GLP-1/GIP Drugs & HRT in Midlife: What the New Data Suggests for Women's Health

All right, if you have listened to me, uh, in the last couple years, I was a pretty harsh critic of the GLP-1/GIP drugs, the semaglutide and the tirzepatide. And here's the reality, is the largest group of people using these medications are midlife women, and it's because you have a lot of things that are shifting in your body during this time period. And I've had a multitude of podcasts about it But what I wanna do today is I'm gonna dial it back. I'm actually gonna walk back some of my heavy-duty judgment about these medications. Now, let me say first, before I get into the science, my judgment was never about the mechanism of the drug itself. It was the prescribing habits of the physicians that were prescribing it. Yeah. So it was really about the prescribing of the medications themselves and the lack of really appropriate consultations with people, particularly around what to eat, how to eat, and make sure they get the right nutrition, particularly protein and just the needed vitamins and minerals. Because let's face it, the medications, when dosed at the range to create pretty significant weight loss in a short period of time, which is often what people are looking for, results in an anorexic-like effect and also sometimes digestive symptoms. And that was always my judgment. But, you know, if we flash forward now a year and a half, 2 years later, 3 years later, after the kind of explosion of using these medications, we do have more data. So, what I'm going to do today is go through the data specifically around GLP and GIP drugs and perimenopause and menopause, and what we're really seeing, and how to really look at this time period as the best, you know, the best scenario. And, if you are considering hormone replacement therapy and these medications, how to look at it because your metabolism is different now. If you've heard me before, when your body drops in estrogen and you have declining levels of progesterone and testosterone is on its steady decline, your cells are not good at burning fat. They're not good at burning sugar. We see sort of a going to sleep of all of that process. And then, you also see insulin resistance and excess cortisol and even changes to thyroid function. And so we do have a different mechanism that's happening than when we were 20 and 30 years old. And so the real, the real thing is, is how to use these things properly so you can help yourself. And it's a real critical part of the puzzle, and I want to talk you through it. Okay, so let me start with the weight gain that we're all experiencing. In case you're listening to this for the first time, it's not laziness, it's not a calorie problem, it's not a problem of you're not working out hard enough. It is a biology problem. During this transition, you have declining levels of hormones, particularly estrogen is the one I'm going to focus on the most. And estrogen does a lot more than just create the feminine features of, you know, T&A. Let's just be honest. It regulates how your body distributes body fat. And actually, in the beginning of perimenopause, we tend to get weight gain in what I like to call the junk in the trunk, the hips and the thighs and the butt. But what happens when we go further into menopause? Your distribution of your weight changes and it starts to show up around the midsection. And this is really changing your overall fat distribution and body composition. And it also controls part of your hunger hormones. Is so— it can affect how the brain responds to fullness signals. What else does that? GLP and GIP drugs. So, when we see that metabolic shift, we also see that our body preferentially stores fat, again, in the abdomen or visceral area fat, and which is more metabolically dangerous, right? It increases inflammatory signals called cytokines. It makes us more insulin resistant and increases our risk for diabetes, heart disease, basically all forms of dying. And, you know, here's the good news. What we do know is hormone replacement therapy actually addresses this in real time. Real hormone replacement therapy, bioidentical estrogen, not the synthetic things, not the horse mare urine, really improves glucose metabolism and fat metabolism. It also reduces visceral fat accumulation. So the fat that you're getting under the muscle in the abdominal area, and it protects against diabetes and metabolic syndrome. Excess cholesterol, and triglycerides. Multiple large cohort studies. Okay, so those are the studies with people in them, not just looking at data, show this. Transdermal estrogen, estrogen used on the, the skin in the form of estradiol, is the kind that bypasses your liver and goes straight into the bloodstream, and it has the best metabolic effect. So a topical estrogen, either in the form of a patch, a cream, or an oil, injectable. But here's the thing, but for some women, right, hormone replacement therapy, restoring those metabolic hormones back to normal compared to where they are today, closer to what you were years ago, may not always be enough. And this might be where these drugs really play a role. Maybe our body composition has already been compromised. So if you've heard me talk before, if you've been overweight for a long period of your life, Maybe it was after kids and you never quite got rid of it. We have a lot of regulatory things that change, particularly in the brain, and we know that our neurological symptoms will set us to a set point. And so, it's kind of like your body goes, "Hey, this is where I've been for a really long time. I wanna stay here and I don't wanna drop below this because my new set point is safe for me." And stress hormones and all those other things play a role. But what we see is we need more aggressive interventions sometimes. And