Welcome. We're really pleased today to cover menopause science and clinical care. This has been a very rapidly evolving area, so we hope to inform you about this. I'm going to be the program chair today, and Cynthia Stunkel and Joanne Pinkerton will be the speakers. So let's get started with this. I don't have any disclosures, and what the objectives are of our session. We're going to increase knowledge of menopause physiology, learn about advancements in menopausal research, draw conclusions from 20-year follow-up of the Women's Health Initiative studies, and recommend therapeutic interventions to improve patient care and outcomes. So we're going to emphasize a key principle in menopause management, and that's personalized medicine. You need to consider the individual characteristics of a patient, including the underlying risk of fractures, breast cancer, and cardiovascular disease, osteopenia and osteoporosis, and venothrombotic events. You need to consider individual symptoms, hot flashes and symptoms related to the genitourinary syndrome of menopause, and then initiate tailored treatment to specific symptoms using underlying risks and anticipated benefits to tell the patient and discuss with them what you're going to do. It's key to integrate all of these components to help individual therapy. So for fracture risk, we recommend FRAX. For breast cancer, the IVAS method. For cardiovascular disease, the ACC, ASCVD. These are all three tools that are accepted for evaluation of patients. I want to remind you that the Endocrine Society guidelines use underlying risk as a key component in decision-making. Well, let's look at this for breast cancer risk. If the risk is low, less than 1.67% at five years, menopausal hormonal therapy is okay. If it's an intermediate risk, 1.67 to 5%, we would advise caution, and if the risk is high, greater than 5% at five years, we would avoid and recommend avoiding menopausal hormonal therapy. What's the basis for making this assessment? Well, if we look at women who are at low underlying risk and we look at their attributable risk for 1,000 women, you can see if their underlying risk is low, fewer individuals will develop breast cancer over time, higher with intermediate, and if they're at high risk, of course, the risk is going to be substantial. So we'll talk about today the results of the Women's Health Initiative Study. We now have the follow-up to that study, which answers most questions about menopausal hormonal therapy, but surprisingly, one question remains controversial. Does estrogen alone increase the risk of breast cancer, or does it prevent breast cancer? So if you look at comparisons of randomized controlled trials versus systemic review of 58 trials, there's complete divergence. So the randomized controlled trials, primarily the Women's Health Initiative Study using conjugated equine estrogen, plus nine smaller trials, 14,000 women, the relative risk is reduced and less, it will be a decrease of seven women per 10,000 persons using estrogen alone. The observational studies, 58 studies with 500,000 women, suggest that the relative risk increases to 1.33, and there will be 11 excess cases per 1,000 person-years. How do we figure out why this has happened? We really don't know. There is a possible explanation, and I'm going to talk to you about the explanation that our group has published, and that is that estrogen induces apoptosis in women starting estrogen several years after the menopause, and therefore reduces the risk of breast cancer. On the other hand, estrogen blocks apoptosis and stimulates cell proliferation in those starting estrogen alone shortly after the onset of menopause, and actually increases the risk of breast cancer. What's the evidence for this? Well, the evidence is really from cell culture. This is a model of starting estrogen many years after the menopause, and in this situation, estrogen markedly increases apoptosis. Yet in the model of starting estrogen soon after the menopause, paradoxically, estrogen now markedly blocks apoptosis, and this is a potential explanation for this divergence. Nonetheless, we conclude that E plus P increases the risk of breast cancer. E alone, the effect remains controversial, but even if it increases the risk of breast cancer, the risk is minimal, if limited to those who have a low underlying risk of breast cancer when they start. So with this introduction and background, I'm going to turn this to Dr. Stonkel. Good morning, at least in San Diego, and I'm very happy to be here participating in this event. I wanted to just bring your attention to the concept that menopause is really having a moment, and so I think this is so perfect that we're focusing on this topic. My disclosures include that I serve on a data and safety monitoring board. I will not be addressing the investigational product, however, in this presentation. So maybe some of you saw this New York Times magazine feature about a year and a half ago that just really took some of the wind out of my sails because it said, we have been misled about menopause. It was really challenging why women haven't been offered hormone therapy. And one of the concerns was that menopause is understudied and undertaught. But I think in this last year's time, it's just really been incredible the amount of attention that menopause has received. The director of the National Institutes of Health was mandated in an act introduced in Congress to help evaluate the results and status of completed and ongoing research related to menopause in women's health and to identify gaps in knowledge and research. So this to me says it's really important that we're getting all this different kind of input. The National Academies has been commissioned with helping the NIH do that review. Time magazine, maybe you saw this, had a pretty extensive article just letting us know if we hadn't noticed already that menopause is finally going mainstream. Lancet, if you're a reader of Lancet, earlier this year had an entire issue dedicated to menopause really challenging us to kind of rethink our approach as a partnership with women and really working to provide women with information and then letting them make their own decisions. There's been new emphasis on menopause at work. In fact, last week at the Menopause Society Annual Meeting, there was an entire new consensus that was revealed that you can find at www.menopause.org. But