Melanie Cole, MS (Host): Patients with higher BMIs may have less successful reproductive outcomes. And recently, new medications, GLP-1 agonists or GLP-1s, are producing meaningful weight loss similar to surgical interventions.

Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. And today, our discussion is really highlighting GLP-1 agonists and treating obesity and infertility. Joining me is Dr. Christina Boots. She's an Associate Professor of Obstetrics and Gynecology, specializing in Reproductive Endocrinology and Infertility at Northwestern Medicine.

Dr. Boots, it's such a pleasure to have you join us today. And I'd like you to start by giving us an overview of how obesity and reproductive outcomes interact. What are some of the specific challenges faced by patients with higher BMIs when trying to achieve successful pregnancies?

Dr. Christina Boots: Thanks for having me today. I'm excited to be able to talk to everyone about this. I think, you know, we know that BMI interplays with reproductive health for women throughout their lifetime, but especially with fertility. And it affects fertility in a lot of ways. So, you know, I'll start by just mentioning that BMI isn't definitely an oversimplification of health predictors. So just because a woman has an elevated BMI, it doesn't mean that she'll be infertile or that that is the reason she's infertile. But certainly, we know that a higher BMI affects all kinds of aspects of their reproductive health.

So, very specifically in terms of trying to conceive, we know that some women will have ovulatory dysfunction, meaning that they're not ovulating in a really consistent and timely way. We know that BMI may play a role in egg quality. We know that it can play a role in implantation and embryo development. And so, there's a lot of different ways that we've seen it lower success rates in terms of trying to get pregnant naturally as well as when we start to incorporate fertility treatment as well.

I'll make one more comment there that we know that women at more extreme levels of BMI also have difficulty accessing fertility treatment. There are IVF centers throughout the country that they have upper limits to their BMI. So, they can't access the procedures that are related to the fertility treatment. So, not only is it playing a role in being able to conceive, but also accessing the most advanced technologies.

Melanie Cole, MS: Well, I certainly agree with you about BMI not being quite an accurate indicator of a woman's body type. It doesn't take into account many things, but we are talking about obesity. And so, I'd like you to tell us about how obesity management, and there's so many medications and things on the market today, can help with some of those positive outcomes for in vitro fertilization and even, as you said, getting a spot at the table, getting a place with a clinic.

Dr. Christina Boots: Yeah. Well, I would say, you know, when we start talking about helping women get pregnant, I think regardless of their BMI, there should be some what we call preconception counseling. So, what ways can we optimize your health? And so, just because your BMI isn't high doesn't mean that there aren't ways that your metabolic health could be optimized as well, too. But especially women with higher BMIs, we do see higher rates of thyroid dysfunction and insulin resistance and diabetes, high blood pressure, hypertension. And so, those things we really want to highlight and then improve upon before they get pregnant.

And so, for all these women, we should really be focusing on that in terms of before we're even trying to get pregnant. But then, once we're there and we're saying, "Okay, we really know we need to help these women be able to get here and they've been struggling to get pregnant," then some lifestyle changes, even without weight loss, can be helpful. So, really focusing on an improved diet, improved activity and movement in our bodies. We do know that some women who have ovulatory dysfunction are ovulating regularly, that even kind of mild drops in weight can help improve the function of their ovulation.

And so, I think, you know, there's data and media coverage, I should say, about that these ozempic babies and GLP-1s and weight loss are going to dramatically improve your fertility. They need to be interpreted with a little bit of caution because we actually don't have any studies that show that if you take a GLP-1 and you lose a bunch of weight, you're going to have better IVF outcomes. That has not yet been shown. We do have about a handful of randomized control trials prior to the GLP-1s really entering the market and being utilized, but these randomized controlled trials that look at utilizing other weight loss medications and lifestyle interventions that show that half of these women go straight to IVF and the other ones lose weight first, and they are getting some significant weight loss, and we see that there aren't better outcomes, actually, in their IVF success. And so, short-term weight loss doesn't seem to dramatically reverse egg quality or quantity or implantation. And so, that actually has not been shown. And so, we shouldn't be offering women dramatic short-term weight loss as a means to improve their IVF success because we haven't seen that happen. And in fact, some of these studies have shown increased miscarriage rates in the women who do conceive that had had pretty significant weight loss in the short term right before.

So, I think we have to be really careful about that and choosing who is most going to benefit and maybe who wouldn't benefit from this. And so, we spoke a little bit earlier. So, I think number one is that those who are metabolically unhealthy. And so, we see if they have insulin resistance and ovulatory dysfunction, there's some of the people who are going to benefit the most from this. And we may see them starting to ovulate and be able to conceive on their own.

I think the other benefit is, as you mentioned, about access. So if their BMI is over a limit at which they can access this care, that this can really help them get into a place where they can reach this really excellent and successful technology for many women.

And I think the third is that sometimes excess body fat makes it actually really difficult to administer fertility treatment because ultrasound imaging is harder or just the procedure is technically more difficult. And so, there are some women that benefit from that.