this is where GLP-1s and really GLP-1 agonists really come in. And this is where the emerging research is really cool, that when you combine appropriate bioidentical personalized hormone replacement therapy, estrogen, progesterone, testosterone, with GLP-1 medications, they might work better together than separately., and this is where this biology starts to converge, and that's what I wanna talk about because I think it's very important. It's a very practical reality that you can take these two medications together and get better outcome. And especially if you are on one of these medications and you're not getting the results that you want, or you feel like you are, uh, plateaued. So what does GLP-1 stand for? It's glucagon-like peptide 1. It's a hormone that is made in our gut. Our gut microbiome helps it, and it tells your brain when you're full or not. And so it sets off sort of satiety and hunger signals, and it slows down also how fast food leaves your stomach, so gastric emptying. And it improves how your body handles blood sugar, particularly at the, at the lining of the intestines, that crossover zone. And it also then increases how much, um, energy our body will actually burn.. And then GLP-1 receptor agonists are drugs that mimic that hormone, right? So this, these bind to that same receptor. So this is that semaglutide. It turns on the same switches and they are extraordinarily effective for weight loss. I am not saying that they aren't, they are probably one of the biggest game changer medications when it comes to weight loss. Um, and they have been on the market for a very, very long time because we were using them for diabetes for a long time. And if we see the averages, the weight loss is between 10 and 20% of your body weight over the course of about 6 months to a year. It's not small and it's also not 20 pounds in 30 days, right? So, we have to be realistic about the outcome. And we also know that slower weight loss, appropriate weight loss without starvation actually results in less weight regain if you stop the medications. But this is where it becomes crucial. Women, um, lose more weight on a GLP-1 drug than men. All right, so a recent meta-analysis found that a woman loses an average of 10.9% of their body weight, while men only lose 6.8%. Same drug, same mechanism, different outcome. Hmm, let's see, this would be a place where women-centric, women-only research should probably be done. So here's why. The most compelling evidence suggests it's because of estrogen, or more precisely, because of estrogen and GLP signaling pathways overlap in the brain and in fat tissue. Isn't that cool? They work on a similar metabolic target and they influence the same enzyme pathways. And when we have estrogen present, whether you're adding it through patches, creams, or other things, or it's your own estrogen, the GLP-1 appears to have an enhanced effect. So this is not definitive proof of synergy yet, but it is damn close, right? If the signal is frequent enough and strong enough, the signal is there. We don't have head-to-head, uh, clinical trials because, uh, let's see what's happening. Oh yeah, we aren't able to get women-centric, uh, research funded in the United States, and that's going to be a little bit of the challenge. But the most compelling explanation is This is why menopausal women respond so robustly to these medications, particularly when they're on hormone replacement therapy. Your body's ability to use these GLP-1 medications effectively may be enhanced by this hormone replacement as an— as a whole. So that's really, really cool. All right, so let's talk about this. It's, it's really the kind of understanding of what's really happening. So So, in 2025, a clinician named Andrew Parker, Dr. Andrew Parker, published a case report in the Menopause Journal. So, this was just a single case report. It was a postmenopausal woman that came in. She was on oral estrogen therapy, doing well, felt great. So, she was on like a Premarin, right? Not something I'm a fan of, but let's face it, that's what she was on. She wasn't having hot flashes. They were controlled. Then, she started semaglutide, the GLP-1 drug sold as Wegovy for weight loss. As she titrated that drug up, something unexpected happened. Her hot flashes came back. Her mood dipped. She felt like her hormone therapy stopped working. Now, I can tell you anecdotally, talking to our prescribers at Minerva that prescribe through telemedicine hormone replacement therapy across the US, we have had other people that have come into us because we do not use oral and saying that when they started the GLPs, it felt like it wasn't working, right? So, here's the thing. So, when she took the GLP up, all of the hormone symptoms that she had controlled with the oral Premarin came back, right? So, when they then brought the dose of the GLP back down, all of the hormone symptoms went away. So, this is Dr. Parker's hypothesis and it's a, a sound one that the GLP drug was temporarily interfering with how she absorbed her oral estrogen. Again, it affects a lot of activity in the gut, and it slows down gastric emptying, right? The GLP-1s do. And this slows down how fast food moves from your stomach into the intestines. And that's actually where some of the weight loss is, is really happening. When you slow down gastric emptying, when you're taking oral forms of birth control or estrogen, you're affecting the absorption window. Which is really interesting, right? So oral estrogen has to pass through our gut and our liver before it gets into the bloodstream, and that whole process is delayed and altered. So you might have lower peak estrogen levels, not for days, but probably just during that initial titration, but maybe, right? So it temporarily lowers your available estrogen even for a few weeks, which