this was an article in the British Medical Journal, you know, how do I cope with menopause at work? And this applies to us as women clinicians as well as to the patients that we see. How do I cope with menopause at work? And then I really enjoyed seeing the President of the United States sign this executive order mentioning the words menopause, actually, and women's midlife health. And some of you might know Carolyn Mazur, who is the chair of this White House initiative. And through the Endocrine Society, we've been communicating with her about some of the priorities for women. So this morning, what I wanted to do is touch on just some of the physiology of menopause. I think that the New York Times article was right, that we haven't been taught enough. Familiarize you, if you haven't been so familiar before, with some of the common symptoms. And then I'm going to touch on options for symptom relief, but I'm primarily going to be focusing on hormone therapy and how we individualize our approach. So just to kind of make sure, I hope there's some trainees and fellows on this webinar, just back to some of the basics. So what is menopause? When we look at the totality of women's reproductive life, menopause is a single point in time. But we can only make that diagnosis by the definitions of the stages of reproductive aging workshop by looking backwards after 12 months without a menstrual cycle. So when does this usually happen? The accepted age range is between 45 and 56, but we know as endocrinologists, we see and we know that women can have early menopause. And we know that early menopause before the age of 45 can be associated with the increase in cardiovascular risk, congestive heart failure, diabetes. And we especially spend some energy as endocrinologists thinking about premature menopause or the gamut from iatrogenic causes, primary ovarian insufficiency, including autoimmune causes, genetic causes, and things like exposure to endocrine disrupting chemicals or heavy metals. And we know that there can be long-term sequelae of this as well. So from a hormonal standpoint, what's going on? Well, this graph looks at two key components, estradiol on the left in orange and FSH, follicle stimulating hormone, in the right in blue. And you can see that my arrow is focused here on the point of the menopause. So we're looking at the years before and after. And opposed to what some of us might have thought in early days, this is not just a smooth glide down the hill of descending estrogen. This is a rough water ride with excursions to very high levels of estradiol. And we think that these excursions are partly responsible for some of the symptoms that women experience during that time. The other thing I wanted to point out from a hormonal standpoint is that while we know that FSH is rising, it's important to remember that that rise in FSH is not just due to a decline in estradiol, but rather it also reflects a decline in inhibin production. And so we just have to work with our colleagues who are learning about treating women with estrogen that this is not like TSH that they're going to get in the normal range if they just give her a little more estrogen. That's not going to happen. So what's going on with women? What happens clinically during this transition? And the transition itself is getting more and more attention lately because we realize that women can be so symptomatic and because we really haven't studied the best approach for therapy during this time. So again, using the formal definitions, the perimenopause includes the years prior to menopause when menstrual cycles change. And they change either by changing in length, longer or shorter by seven days compared to the usual cycle. Or in the late menopause transition, women will start to have episodes of amenorrhea that will last for at least 60 days or about two months time. But that's not the only thing that's going on. And women will also develop vasomotor symptoms. In fact, some women will start having hot flashes while they're still cycling. And we know that these can occur early, a decade before the final menstrual period. They can be associated with but not necessarily fully cause depressive symptoms, anxiety and insomnia, awakening at night and trouble getting back to sleep. We know that as estrogen levels decline that women can experience vaginal dryness. For some, that's discomfort with intercourse. For others, they can be symptoms primarily related to the urinary tract like recurrent infections. And as endocrinologists, we're interested to know that bone loss begins even before the final menstrual period. So I like this graphic, which really just shows a number of these symptoms, starting with the menstrual cycle alterations, because that's the formal definition. But I want you to know that vasomotor symptoms can occur early. There's even one more new earlier symptom of women just reporting that they just don't feel like themselves, you know, something's not right, is what I had a patient say to me once. Again, realizing that vasomotor symptoms can affect a vast majority, 80% of women, but there's quite a continuum between like, yeah, I have an occasional hot flash, and I'm saying to you, please do something about this because I'm absolutely debilitated in my life. Along with the hot flashes, and I used to attribute sleep disturbances to vasomotor symptoms, but we are learning now that sleep disturbances might be part and parcel, is own separate set of symptoms. So there's some interrelation with these things, and possibly in a mechanistic way, there's some interrelation. Similarly, the mood symptoms can be associated with vasomotor symptoms, but in vulnerable women who've had, for example, postpartum depression before, they can just be more vulnerable during this menopause transition. And finally, one of the things that frightens our patients is in the realm of cognitive complaints, and women will actually complain of brain fog. The good news about this is it's fairly common, and I think the better news is that when we follow women longitudinally, prospectively through this transition, for the vast majority of women, it gets better. So even though your patient might say, I'm worried about Alzheimer's, could I have early Alzheimer's? It's probably not, yet this is a very disturbing symptom for women. We've also learned from the study of women's health across the nation, a