Welcome to CME on ReachMD. This activity, entitled “Updates in Vasomotor Symptom Treatment” is provided by Omnia Education.
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Providing care to women transitioning to the menopause remains fraught with complex and disparate issues that creates a considerable unmet clinical need for those women. The latest data on menopause management and cutting-edge information on evolving treatment was recently presented in San Diego. I'm talking, of course, about the 2022 American College of Obstetricians and Gynecologists Annual Clinical and Scientific Meeting. Now we'd like to break down some of that information for you so you can carefully consider and integrate the latest research and scientific advances into your clinical practice.
So let's get started. This is CME on ReachMD, and I'm Dr. Lee Shulman.
And I'm Dr. Nanette Santoro, Professor and Chair of the Department of OB/GYN at the University of Colorado School of Medicine.
Dr. Santoro, we learned so much from the latest research presented at ACOG. Before we delve into conference coverage, can you briefly contextualize the physiologic basis of menopause? What are the specific risk factors that are probably most important to our diverse audience?
We know that hot flashes are very, very common. They're the most common symptom of menopause. And the basis for menopause is basically that ovarian follicles have a finite span in the human ovary. And there are very few to no responsive follicles left in the ovary, and in the absence of granulosa cells, there is no estrogen. And in some way, low estrogen, and even before menopause, fluctuating estrogen, impacts thermoregulation in the body. And the hypothalamus and pituitary are pumping out FSH and gonadotropin-releasing hormone, trying to get that ovary to respond. And this leads to some changes, as we now know, in neurons in the brain that give rise to this narrow thermoregulatory zone where women are not comfortable at higher temperatures, and that's expressed as a hot flash.
About 80% of women will endure hot flashes. About 10% have moderate to severe vasomotor symptoms every day. And we know that this has a cascade effect so that the hot flashes will cause awakening at night, quite often, and then lead to a concurrent sleep problem – concentration during the day, fatigue during the day – because a woman hasn't gotten adequate sleep. So energy levels can be a problem. And there are impacts on a professional woman's work life and on her social activities, so they interfere with daily living.
We also need to recognize that there are patient-specific risk factors and, I'll use the phrase, community-specific risk factors. We understand that issues that reduce systemic estrogen levels, things like smoking, for example, or BMI [body mass index], that can also impact systemic estrogen levels – estradiol levels – can impact the severity of hot flashes, the frequency of hot flashes.
There's also a cultural issue. We know that from work that we did when I was at the University of Illinois at Chicago, where we were able to present clear physiological evidence of a hot flash in a woman who said she wasn't experiencing a hot flash. So cultural mores, certain ethnic racial groups tend to experience and speak about the hot flashes more than others.
Dr. Santoro, can you discuss how the suboptimal management of menopause relates to that individual and public health burden of VMS, of vasomotor symptoms? Can you describe any studies about specific regional or practice patterns that may be particularly relevant to our audience?
It's very interesting because the UK is beginning to embrace the inconveniences of menopause and the bothersomeness of symptoms as a real issue that needs to be addressed in the workplace for women. I think that we are behind them in the United States. I think this probably would not go over well in a discussion of US women. But they are talking about workplace concessions, allowing women during this period of life to go to work later, have flexibility in their working hours, and to be able to arrange their paid time off around their symptoms. So accommodating to the symptoms is one way that we can deal with this. And here is where I think we are not doing a great job in the United States, because we do have good data that work absenteeism is increased, and we have substantial evidence that mood is disturbed in up to a quarter of women significantly during the menopause transition.
I think it's critical that these studies help raise awareness and improve educational efforts nationwide to ensure that women are offered appropriate treatment, appropriate evaluation, regardless of specialty, regardless of the region.
For those just tuning in, you're listening to CME on ReachMD. I'm Dr. Lee Shulman, and here with me today is Dr. Nanette Santoro. We're just about to discuss the benefits and risks of hormone therapy and the latest advances with nonhormonal options.
We are not adequately training our trainees in our workforce in how to treat this in a flexible fashion, how to deploy hormone therapy, how to use alternatives to hormone therapy, and learning about what may be new that's coming down the pike.
I could not agree with you more. You know, when we look at how hormone therapy works, as you just mentioned, highly effective approach, not just for vasomotor symptoms, but for some of the other estrogen-deprivation effects of menopause, whether it's vulvovaginal atrophy or bone mineral density loss. There has been a continual drumbeat since my residency in the 1980s about a misperception, and when I say misperception, the way that menopause therapy using hormones is invariably presented is that the risk far outweighs the benefit. And I think for those of us not just involved in menopause research or care, it clearly is that the benefit far outweighs the risk. And yet, from the way certain studies were presented, were performed, how the outcomes of those studies were performed, we are left with not just generations of non-ob-gyns who will not use hormones, who tell patients that they are not safe, we're left with a considerable percentage of ob-gyns who will not use hormones, who believe them not to be safe. Primarily because of what you just said, is that in our residency programs, not just – forget about medical school, but in our residency programs, residents are looking to get the requisite number of surgical cases or deliveries or obstetrical experience. And it's invariably, at our place and hopefully not at yours, but our residents pull themselves out of their clinic time because there's a case to do or they're limited in their hours and, therefore, they need to be on labor and delivery because somebody is out there. They are left without real, adequate training in menopausal medicine.
Take that and add to that clear racial disparities in our patients as far as being offered menopausal therapies or accepting menopausal therapies.
So education is not just something that needs to get out to healthcare providers, it also needs to be presented to patients, because unfortunately, the lay population has been bombarded by the perceived lack of safety of hormone therapy. But in some sense, that refusal to use hormone therapy has led some to look for nonhormonal interventions that would be perhaps more acceptable to patients who are suffering from vasomotor symptoms, which, again, is the most common and, for the most part, the most debilitating aspect of menopause.