is enough to bring back all the symptoms. So here's the reassuring part. This appears to be temporary and doesn't appear to be true when we talk about topical forms of estrogen. But, you know, this also brought me to another question because, you know, I can't help but come up with questions. If GLP-1's slow gastric emptying potentially affect the effectiveness of the absorption of estrogen-like pills, what could it possibly be doing to women who happen to be on birth control? Birth control is synthetic forms of estrogen and/or progesterone that require first-pass liver metabolism. So, digestion through the gut, first pass to the liver to then create these byproducts that irreversibly bind to the receptors in your ovaries so you don't ovulate. Makes me start to wonder that we really probably also need some studies looking at effectiveness of birth control with the use of these medications. Now, obviously, that's not my age group, right? That ship has sailed. But it does make me wonder about how that would work. So, so the route of estrogen really matters, right? So if you're currently on an oral estrogen, like a tablet or something like that, something that you swallow, you know, and you're thinking about starting a GLP-1, it'd be important to watch and see if you're actually getting symptoms coming back because of that, right? And again, I would recommend going on a topical form because you also don't see the blood clotting risks and other risks associated with oral estrogen. But if you see it coming back, that's important to note, right? And so, so here's the other bonus thing, right? So if I'm doing a transdermal estrogen, guess what it has shown in the research? It has a better metabolic profile. It doesn't increase our triglycerides in the same way oral estrogens do. So, when we talk about oral estrogens like Premarin, we know it increases clotting factors, particularly anybody that might have like Factor V Leiden or MTHFR or anything where they have clotting risk. Oral estrogens because of first-pass liver metabolism increase clotting risk, but they also have a negative effect on triglycerides and a little bit to cholesterol as well. They don't have a positive effect on cholesterol. Topical estrogens do. So topical estrogens reduce your triglycerides and have also shown to reduce cholesterol levels, keeping them in a more favorable effect, which is more favorable to your cardiovascular system. So if we're taking a GLP-1 for metabolic reasons, weight loss and diabetes risk, or triglycerides, or the— just the inflammatory response, you're gonna see a better estrogen effect by a topical form., and that would be better. Um, standard transdermal doses. So when we look at some of the research, it's gonna be your patch doses, like 0.025 to 0.075 milligrams. Um, your progesterone obviously can be oral and micronized, 100 to 200 milligrams, which you would take at bedtime. These combinations work beautifully when we're looking at the research along with GLPs. Right? You get a stable estrogen dose from the estradiol patch. You get the progesterone at night for endometrial support and also sleep. And really, you don't have any interactions from a GLP-1 drug. Now, what's interesting is when we use our topical forms of hormone at Minerva, we're using a bioidentical hormone in jojoba oil with really, really good absorption. And we're able to also dose it multiple times a day. So you get a little bit of the normal diurnal rhythm of hormone that you get. Particularly at night to help with sleep. And again, it's a topical form, so you get better overall effect without that agitation or potential interaction with the GLPs. Alright. So, what does the research actually show about lean body mass? Because again, this is what I was pissed off about because if we look at the original studies looking at GLP and GIP drugs, we saw weight loss, right? Again, we put on our thinking caps when we're thinking about studies. We have to look at the language because it's really important. Weight loss is different than fat loss and it's different than lean body mass, right? What we want is fat loss. Overall weight loss isn't awesome if I'm losing muscle mass. So, here is where the combination really shines. And, I hear this a lot from women. They'll be on GLPs and they're— the first question is like, am I going to lose muscle with fat? And the answer on is, is really it depends. It depends how much you're taking these medications, whether you're getting enough protein and lifting weights, and also what kind of hormone therapy you're using. So a recent meta-analysis that looked at body composition changes with different GLP-1 drugs, so they looked at both Wegovy or or tirzepatide, and they also looked at semaglutide. And here's what they saw. Yes, you will lose some lean muscle mass. On average, about 25% of the total loss would be muscle mass, but the degree varies. So, if we look at tirzepatide, which is Mounjaro or Zepbound, this is a dual GLP, glucagon-like peptide-1, and a GIP agonist. It produces the greatest overall fat loss and weight loss relative to semaglutide, right? There is a new one coming out, retratetide, that will be out that's even going to be better because it's basically a combination drug like that and then a glucagon, um, addition. So, it just works a little bit better. But right now, tirzepatide has the best effect, but it also has some of the worst lean muscle mass preservation. Semi-glutide and Ozempic is in the middle, and the weight loss is acceptable with an okay lean muscle mass, right? And then if we look at the existing diabetes medication, liraglutide is the only, um, it's known as Saxenda if you wanna think about it from the brand name. It's the only GLP-1 drug that achieves significant weight loss and fat loss while not significantly reducing