prospective longitudinal study that's followed women for upwards of 20 years now, that the peak incidence of vasomotor symptoms is during the late transition. We've learned that there are racial differences, that black women have a longer duration, an earlier onset, and more severe symptoms than do other groups. And we've learned that Asian women or Hispanic women are a little less affected. So I think this just helps us really tune in when we look at our patients to be mindful that they might be experiencing differences simply on a genetic basis. We know that women who are obese can have an increased risk of vasomotor symptoms, particularly during the transition, and we know women that have been smoking can have an increased risk. So lots of things that can contribute to this. So what can we do about it? And I'm happy to say that in the decades that I've been thinking about this and studying this and working with women, that there has been an expanding number of options. This morning in our presentation, I'm going to be focusing on estrogen, but Dr. Pinkerton will be reviewing these other options that are available. And it's important that we're at least familiar with all these so we can really advise our patients that they do indeed have a choice. So one of the biggest questions is what are the risks and the benefits of menopausal hormone therapy? It's a little bit frustrating and humbling that we really don't have an adequately powered randomized trials with outcomes, meaning breast cancer, heart attack, stroke, rapture, specifically conducted looking at younger symptomatic women who are just the women who are going to be coming to your office to ask for help. But the best available evidence that I think has really been very good comes from the younger women, I love calling 50 to 59 young, or women 10 years since menopause, and subgroup analysis from the Women's Health Initiative, a large 25,000 subject NIH-funded trial that started about 30 years ago. So this data provides trends, few significant differences. And in case you're just getting interested in menopause or you're just starting to think about this, I just want to let you know this reference in JAMA with a very good, concise review of the Women's Health Initiative that just came out this spring. So very, very current. So one of the components of the details that has been presented, I think is really helpful when you say, how can I convey risk to my patient? It's so hard talking about percentages. And we put this in absolute risks and use these numbers in our discussion. This is from the WHI numbers, but we use this in our Endocrine Society Clinical Practice Guidelines for combined therapy in the WHI, which use CEE.65 and MPA daily, 2.5 versus CEE alone in women with a hysterectomy. There were more events predominantly, cardiothrombotic events. And there was about a three per thousand women over five-year increase in breast cancer. I think it's important to let women know this number. Some will say, are you kidding me? This doesn't sound like that much of a big deal at all. That means that 997 out of a thousand women won't get breast cancer, but for some women that risk is terrifying. So I think we need to explain these risks and benefits in the way of fractures, reduction of diabetes, and mortality benefits, especially for CEE alone. So I hope that's helpful. The other thing that people wonder about is mortality. And this also comes from the WHI. Again, the good news, looking at long-term, all-cause, and cancer or CBD mortality, there was no increase. No one in the WHI died because of using hormone therapy. What I think is very encouraging is that women who had a hysterectomy with CEE alone, particularly if they had bilateral salpingo-oophorectomy, and for those that meet criteria for early menopause less than age 45, they had a mortality reduction of 40%. So this really motivates us and I think guides our recommendations for initiating therapy early and continuing it until the age of natural menopause, especially in women who have had surgical menopause at a young age. So you're telling me a lot of details. How do I sort out if this is right for my patient or not? And in our Endocrine Society guidelines, we set forth a pattern, a way to, a recommendation to go through this to help you with your patients. The first is just individualizing how bothered is she? And I think if you ask and you listen, she'll let you know very clearly, especially since women are hearing all this in the news in the last year or so. Number two, what does she want? She might say, don't talk to me about this hormone stuff. I am not interested. And you're okay. I've got a half a dozen other things that work really well. And then the third thing is, will therapy be safe? And that's where it gets a little bit more challenge. And that's where I think the onus is on us. So Dr. Santen already revealed that we need to look at things like contraindications, baseline risks of heart disease and breast cancer. He talked to you about the cardiac, about the breast cancer risk. I'm going to just mention briefly about the cardiovascular risk. And I don't want you to be intimidated by this graph because it's really just a very compact set of data. But to remind you that we are looking at women less than 10 years from the final menstrual period who are under age 60 with symptoms, women who do not have a history of cardiac events, cardiovascular events, estrogen-sensitive cancers. And then literally going through, as he said in his presentation, go through the questionnaire, go through the calculation. And I know that you all know how to do that. I would just also bring to your attention that some of the tiebreakers, if you have a patient in an intermediate zone, are some of the adverse pregnancy outcomes and early menopause, which is not shown on here. And then the recommendations, and this has been consistent. I like this because it's in the cardiology literature showing some interdisciplinary attention. A risk less than 5% is what's recommended for kind of across the board choice of hormone therapy. Intermediate risk using recommending transdermals. And then if she's at high risk, suggesting that probably she might want to think about another option. The only other factor is whether or not she has a uterus, no uterus, estrogen alone. If she has a uterus, there are a variety of progestins available, or the combination