But I do think there's some downsides to that, that it takes time to have meaningful weight loss, even with these amazing medications that are now available. But we have to have a sit-down individualized conversation about who's most going to benefit from this because if you're 38 years old and you're going to take a year or two off to get this meaningful weight loss, well, actually your egg quality is probably going to decline more than we suspect weight loss is going to help.

And so, we'd have to have conversations. And for some women, that may mean that you're taking a shorter time off, that we freeze eggs or embryos ahead of time and then make the weight loss before we conceive. But we need to have some really thoughtful, individualized conversations about how best to strategize around that.

Melanie Cole, MS: Really you've hit a great point, those thoughtful conversations, the shared decision-making, and certainly patient selection. And as we get into a little bit more and learning that the studies are really not showing definitive proof yet. Why don't you tell us just a little bit about how GLP-1s work in the first place? How do they work to treat obesity? I mean, they are just definitely all the rage and how are they working to balance neuroendocrine hormones imbalances? Tell us a little bit about them in the first place.

Dr. Christina Boots: Yeah. Well, I think I'm excited about these medications as so many of us are. One big primary reason I talk to my patients about, you know, this is the first time that we have medication that really targets the hormonal imbalance that we see that is associated with obesity and a high BMI, that for most people, it's not just because they, you know, ate too many Snickers and didn't go to the gym, that there's something genetically predisposing them and metabolically adjusted here that's causing this. And so, their bodies are really focused on storing calories rather than using them. And that may have been evolutionarily benefit when we were cave people and there were famines and droughts and we needed to do that. But nowadays, we don't need to store our calories. We have refrigerators and grocery stores and Instacart and all of those things.

And so, I think for the first time, society is really starting to see that these medications that are targeting the hormonal imbalance that happens with this metabolic adaptations that we have with the excess fat being there, that is really exciting to have them. And so, the way they work is that the glucagon-like peptide is an incretin hormone that's secreted by your gut. So when we eat food, our gut recognizes that glucose is coming in. And so, it tells our body to release insulin. These GLP-1 receptor agonists, these new medications target the receptors of these hormones and hold on to that hormone so that its effect lasts longer. And so, the primary weight loss benefit we're seeing is both from the central signaling that happens to our brain to decrease appetite, but also in slowing our gastric emptying. And so, we feel more full, and that sort of food noise a lot of patients struggle with is decreased. And so, that's probably the primary way that we're getting this such significant weight loss.

There's a lot of other effects that are happening as well too, that it targets our white adipose cells and increases the lipolysis. It increases glucose uptake. There's even some data that's showing that the thermogenesis in our brown adipose tissue has been increased with that. So, for those who don't speak this language, you know, it just means that the amount of calories we're burning just by sitting here and breathing is going to be increased as well too.

So, there are receptors to this GLP-1 hormone, you know, throughout our body and our skeletal organs and our kidneys and our brain. And so, it's pretty profound how it works through multiple different systems.

Melanie Cole, MS: Well, it's a pretty exciting time in obesity medicine in general, really. Things are moving very quickly. And when we think of reproduction and infertility, PCOS comes to mind. It's often associated with obesity, but many times not. How do the GLP-1s affect patients with PCOS? And have we seen any benefits in terms of successful pregnancy outcomes?

Dr. Christina Boots: Yeah, yeah, I think we're starting to and there's a little bit of data. Most of the published research are on still the older generations of the GLP-1s, but I suspect that not just for the women with PCOS who are trying to get pregnant, but those who are just trying to live their lives before and after pregnancy as well too. But polycystic ovary syndrome by definition means that women have ovulatory dysfunction and some metabolic dysfunction as well too. So, we see higher rates of insulin resistance, diabetes, hypertension. And so, women who have this metabolic dysfunction and their excess adiposity and ovulation dysfunction are probably some of our fertility patients who are most likely to benefit from improved lifestyle and weight loss. And so, these GLP-1s are targeting just that. And so, we are seeing improvement, certainly in the way they're using glucose, their sensitivity to insulin, and we're seeing them ovulate better.

You know, the GLP-1s, you have to be thoughtful about how you're using them as well, though, too. You know, we talked about using them in preparation for pregnancy, but these medications really shouldn't be used during your pregnancy. We don't know what they'll do to a growing baby's metabolic health. And so, we really shouldn't be on them while we are pregnant. And so, these are medications that need to be stopped in advance of actually conceiving.

Melanie Cole, MS: Well, I'm glad you brought that up because obviously, you know, we're going to look into the complications of using them during pregnancy, but we haven't discussed the complications of them in general, concerning anesthetic procedures, obviously you just talked about pregnancy, but what complications have we observed with these medications?

