Hot Flashes, the KNDy Mechanism, and the New Non-Hormonal Pill

I gave you the headline from this study from Avis 2015 that frequent hot flashes run in a median of 7. 4 years in duration. But we need to walk through the study behind that number because the design is what makes it trustworthy and impacts the current treatment approach. So for most of the 20th century, the clinical assumption was that hot flashes were transient. They clustered around the final menstrual period, lasted a year or two, and then were gone. And that shaped how doctors counseled patients. Just hold on, this too shall pass. That assumption turned out to be wrong. Uh Dr. Nancy Avis and colleagues at Wake Forest published their analysis in JAMA Internal Medicine in 2015 using the SWAN cohort. The SWAN uh study did something that most studies of menopausal symptoms don't. Women were enrolled before the menopausal transition and followed through it with annual symptom assessments. So instead of asking a 60-year-old to remember when her hot flashes started and stopped, they measured the symptoms in real time across the entire transition. So they looked at 1,449 women who experienced frequent vasomotor motor symptoms during follow-up, defined as symptoms on six or more days in the last 2 weeks. The question was simple: From first onset to last occurrence, how long did the symptom phase actually last? The answer was a median of 7. 4 years. And for women with frequent symptoms, the median persistence after the final menstrual period was 4 and 1/2 years. The duration also varied by race and ethnicity. African-American women had the longest median duration, about 10 years. Chinese-American and Japanese-American women had the shortest, around five and just under five years respectively. As with the timing data we covered earlier, these differences track the same social and structural factors rather than ancestry itself. So a 50-year-old who hears that hot flashes last 7. 4 years on average is in a completely different treatment decision than one who they last 6 months. Seven plus years of moderate to severe vasomotor symptoms affecting sleep

concentration, and quality of life is a clinical problem that's probably worth treating rather than just saying, "Hold on, it'll get better soon. " So, why do hot flashes even happen in the first place? In the early 1990s, two neuroscientists named Dr. Naomi Rance and W. S. Young looked at autopsy brain tissue from postmenopausal women and noticed something unique. A specific cluster of neurons in the arcuate nucleus of the hypothalamus were larger than in age-match premenopausal women. The neurons were specifically enlarged in women whose ovaries had stopped producing estradiol. Now, it took the field another 15 years to figure out what those neurons did. They are now called KNDY neurons after the three molecules that they produce: kisspeptin, neurokinin B, and dynorphin. They project to two places. They go to two different areas. One is the reproductive axis, the other is the temperature regulation center of the hypothalamus, a region called the median preoptic nucleus, which is part of the brain that decides whether you're too hot or too cold. Now, across the reproductive years, estradiol restrains these neurons. The neurons fire, but at a controlled rate. When estradiol falls in the menopausal transition, that break lifts. The neurons enlarge and they fire more. They release neurokinin B onto NK3 receptors in the thermoregulatory center. The result is a destabilization of the thermoneutral zone. That's the range of core temperatures that the brain considers acceptable. A small, normal rise in body temperature that the brain would ordinarily ignore now triggers the cascade. Peripheral vasodilation, vessels get bigger, you sweat profusely, a few minutes later, it goes away. happens again. So, if you block the NK3 receptor on the KNDY neurons themselves, just that specific receptor in the thermoregulatory circuit, you should be able to stop the cascade without any hormonal effect whatsoever. Two trials were done to test this, the Skylight trials, both published in 2023. They tested fezolinetant, an NK3