lean muscle mass. But it doesn't come close to the outcomes of weight loss data for tirzepatide and semaglutide. And so therefore it has not been approved for weight loss, but it has been used for a long time in diabetes. So here's where this really becomes important for women who are in perimenopause, menopause, or postmenopause. You're already at risk of what they call sarcopenia—lean muscle mass loss. Muscle loss due to just loss of hormones and aging. Preserving lean mass is not just cosmetic to look good in a shirt, a sleeveless shirt. It is so, so very important about your metabolic rate, your bone density, your strength, and your ability to move and your freedom later on in life. So if you're choosing a GLP-1 drug, lean mass matters to you, and we have to understand the considerations and look at it. Now, here's something that really surprised me. So we know that hormone replacement therapy coupled with a GLP or a GIP drug is going to help be a little more metabolically active, hold on to lean muscle mass, and support you. And so this is really interesting. So the second hormone in that GIP drug, right, tirzepatide, that second part of that drug mimics a, a basically a hormone that can affect bone benefits. So a study looking at postmenopausal women showed that the GIP drug tirzepatide, when given as a hormone analog, right? So given sort of like that hormone, it directly inhibited bone reabsorption and increased bone formation. That's impressive cuz that's what estrogen does. Essentially, it told the bone cells to stop breaking down and to start building new bone. And that's actually the opposite of what we see in perimenopause, menopause, and postmenopause when women have not been treated with hormones, right? This is where bone loss accelerates. So that's really awesome, because if I'm on hormone replacement therapy at adequate levels to protect my brain and my heart, my bones, and I happen to be using a GIP drug like a tirzepatide, what I'm gonna see is preservation ideally of, of muscle mass and particularly bone mass if I'm doing the right things with my diet and my lifestyle and my exercise at more amplified levels because we've got multiple hormones that are actually talking directly to the bone. Now, here's the early research, right? This is what this is. But we don't have any long-term data on bone density long-term on these medications. And particularly, you know, looking at women over longitudinal data. But the mechanism is pretty compelling, and that's helpful because you run the risk of expanding weight loss for somebody who might need to lose weight or be pre-diabetic, and the wrong drug selection can accelerate bone loss. Because one of the other things that conventional physicians often assume is that if you're a woman and you're overweight, or let's say African American, they just assume that your bone mass is going to be good, right? And that's not necessarily true because the other thing we see in obesity research is we see fatty deposition in the bone inside the trabecular bone, which is kind of the interior of the bone, in people who are obese and also sedentary. So just being heavier doesn't necessarily always mean that we might have great bone mass. So, when you're working with somebody metabolically and you're working on, let's say, weight loss and you're in that perimenopause-menopause zone, we— the right selection here can make a difference and we wanna preserve that, which of course, you know, I've always been a proponent on really getting a bone density long before you need it, right? We should have it long before perimenopause. We should have it while we're in the transition and we should have it every couple years afterwards. Alright. So, how do we combine— how do you combine these therapies based on the research, right? So, let me give you a framework that you can actually use. If you're not on any hormone therapy yet, right? Let's say you're kicking tires, you're looking at it, and you're considering that and maybe a GLP drug. Start with the transdermal estradiol, right? Start with getting on a therapeutic dose. No, I can't talk doses with you. I'm not an MD or a DO. I don't prescribe. But what I can tell you is it's individual. Two women can take the exact same dose and have a completely different blood level. We absorb it differently. We have different capacity to absorb in different ways. The patches have different absorption. So the reality is, is you need lab testing to make sure that your symptoms are improved and that you're also in that zone where we see metabolic and bone-protecting and heart-protecting effects. And we also need micronized progesterone at least 100 to 200 milligrams potentially up to 300, 350 if you have sleep issues. And we also probably need some testosterone too because it helps preserve lean muscle mass. Give that 4 to 6 weeks to get going because again, they are metabolically active. Estrogen tells the fat cells to give it up, tells the body to be less inflamed. It improves insulin sensitivity when it's back online at the right amount. So you wanna give it that time period. Then you can move into the GLP-GIP zone and start adding it. And then you can also, you know, slowly titrate up. But what you'll find is you may not have to take that dose as high to get the same effect because you have this layering effect of estrogen and the GLP. Now, if you're already on hormones, rock on. You're already one major step ahead. And you can go ahead and start the GLP. And here's the thing too, if you're using the standardized doses, right? So 30% of all medications are used off-label. So I do find it interesting when, when physicians online are lambasting off-label use of medications. Also, compounded medications are used every day at the hospital. It's not like it's only used by functional medicine