of estrogen combined with basodoxifen, which has a remarkable track record of leading to early amenorrhea. So women are less likely to bleed on this combination. So when we think about hormone therapy, I don't know about you, in Southern California, we're challenged a lot about compounding as an option. And we like to emphasize, and Endocrine Society stands behind this, that we recommend FDA approved bioidenticals, meaning a structure similar to that that we see in Mother Nature. And I can tell you, if you look these up, there are so many options, doses, I think you'd be hard pressed not to find something on this FDA approved list to offer your patient for her symptoms. We're starting to lean more rather than oral therapies towards transdermal therapies, particularly realizing that there's less effect on some of these cardiovascular risks. And so that would make transdermal therapy more appropriate for patients. And I know that we're seeing more women now at earlier ages having metabolic syndrome or some of these other cardiovascular risks. So bearing that in mind, but then I have to tell you in some humility that while we have observational studies to suggest that safety might be improved with lower doses, oral estradiol versus CEE and transdermal versus oral, we really don't have the gold standard randomized controlled trials. So maybe this is something the NIH can be thinking about, or you can be telling your congressperson about. Okay, so progestins, again, there are a number of choices. This is essential if women have a uterus. I just wanted to mention that there's a lot of popularity of the levonorgestrel IUD. Some women who are having irregular heavy bleeding during the menopause transition can find relief with the use of this. It thins the lining of the endometrium. And then although it is not FDA approved for this indication, a lot of clinicians are then as women start having vasomotor symptoms, adding on low doses of estrogen to help with the symptoms and having endometrial protection with the levonorgestrel IUD. So the last question and the last symptom that I wanted to make sure that we addressed was genitourinary syndrome of menopause. This is one of those that, you know, your patient may or may not come in and say, by the way, I'm having vaginal dryness, or by the way, sex is uncomfortable to me. And you may have noticed, wow, this is your fourth UTI in the last year. So I always tell our residents, our fellows, our students, even if you don't really engage in writing for hormone therapy, at least please ask your patient. But some women are actually still shy or reluctant to bring this up. And just to remind me that this nomenclature changed from just vaginal atrophy, which no one wants things atrophying, about a decade ago. And it was expanded to really say that the entire perineum can be affected because embryologically there are estrogen receptors in all these tissues, including the urethra and the lower third of the bladder. This is a very common symptom as opposed to hot flashes that can resolve probably for a fairly large number of women. This doesn't get better with time, it only gets worse. So it needs to be treated. And so if it's bothersome symptoms, then we can offer treatment. And just as I showed you the table, there are a lot of things available. Some women find relief from aisle number four at their CVS or Walgreens, just using daily moisturizers or lubricants. Systemic hormone therapy in the low doses we use now is not often adequate, so you might need to add your therapy. There's a systemic serum, a spemaphene that helps with vaginal symptoms as well as some sexual responsiveness. And finally, there are a number of options of vaginal therapy or DHEA, which is metabolized in the vagina to both estradiol and androgen. So with that, menopause is a universal event for all of us that live long enough. Menopausal symptoms, primarily vasomotor and genitourinary syndrome of menopause are common, can vary a great deal from women to women, and can get better with menopausal hormone therapy if you and your patient think that that's a good and a safe idea. And finally, this is an individualized science and annual shared decision making about continuation is very important. Thank you for your attention. Well, thank you very much, Dick and Cynthia. That has been great. I really wanted to focus today on managing vasomotor symptoms due to menopause. And I do have disclosures. I will talk both about FDA approved and non-FDA approved off-label use. I do have grant support that went to UVA for Bayer Oasis 2 clinical trial. I've been a consultant for Bayer and Pfizer, UpToDate and Merck, and I'm on several editorial boards. And Cynthia talked a little bit about vasomotor symptoms, but they can start during the perimenopause and they can go up for 10 to 12 years. The median, as she said, is about seven years. But it's important to know that about 10 to 15 percent are going to have severe hot flushes, which are going to disrupt their normal functions, such as meeting, sticking to a schedule, getting adequate sleep, being able to concentrate. And that despite experiencing these bothersome menopausal symptoms, 50 percent delayed seeking care greater than six months. And despite the availability of prescription and non-prescription therapies, a very high proportion of women remain untreated. Cynthia talked about the difference in some of the race and ethnicity issues. They are more frequent, last longer in North American and Hispanic women, and less long in Chinese and Japanese women. And I think that it's also important to know that Fabian just showed at the Menopause Study Center that when they did a study of Optum databases, FDA approved hormone therapy use among menopausal women declined from 4.6 percent in 2007 to 1.8 percent in 2003. So understudied, and I would also say underused. So I want to do a case study. Amanda, this typical patient that we see, she's in her late 40s. She's got hot flushes, fatigue, irritability, frequent severe hot flushes, day and night, and weight gain. Hot flushes are occurring six to eight times per day, moderate to severe intensity. Her last period was about six months ago, so she doesn't meet the criteria of 12 months of amenorrhea. Please talk to her anyway. Her disrupted sleep is three to four times a night. Sometimes it just covers on and off, but sometimes it's soaking sweats and she has