[clears throat] receptor antagonist, taken once daily as a pill. Skylight 1 randomized over 500 women across three groups. One group got placebo, one group got fezolinetant at 30 mg, and the third group got it at 45 mg. Skylight 2 reproduced the design in a separate group of over 500 women across seven different countries. Both trials required at least seven moderate to severe hot flashes per day at baseline. So, these were symptomatic women, the actual population the drug would be used in. What they found was that fezolinetant at the 45 mg dose cut moderate to severe hot flashes by about 60 to 65% from baseline. The placebo-adjusted reduction was about two and a half episodes per day at 12 weeks. For context, hormone therapy reduces hot flash frequency by about 75 to 90%. Fezolinetant reduces it by 60 to 65%. So, it's smaller than hormone therapy. This can still be clinically useful though, because it works for women in whom hormone therapy is contraindicated. The FDA updated labeling on fezolinetant in 2024 with a liver toxicity warning. Liver enzyme monitoring is recommended for the first 3 months as a result, but the bigger picture here is the arc from mechanism to medicine. A neuroscientist looks at autopsy brain tissue in the early 1990s. It takes 15 years to figure out what those neurons do, and the mechanism predicts where to intervene. A drug is subsequently designed to hit that target, and two independent randomized control trials replicate the result, subsequently resulting in FDA approval in 2023. From first observation to approved treatment, it's about 30 years. That's pretty fast by drug development standards. So, Austin, who is actually

the patient that you're considering for one of these medications when you're working through this, and how do you position it relative to menopausal hormone therapy? — [snorts] — Yeah, this is a this is an important one and one that's been coming up more and more frequently since these NK these NK antagonists have become available. And part of the reason why is that menopausal hormone therapy works really well for vasomotor symptoms, for hot flashes, and for night sweats. But unfortunately, there are some potential risks, some potential downsides, some unique considerations to using hormone therapy. And so there are some women for whom menopausal hormone therapy might present unacceptable risks. And even in those situations, there could sometimes some room for maneuvering, particularly with you know, informed consent and close monitoring and things like that. But you know, classically, women with a history of hormone receptor positive breast cancers, certain types of blood clots, particularly things like pulmonary embolisms that can be you know, potentially life-threatening, women with certain forms of active liver disease or unexplained vaginal bleeding, things like that. Those are situations where the risk that may be conferred by putting someone on estrogen might be too high. And so then the alternatives historically have been various

non-hormonal agents to manage vasomotor symptoms and things like hot flashes and night sweats, to include medicines like gabapentin and certain types of antidepressant medicines that are kind of used off-label in that context. And those work okay, but not nearly as well, and they have their own unique considerations and downsides and cons as well. And [snorts] rather than saying, well, now, you know, women have to either suffer with these symptoms or they have to quote-unquote fail these other medicines, I like to flip that framing and say these other medicines have to fail them before they can be considered for the use of something else. And so now that we have these, these are medicines that work via non-hormonal mechanisms to more directly address the mechanism of the vasomotor symptoms to your point about how these neurons work. So rather than using kind of off-label medicines that work in other ways to, you know, offer a smaller benefit, we're directly attacking the mechanism in a non-hormonal way for women who either should not potentially use hormone therapy or for those who maybe have a bit more caution around the use of hormone therapy or maybe they've tried hormone therapy before and they had side effects that they didn't like from it and they stopped and they want to try something else instead. Um there are, you know, all these groups of people who now they just have this option available. I would still say that more often I'm using hormone therapy um to treat these types of symptoms, but I do keep this option in my back pocket for situations where somebody is too high risk and really wants the symptoms addressed or has tried hormone therapy before and didn't do well with it. The last thing I'd mention is there's a newer agent compared with the one that you mentioned. Um it's a combination NK1 and NK3 antagonist called elinzanetant um and that's a dual antagonist that has actually better efficacy and does not have that same liver risk, which is nice because then you don't even have to worry about uh doing the liver enzyme monitoring up front for the first 3 months. As with any like relatively newer medicine, of course, these are a little bit more expensive than the traditional non-hormonal options, maybe a little bit more difficult to access um in various situations, but sometimes we're, you know, we jump through the hoops that we need to jump through to get person on the therapy that's most likely to benefit them. — I really wish that, you know, most of the time the trade name is far better than the generic, but in both of these cases, they're still bad. And I just feel like I'm available for consultation. Okay? Like if you need me, I'll I'm here for you. — Mhm.