Dr. Christina Boots: Well, part of the reason there's so much popularity is that they're actually tolerated very well. And prescribing them is relatively easy in that you're not having to, you know, strictly monitor lab levels and things like that, that they're actually really well tolerated. The most common symptom that we're seeing in our patients, and what's been reported in the research as well, is mostly GI. That nausea, altered bowel movements, more on the end of constipation are pretty significant. The medications are administered initially as a slow dose that you slowly titrate up. So, the newer generations are a once weekly subcutaneous injection and the recommendations are to not increase that, that you stay on that dose for four weeks and then you increase to the next dose. And certainly, that may need some adjusting if patients aren't tolerating it very well. There are bigger complications like things like pancreatitis and there are certain patient populations that are contraindicated to use this medication.

But important things that we do talk about when we prescribe it is that the current anesthesia guidelines, so anytime you're going to be put to sleep in order to have a procedure done, because you're at risk of aspiration, meaning that your gastric contents kind of move up while you're sedated that there's concern that because the gastric emptying is slower, that this medication should be stopped for at least a week ahead of time. But I would encourage our patients, you know, those are the current anesthesia guidelines, but those can always change, and there may be particular guidelines in each anesthetic office. So, they should always ask about it when they're planning something and then, of course, as I mentioned, prior to pregnancy.

Melanie Cole, MS: When you say prior to pregnancy, what about during fertility treatments? Are we stopping them? Once you start, if someone's going in and they've lost some weight on these GLP-1s, and then they get into a fertility clinic and they start their IVF, is that when we cut off the medication? Does it continue through that?

Dr. Christina Boots: It depends. It depends. So, everybody's approaching this a little bit differently. And there are no concrete guidelines around this. You know, in the semaglutide FDA agreement, it says you should be off of these medications for eight weeks prior to conceiving. So, it depends on how your fertility treatment is set up. So, I do have some patients, especially those who are trouble accessing IVF, that actually we have them stay on their medications as they're going through their IVF cycle to maintain their decreased BMI and not having weight regain, but with the plan to freeze their embryos so that they're not getting pregnant in the same cycle that we're creating the embryos in.

And then, once we have this ideal number of embryos and we feel comfortable that we're at a good weight, then stop that medication and within a month or two as recommended, we'll then help them get pregnant and do what we call a frozen embryo transfer.

Melanie Cole, MS: This is such an interesting topic and really such an interesting time for this topic because we're just hearing so much about it. And as we get ready to wrap up, Dr. Boots, how do you feel that obesity management should be integrated into reproductive preconception care models, including GLP-1s, but also some of the conservative management that you discussed earlier. How do you feel this all ties together? And while you're answering that, who ties it all together? You're an Obstetrics and Gynecology specialist. Then, there are our reproductive endocrinologists, you're also one of them. But then, there's, you know, the fertility specialists, and then we've got people in the Weight Management. It's multidisciplinary, really. So, tie this all together for us.

Dr. Christina Boots: Everybody. I think we all need to be working on our patients and helping their health and well being. And I think primary care physicians, general gynecologists, you know, in my ideal world, we'd be talking about this, you know, at every just annual visit. You know, how do you feel about your way? Do you think you'd benefit for some extra nutrition counseling or motivation to, you know, just move our bodies more and having really good access to those who want more information and need some motivation to meeting with dietitians who are really motivated and thoughtful and kind and willing to meet patients and using evidence-based medicine during that. And so, man, I wish every annual visit would be talking about that.

And bringing up when do you think you might want to start your family and what's your ideal family size. Because if you want two kids or six kids, then we should be starting, you know, sooner rather than later. So, having these conversations even before they get to the fertility specialist would really be ideal.

But then, I think we have to sit down and, as I said earlier, that we have to be pretty comprehensive but also individualized in our treatment. You know, I haven't had a patient come to me who wasn't aware of what their body size was and what influence that has on their health and hasn't tried to modify their body size in some way or another. And so, how motivated they are, what things they've already tried or haven't tried. But, gosh, if they've been struggling with their BMI for a decade or more and really have felt like they've optimized as much as they realistically and possibly could at home with their lifestyle, then I think these medications can be really great. But they're not for everybody for those same reasons that I mentioned. And I think we have to think about the time of fertility. And if you're 27, you still generally have some pretty good egg quality and quantity left. But when we're approaching our 40s, we really got to worry about those with a decline in our fertility. So, it's got to be all of it.

And I think we here at Northwestern and in the Reproductive Endocrinology Department have worked really, really hard to create a really well-rounded, multidisciplinary team with pharmacists and a nurse practitioner and nurses and dieticians. We have a program here at Northwestern, we call it the PEARL Clinic, which is an acronym, but we also involve Maternal Fetal Medicine and the Center for Lifestyle Medicine as well here too. So, we're all working together to really try to provide as much care as we can for all of these patients

Melanie Cole, MS: Beautifully said. And it's not like we all don't know what we look like, right? And you said that perfectly. And when people have weight issues, they do know that these exist, but that thoughtful conversation with their provider is so important, Dr. Boots. And I'm so glad that you brought that up. And thank you so much for joining us and really sharing your incredible expertise with us today.

And to refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org/obgyn to get connected with one of our providers. That concludes today's episode of Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. Thanks so much for joining us today.

Dr. Christina Boots: Thank you.