to change her sheets or bed clothes. She's got mood swings and irritability that's affecting her partner, her work, her family. She's tried black cohosh, ashwagandha, soy supplements, magnesium. She is miserable and she comes to you for help. Her sister had breast cancer at age 60 and she does not want to take hormone therapy. So just setting the stage. We do have self-management techniques and many women use these or read about them, but there's really no strong evidence that these lifestyle changes actually work, particularly if they're very bothersome. Cooling techniques, avoiding triggers, exercise, yoga. Moderate exercise might help, but if you do high intensity or rapidly increase in intensity, it may worsen. And we always recommend a healthy diet, even though we don't know for sure if that's going to make a change in, um, in your hot flushes. Before these new therapies, before the neurokinin antagonists came in, this was our landscape. So we had gabapentin, which we would start at a hundred milligrams if you're super sensitive or normally 300 milligrams, add a second dose, take those at night, maybe add another dose during the day. Taking at night because the biggest side effect is dizziness and fatigue may help migraines, may help sleep disorders. Um, but you have to take, um, balance out the side effects. And then we have our low dose antidepressants. So we have SSRIs. And, um, prior to, um, a year ago, peroxetine mesolate low dose 7.5 milligrams per day was the first approved non-hormone therapy. Your insurance companies want you to use peroxetine 10 to 20 milligrams per day because it's less expensive. And escitalopram 10 to 20 milligrams per day was actually tested against estradiol 0.5 and worked as well in women who were not defined as having severe symptoms. And you do have to worry about this CYP2D6 inhibition. So some of these need to be avoided in tamoxifen users, but they may also help mood even though we're not dosing them for depression. And then SNRIs also work. And Lafaxine is one of the most common. Um, and 37.5 to 75 milligrams are common doses. You can go up to 150, but you're more likely to get side effects, um, nausea and dizziness, kind of adjustment week for the first week, but they may be safe in tamoxifen users. And then oxybutynin was an interesting one because it's used for overactive bladder, but it turned out that when you take five milligrams three times a day, they showed a significant reduction in hot flushes along with the side effects of dry mouth and urinary difficulties. And we're also worried about cognitive issues. So we avoided in the elderly, but if they have an overactive bladder and they're young and they also have hot flushes, it's a great idea to try that. Um, side effects do appear dose dependent. The benefits are dose dependent. And then Clonidine is not commonly used as an antihypertensive alpha 2 androgenic agonist, um, because it often lowers blood pressure and the data is inconsistent. So in 2023, the menopause society updated their non-hormone position statement. And, um, on the left, you can see the ones they recommended cognitive behavioral therapy. And at the most recent menopause society meeting, um, two weeks ago, um, we heard that virtual reality, imagining that you're immersed in snow might reduce your hot flushes. Clinical hypnosis, I think it's easier to find in California than here in Virginia. The SSRIs, SNRIs, Gabapentin, um, used off label. We do now have Fesalinitin, the first NK3 receptor antagonist approved by the FDA in May of 2023. And then Oxybutyn, weight loss, and then stellate ganglion block has been shown to work, but you need a really good anesthesiologist to do that because it's up here. Um, and then all the other things that they looked at, they said, we just really don't have good lack of data to tell you that this works. I will pull out acupuncture specifically. It hasn't been shown to work better than sham, but, um, when it works, it does work for about six months. So it's a nice non-hormone that you can try. All right. So where are we going? So there's new pharmacotherapeutic options that we hope are going to better manage these vasomotor symptoms. And I'm going to give you a little bit of pathophysiology. Having said that, Victor Navarro did this at ACOG and he will, he knows this much better than I do, but essentially you have hypothalamic candy neurons that become hyperactivated when estrogen levels drop and they stimulate the thermoregulatory pathway causing hot flushes. And these candy neurons have receptors for NK3 and NK1 and their ligands, neurokinin B and substance P. So you see in the diagram, you know, the arcuate of the median eminence, and you can see these coming down through the GNH or a problem down into the pituitary gland where we think that they have an effect. And this is also where we think our antagonists are working. So just one more picture showing your GNRH neurons up at the top, and then remember that when the estrogen levels decline during menopause, these candy neurons become hypertrophied and hyperactive. These pulses are going to go through the median eminence. You can see it on the left-hand side, hypothalamus, median eminence, and the anterior pituitary, and activate the thermoregulatory zone. The way I talk to patients about it is your thermal zone, used to be nice and wide. With menopause, if you're symptomatic, it narrows, more likely to get hot, more likely to get cold. Now we're starting to learn the pathways that are actually triggering that. Okay, so the ones that are currently being looked at are NK1 and NK3 antagonist. And again, they're coming, they're affecting these hypothalamic candy neurons. And what we think is that when you antagonize them, that you actually disrupt the signaling pathway and potentially attenuate vasomotor symptoms. There are several that are in phase three and four trials. Fezalinitin, FDA approval last May, 2023. Elanzenitin, phase three randomized clinical trial of phase four on breast cancer patients and those at risk for breast cancer. Oasis 4 is underway, and it's been submitted to the FDA. And we'll see what happens with that. Cynthia asked me to give you a little bit of history. So back in 2017, Pragenol came up with MLE-4901, but they reported that there was a rise in transaminase concentrations without a rise in bilirubin levels. This led to a discontinuation of the trial. It