I agree. I mean, vasomotor symptoms really do seem to be the thing that drives treatment. And I just want to call out a couple of presentations at ACOG because the DePree presentation was about the treatment – real-world treatment for menopausal symptoms in the US by practitioner type. So the good news on this work was that ob-gyns are doing a little bit better than other specialists. They were more likely to use hormone therapy, 76% of them versus 64%. And they more commonly gave patients prescriptions, 63% versus 57%, compared to other PCPs. So I think those are encouraging, but there's clearly opportunity to do a whole lot better.
I'm going to talk about the glass being half empty. I think I'm more concerned by the 24% who are not willing to provide hormone therapy. And that, to me, is a somewhat frightening number. If you told me that 76% of internists were willing to provide hormone therapy, that, I would feel good about, but that there is a quarter of gynecologists who, for whatever reason, are not willing to provide hormone therapy, I think, just highlights a profound issue in our specialty and in our training that needs to be changed.
So, Dr. Santoro, can you talk about NK3R antagonists, a brand-new class of drugs that really shows promise for treating vasomotor symptoms? Can you put their use into context for us and provide some insight into the latest data presented at ACOG?
I just want to begin with the rationale for nonhormonal treatment because, you know, there still is fear of hormones, although they are not nearly as feared as they used to be. And I think we're a little bit of a victim of internet disinformation there. But there are clearly groups of women for whom hormones are absolutely contraindicated or they absolutely will not take it. And we have developed a few treatments.
The ones that really have withstood clinical trial evidence, although they're not FDA-approved, include gabapentin, SNRIs [serotonin and norepinephrine reuptake inhibitors], most of the SSRIs [selective serotonin reuptake inhibitors] except for paroxetine mesylate; that is FDA-approved. And we know very little about their mechanisms of action. They do have some improved efficacy compared to placebo in consistent clinical trials, but they don't come close in efficacy to hormones. So they do some improvement of quality of life.
The real exciting area here is the NK3 receptor antagonists. The NK3 receptor, for those of you who do not have this leaping to mind, is found on a neuron called the KNDy neuron, which is in the hypothalamus, which is believed to be the thermoregulatory center of the brain. And it was found by a female pathologist, Naomi Rance, that those neurons proliferated after an animal's ovaries were removed. She also saw this in the brains of women that had had their ovaries removed, as well, and thought maybe there's a linkage here. Then in some animal studies, by blocking that receptor in hot flash models, they were able to produce what looked like a relief of the hot flashes, and very complete relief.
So this has then led to a variety of compounds that are in various stages of clinical trial development. One has been abandoned; one has picked up after COVID. There are some that are dual NK3 and NK1 antagonists. And they are all in the process of testing.
The one that I can tell you the most about and that was presented at ACOG were the 12-week results from the SKYLIGHT 1™ clinical trial that was looking at fezolinetant. And fezolinetant is a specific NK3 receptor antagonist and was used to treat moderate to severe vasomotor symptoms in the classic study design based on the FDA guidance. Women that had at least 7 hot flashes a day or more than 50 a week were randomized to placebo and 2 doses of fezolinetant. And at both doses, there was a dramatic decrease in hot flashes. It was better than placebo at both 4 weeks and 12 weeks. And it was approaching the level of efficacy that we see with hormone therapy, which really kind of makes those of us in the menopause world who have to turn patients away from hormones because they can't take them and who still have bad hot flashes, it made us jump for joy. Because this is something that we may soon be able to offer patients.
I think it's important to recognize with this class of drugs, at least those that have gone through their initial trials, is not only, as you mentioned, the considerable reduction in hot flashes experienced, really, at several doses, but as opposed to the SNRIs and SSRIs, really, with little to no adverse events. A lot of my patients are on SSRIs say their hot flashes are better but they have reduced libido; they don't feel well; they feel fatigued. What we see in some of these, in the trials of these newer molecules, is the reduction in hot flashes. We don't see those other adverse events or side effects; it is incredibly promising.
Well, this has certainly been an amazing conversation. But before we wrap it up, Dr. Santoro, can you provide a couple of take-home messages?
I think it's very urgent that we address how difficult vasomotor symptoms and menopausal symptoms can be for patients and how significant their impact is, and we need to do a better job of treating them. We need to consider the challenges with the current hormonal therapies – there are both real medical contraindication-type challenges and patient-driven challenges – and weigh the latest data on nonhormonal therapies and how that might modify clinical practice, because there is, without question, a huge unmet patient need here.
I think in that huge unmet need we need to encourage all clinicians who see that menopausal woman, whether in a gynecology office, whether in a family medicine office, internal medicine office – the need for every clinician to appropriately screen and consider all patients to be available for appropriate treatments, obviously, whether they be hormonal or nonhormonal, to assess whether or not an intervention will be appropriate, will be safe. This is not something just for a woman's healthcare provider. This needs to become ubiquitous throughout the country.
We also as clinicians need to ensure that the right patients get the right treatments based on efficacy, safety, comorbidities, symptoms, and individual risk tolerance. There are lots of misperceptions out there. We all recognize that the garbage that patients are reading day in and day out about a lot of things, but in particular about this. We need to provide accurate, poignant, patient-specific information so that we can empowerwomen to make the right choices for themselves and really to gain the benefits and the quality of life that they not only deserve but are likely going to need as they are going to be living a third to perhaps even a half of their lives in this menopausal state. So it's just critical that we be advocates not just to our patients but to our colleagues as well.
I want to thank our audience for listening in today. And thank you, Dr. Santoro, for joining me and sharing all of your valuable insights. It was phenomenal speaking with you today.
My pleasure, always a joy speaking with you, Dr. Shulman.
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