off the street because it's about to clean this whole town. Now that's the same 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 when look endometriosis, we have a long history of medical interventions for endometriosis that can harm how the gut functions.

We also, um, see a lot of women who have small intestinal bacterial overgrowth. We also see women who have adhesions on their intestine. And that's affecting how they function. Now, you introduce a medication that may slow down gut motility, um, especially if they start you at a higher dose with some of these.With this, you use the GLP one slows down your gut motility. Small intestinal bacterial overgrowth might get worse. Migrating motor complex might 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 [00:23:00] inflammation. It, 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. Is it endometriosis? Is it my bowels? Is it that I like? Pulled, 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, they can feel a lot like endo belly endometriosis, um, 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, you know, everyone always thinks fecal incontinence and urinary incontinence, but the, uh, hypertonic state of [00:24:00] endometriosis, if you, those, my video friends who's watching, um, the sloppy Dr. Brayton today all day because I'm like, I'm not getting dressed.

That, um, that song from like the nineties, I think is like, I'm bosse, but my, in my head, it's been, um, I'm sloppy Anyhow, you can see me shrugging my shoulders right now. And that is what our pelvic floor is like because we're guarding all the time. So we've got this hypertenicity, we can have difficulty entering, emptying our bladder, emptying our bowels.

It can also be cyclical as well. And if you're already having those problems and you're on a GLP one like that should have been screened for first. If you're not having regular bowel movements, you have incomplete void. So that's like you go poop and it doesn't feel like you're finished. That should be addressed before starting you on a GLP one.

Because that can be a reason that you feel so much worse. Okay. I have just shared a bunch of information. I would love to hear your thoughts. Have you tried a GLP one? Has it been successful for you? Was it not successful for you? Are you hearing all this talk about GLP [00:25:00] ones and endometriosis that's spiking your curiosity?

I would love to hear so much more from you in the comments because the way that so many of us learn as clinicians is by listening to people's lived experiences that absolutely has value. Okay, check it out. If this episode was helpful, if you like hanging out with me, make sure you subscribe. Leave me a comment, share this with someone who needs to hear it, and certainly amplify this message.

If you think we should have more research in this area for endometriosis, I would love to hear from you. Alright, I will see you next time.