was three participants, but their transaminase levels went up to six times the upper limit of normal, putting it into the highest category. And subsequently, development was discontinued. Now, it's believed that the elevation in these liver markers is idiosyncratic, related to the chemical structure of an individual NK3 receptor antagonist, not related to the class of medications. And Fezalinitin is completely different from MLE-4901, and Elanzenitin is completely different from Fezalinitin. So these structures are very different. So what's going on? Fezalinitin is available at 45 milligrams. It's a daily pill, and it reduced the frequency of vasomotor symptoms about 65%, significantly greater than placebo. Similar to the 75% reduction that's seen with hormone therapy, not tested in head-to-head trials. Very rapid efficacy within a week, appearing to have a very good safety profile, including endometrial safety. And when it was approved, the FDA recommended baseline LFTs, and every three months for nine months, and I'll show you why. And I also wanted to make a point that the data from these different neurokinin receptor antagonists indicate that the partial degree of gonadotropin suppression isn't leading to either estrogen deficiency symptoms or bone loss. And we've got two good 52-week trial data showing that the only loss in bone density is age-associated, which is important. It doesn't help it, but it doesn't make it worse. So this is Fezalinitin. This was published in JCM in 2023, and we have on the left is frequency, on the right is severity. These were women who had severe hot flushes that were enrolled in the trial, very frequent. You can see they were having about, on average, 12 hot flushes a day. You can see the rapid decline that we saw, particularly with Fesalinitin. The higher doses in the light green and 30 milligrams is in the other, and then placebos in the pink. We had a placebo effect. We see this with all of our hormone therapy trials and our non-hormone trials. But both the 30 and the 45 milligram worked pretty well out at 12 weeks, significantly improved compared to both baseline and placebo. If we look at vasomotor severity, which is really important because it's the severe ones that are the most bothersome, they disrupt your sleep or your activity, you can see that we did start to separate out the higher dose of 45 milligrams from 30 milligrams, and both were better than placebo, but the 45 milligrams was statistically significant. So this is why that's the dose that was brought forward. Now the next piece that I want to talk about is the hepatotoxicity, and this is four quadrants. So you want to be in the lower left-hand quadrant. That means that you're within the normal range. Temples corollaries when you're around two, but not more than that, and you can see a scattering of placebo, 30 and 45 milligrams. And you don't see anybody in the two upper quadrants where you have hyperbilirubinemia or levels that are greater than six, what's called High's Law. We just didn't see any of those. And in the 52-week Skylight Fasolinatant trial, in the Fasolinatant group, 98.2% had normal liver function test and 99% in the placebo group, so just not seeing a major marker for liver test. So then the next piece that comes along is that many of you will have received in your email a FDA drug safety communication warning about a rare occurrence of severe serious liver injury with the use of Fasolinatant. So it was a post-marketing report. Patient had elevated liver blood tests that began about 40 days after she started the medication. Fatigue, nausea, itching, yellow eyes and skin, light colored stools, dark urine, pretty much anybody would have said, need to check those liver tests. And they were elevated. She had both abnormal liver enzymes and bilirubin levels. After stopping the medicine, her symptoms gradually went away and her blood test values returned slowly to normal. But this has caused the FDA to be concerned enough that they are now adding monthly testing for the first two months. So you would do baseline, month one, month two, month three, six, and nine. And then you say, what do you do? Well, we don't know because the longest trial goes out to 52 weeks. So in my own clinical practice, I'm going to continue doing them every six months probably, but there's nothing that the FDA has commented on that. So now I want to talk about Elanzanitant with a disclosure that I was one of the PIs and lead on OASIS-2, phase three trials, dual. So it works on NK3, getting the hot flushes, but also NK1. And we think maybe through substance P that that might help sleep disruption. So we saw a reduction in frequency and severity of the hot flushes, rapid improvement with frequency at week one. We also saw using patient reported outcomes and improvement in sleep disturbances and menopause quality of life. And the safety profile was very favorable, headaches, fatigue, and no liver issues. And I'll show you a little more data. So this was the mean change in frequency of hot flushes over time. And what you can see, and it's flipped compared to the way Fasalenitant did it, but here is our placebo in gray, 12 weeks, then they switched over. And then this is one in blue line is when they're on Elanzanitant and then when they went off. So you can see we had a nice robust, about 50% improvement, but then what you can see is with Fasalenitant, we had a more significant decline, which actually continued until the end of the 26 week trial. And then similar to the people who transferred from placebo to Elanzanitant, the hot flushes started to go up. And you say, why do I have two trials on one slide? Because they were done in different sites, different investigators, different populations. And those graphs are almost superimposable, very similar results. Same thing for OASIS-2, placebo effect, switch over to Elanzanitant, rapid decline, continues all the way to the end of the 26 week trial. And Elanzanitant, again, rapid decline, maintained all the way through, continuing to improve a little bit to the end of the trial. And then we followed them for four weeks off. If we look at severity, this is where I think Elanzanitant may work a little bit better. Here's that same trial, OASIS-1 and 2. Here's our placebo. You see, we're not getting as much improvement with severity with placebo in either trial, and that's what we see in the hormone trials. But