people. Medicines are compounded to the patient in many, many ways. A lot of IV therapy and other things are compounded to the patient. So the traditional drugs, the brand name drugs, are metered in doses that cannot be altered. And for some people, those doses cause a lot of symptoms. Could somebody do microdosing or a lower dose more times a week to get to a therapeutic dose but not cause that high bolus dose of once you take this really big dose, you get nauseated and basically shit yourself for 3 days? Right? Let's face it, lots of people are doing it. So, if you're on the brand names, you're gonna have digestive symptoms potentially at those higher doses. You can use compounded doses and work with your prescriber to figure out your personalized dose. So, it doesn't mean you can't do it if you've had symptoms before. And some people do better on, let's say, tirzepatide and/or semaglutide than the other. So, all that to say, if you're adding these hormones, Personalization is important and being able to figure out which one works best for you. But start with the hormones first before you put in the GLP-1, GIP medications. And then if you are really concerned about osteoporosis or already has some risk factors for that, the most evidence today is that, you know, if we look at the most evidence, the most clinical support, tirzepatide. Semaglutide has been around longer, but tirzepatide is probably the one that's going to do the best. Alright. So, here's what we do know and what we don't know because, you know, that's always my thing because you deserve the honest truth. We don't have large randomized controlled trials comparing hormone therapy to hormone therapy plus GLP-1 drugs. We don't in menopausal women. And, we don't have long-term safety data on this kind combination. However, we have had women on hormone replacement therapy and on drugs like Saxenda, which is another, uh, GLP-1 drug, um, for diabetes for a long period of time. So we have history, we just haven't done head-to-head clinical trials. Um, and we don't know for sure if the order matters, but if we look at just the biochemistry and the biology of the body, we know that hormones first restores the metabolic function and the normal function of your body. And then adding GLP-1 and GIP is just sort of ramping up things that are already happening. Um, what we do have is promising preclinical evidence, right? We have, uh, case reports, we have metabolic data really suggesting this kind of convergent pathways. We have anecdotal data, we have observational data. So let me speak a little bit to observational data. Where does observational data play a role in setting clinical recommendations? Here's a really good example. So when someone says you can't do that or you shouldn't do that cuz we don't have clinical trials, we never ever did a clinical placebo-controlled trial of smoking and nonsmoking to prove or negate lung cancer. Why? We had enough observational data to figure out smoking caused lung cancer. So when you have enough signals and enough observations to know something is true, there's no need to then create a clinical trial that is expensive and already verifying what is noticeable. We use that kind of data all the time to make large clinical recommendations. It's never just clinical trials, right? So I look at this and say, hey, we got enough data to at least understand that these things have synergies, right? And the evidence is not just there, um, not just theoretical, it's really also biologically plausible and likely, um, but it's not certain, right? As you very well know. So I want you to think about this. So we— I covered a lot, right? I covered why menopausal women gain weight, what happens, how a GLP-1 drug works, The critical kind of factor of like delivery mechanism matters. We wanna use transdermal to get the best, best effect. Oral estrogens have a differing effect when used with GLP-1 and GIP-1s. And that includes women, if you happen to be in your 40s taking birth control to either control your symptoms or again, that potential pregnancy window is there, be aware that there may be absorptive differences with these medications like semaglutide and tirzepatide. And I would just be kind of cautious because if it's absorbing differently and hitting the bloodstream differently, it may affect the effectiveness, and we haven't studied that, you know. And so here's what I want you to walk away with: you don't have to choose between feeling like yourself hormonally and addressing maybe the excess weight that you may have that you don't want. Uh, you can use these things together, and especially when you put them together with sound dietary recommendations with protein intake and making sure you exercise to preserve and hopefully at least preserve muscle mass, if not try and put some on while going through the weight loss. This is important, right? And you have to also understand that when you're working with your practitioners, that they do personalize your care. Again, what is one woman's perfect situation is another woman's poison., right? And so, you need to make sure that you're working with somebody that's actually doing the work and helping you understand your personalized needs and testing for it, right? And testing for it. We don't want you to be dismissed. And that's really why we created Minerva. It's why I get on here once a week to rattle your cage about what you need to know. We do really want you to have the best next season. So, I wanna thank you so much for listening to Menopause Mastery. If you happen to be listening on your favorite podcast platform Or if you're watching me on YouTube, thank you so much. Don't forget to subscribe, drop a comment, let me know what you think. I'd love to know what you would like to learn about so I can share more information.