here we see that rapid improvement in severity, and then a continued decline in severity until you stop the medicine. And OASIS-2, the same thing, the rapid decline, continued decline. And when you switch over from placebo to Elanzanitant, again, you see a decline. So this was very impressive results. We were really, really excited to see these results. And we found that 80% of women had a 50% improvement at the end of the 26 week trial, so very strong improvement. These were the most frequent treatment emergent adverse events for OASIS-1 and 2. OASIS-1 is on top. You'll notice that there's more in the first 12 weeks than when we switched everybody to Elanzanitant, which was an interesting finding. But it was headache, fatigue, and arthralgia in OASIS-1, and in OASIS-2, it was headache and fatigue. But the symptoms got better over time, and you had fewer of them when you switched from to Elanzanitant, which may say something more about methodology of clinical trials, that people are paying attention to all their symptoms right at the beginning, but minor things. So Amanda's bothersome, and what I don't have in here, is that there was an improvement in sleep and improvement in the menopause quality of life. We did not see any endometrial hyperplasia. There were no abnormal liver tests seen in the 26 week trial. And there was no significant hepatotoxicity signal seen in the 52 week trial, and I'm not presenting that data. It was just presented at the Menopause Society, but similar results, statistically significant at 12 weeks, maintained out to the end of the trial, statistically significant from placebo, and again, the same types of symptoms of headaches and fatigue, except in that trial, they had some COVID-19, and then no evidence of any hepatotoxicity. So let's go back to Amanda for a minute. Hormone therapy would be fine. She's 60. She's within 10 years of menopause. However, she has a fear of estrogen, and that fear of breast cancer is driving her choices. Race and ethnicity may play a role in whether they trust the providers, where they're getting their information, who they believe. And so to improve this, it helps to have written or pictorial information that is culturally appropriate, and to talk about what lifestyle supplements the patients tried, and her goal of treatment. She was a good candidate for hormones or any of the tested non-hormone therapy, SSRIs, SNRIs, gabapentin, but she was not willing to take any of them. So after we explained how the neurokinem receptor antagonist worked, and that it only treated her hot fleshes, it wouldn't treat her bone loss or her vaginal symptoms, she was excited to try it. And this is where I want to just talk and really stress what Cynthia said, the gap between evidence and personalized care. You've got to look at breast cancer, cardiovascular risk assessment, bone risk. And on the left-hand side, exactly what Cynthia talked about. Under 60, within 10 years of menopause, think about hormones, what's the best formulation, do the benefits outweigh the risk, and then continue to reassess them annually to determine if it's still needed or if you can change the dose. In that group that's kind of in the middle group, maybe they're less than 60 or within 10 years, but they've got some contraindications to hormone therapy, do the risk outweigh the benefits, breast cancer, cardiovascular disease, thromboembolism, there are other comorbidities, then you think about non-hormones. Or if they're asking at more than 60 or 10 years from the onset of menopause, in general, risk outweigh benefits, consider the non-hormone. And I know you're going to tell me you've got a patient who's 65 who feels like she's 52 and she wants to take about hormones, and you just got to do your risk assessment. That's a tough one. So I want to just remind you and end by saying this is a collaborative process between the patient and the healthcare provider. Because when you engage and empower the patient to do shared decision-making, it's going to make much more likely that she will listen to you and try what you're recommending. You're going to give all of the alternatives, evidence-based treatments, talk about what you know and you don't know, learn from the patient, incorporate her preferences and values, and also talk about when you think what she wants to do is not safe. That's okay also. And then I wanted to end at the very end with these education resources. Some of them are societies, so Endocrine Society, ACOG, the Menopause Society, Society ASRM, and then some of them are more predominantly for consumers, Red Hot Mamas, Let's Talk Menopause, Society for Women's Health Research. But all of these groups have evidence-based information and may be the right place to send and many more are coming along. And then I'm going to respond to one of the questions. There's a lot about progesterone. So progesterone has been shown to actually does help sleep. It makes you drowsy. You take it at night. We do often use it during perimenopause because many women seem to have some estrogen excess. They're not ovulating regularly. We might start it during the second half of the cycle. It might help with bleeding issues. And so we do use it very commonly for that. For Cynthia, there were two questions. One is about perimenopausal weight gain and what is about talking about the meta-analysis on dementia. Can you answer those two questions? So the weight gain thing I like to say is true, true, and terrible. But I don't know that we know that it's really just the menopause. It seems, and this has been very carefully looked at in the SWAN trial that, or not trial, the prospective longitudinal study, that what happens is that any weight that's gained is really due more to aging. But what something does happen in menopause, and any woman who's experienced this can tell you, is a redistribution of fat tissue. And so it seems that the fatty tissue, even if necessarily it doesn't increase the total There's a redistribution between fat and lean tissue. We see it primarily in the abdomen is where most women will complain about it. The only thing I can say about this is that Lou Culler out of Pittsburgh did a randomized trial 20 years ago that they called the Healthy Lifestyle Trial. I like to call it the Pay It Forward Trial because they took women who were either late premenopause or barely entering perimenopause and had them adopt an exercise program and just kind of cut the total amount of fat in their diet. And it was amazing. They really could avoid weight gain, some of the weight redistribution, and some of the lipid deterioration that we see during the menopause transition. There are a lot of metabolic things as endocrinologists that we're interested in that do happen. And probably the best place where that's summarized is El Cadre's article a couple of years ago in Circulation, looking at the menopause transition as a metabolic pathway. And so one of the big things that they talk about is this weight distribution. And that is one of the largest, I think, cosmetic problems that women complain about. And, Joanne, the other question you asked about was about dementia, the meta-analysis on hormone therapy. Is there any kind of a signal for dementia? And I'll tell you what Polly Mackey said, and then I'll let you answer. She said that she did think that there is a signal of dementia with hormone therapy use, even though we've got brain fog gets better, we've got some biochemical stuff. So I'm going to ask you that question, but remind everybody to scan your QR code. We're going to go a couple of minutes over to keep answering a few more questions with permission. So Cynthia, what do you tell people about dementia and hormone therapy? The main huge study was, again, the Women's Health Initiative that showed that on estrogen alone there was not an increase, but in women over 65 using combined hormone therapy with CEE and medroxyprogesterone acetate, that there was an increase in dementia. To the best of my recollection, looking at women in their 50s, that there did not seem to be a marked increase in dementia. But it's really interesting, and there are trials ongoing right now looking at a link between vasomotor symptoms and white matter hyperintensity, thinking that almost like small increased white matter densities in the brain that might be associated with later onset. So I would say that there are some amazing teams that are investigating this now, looking at things like objective versus just subjective hot flashes, doing very careful neuroimaging, and I think we're going to know a lot more about this in the years ahead as the work of people like Polly Mackey and Rebecca Thurston come to fruition. I think I was cut off before, but if I could ask you, a lot of my patients start hormone therapy at age 50, do very well on it, and when they're 60, they don't want to stop. How do you approach that issue? So we don't like to initiate it past 60. That's a very individualized discussion that we have. But if somebody is staying on it, that's a different issue. And so we will look at risk, benefits, bones, cardiovascular, lowest dose transdermal, micronized progesterone. But ACOG and the Menopause Society have said that there is no, you don't have to automatically stop at 60 or 65. And that leads into a question from the chat, which was, what age has fesalinitin been tested in? And both of the neurokinin trials have pretty much looked at women 45 to 65, but they do have phase four that is going to look at older women, because we do have women having hot flashes that continue in. So that was one issue. And then, Dick, I'll ask you this. Somebody wanted to know, could you use estrogen for prevention of heart disease? How would you answer that? So all of the recommendations that we have suggest that we shouldn't use estrogens for prevention. And what I do, basically, is try to sit down with the patient. I don't always follow all the guidelines rigidly. And if the patient doesn't have any contraindications, and probably some indications of estrogen, I will use it. But I don't use estrogen strictly for the prevention of heart disease. We do have the statins. We have Cetia. We now have the PCK, S3, S9 inhibitors that are very effective. And I think we have so many other therapeutic modalities for preventing heart disease. I would, for this issue, I would generally go with the guidelines, and that is that we don't generally use estrogen for prevention. One of the other questions that we got asked was neurokinins in brain, because estrogen seems to help that brain fog. And what I can tell you is that when you improve hot flushes and sleep, and have fewer awakenings, brain fog also may improve. So I would give it, I would expect it to work. When we looked at elinsenatant, it actually improves sleep disruption and quality of life. So I think that you can tell people that they should get a benefit, and we'll just have to wait and see how it plays out for those active women. Personal case, I had somebody who went on fesalenatant, and it dramatically worked, and I think because she started sleeping for the first time. And then one of the other questions was, Cynthia, for you quickly, how long do you keep somebody on estrogen vaginally if you're using it for GSM? Forever. Forever. Short answer. Okay. Yeah. Forever. Forever. And then the very last question was testosterone. Testosterone is a big issue. Many people are getting these pellets and having super physiological doses, and they feel well, but we don't know any safety data with that. When we did a global consensus on testosterone, it definitely helps libido in those women who have early surgical menopause. And if you want to try it at low doses, off-label, compounded, you can try it for three to six months. If it's not working by six months, you don't want to do it, and you should check blood levels to keep it within a close to the range, and the range numbers I've heard are 50 to 70. But again, we don't have any science on it. Anybody want to make a last statement, because they're about to cut us off? Yeah. So I just want to thank Joanne and Cynthia. Wonderful presentations. I think you've learned a lot about this. When you look at the slides, if you do, there are some very good references that cover most of what we've talked about. And so you can find those. Many of them have been written about the three of us and some others as a team. But thank you very much for your attention. If you have any additional questions and so on, I understand you will have the slides online and can go over things in detail. So thank you all very much. Thank you. Bye-bye.

menopause

personalized medicine

Women's Health Initiative

hormone therapy

neurokinin antagonists

cardiovascular disease

breast cancer

patient evaluation

shared decision-making