'My goal today is to create a room full of hot flash experts,' said Dr. Genevieve Neal-Perry.
Dr. Neal-Perry is the chair of the Department of Obstetrics and Gynecology and the Robert A. Ross Distinguished Professor of Reproductive Endocrinology and Infertility at the University of North Carolina School of Medicine in Chapel Hill. She presented 'Rewiring the thermostat: from the thermoneutral zone to KNDy neurons and targeted menopause therapies' at The Menopause Society 2026 Annual Meeting, held October 20 to 24 in San Diego, California. Her talk was part of the plenary symposium 'Beyond hormones: emerging and established pharmacologies in perimenopause and menopause management.'
A typical hot flash comes without warning, rises from the chest upward, and brings flushing, sometimes with anxiety and a racing heart, Dr. Neal-Perry explained. But many women notice only the anxiety and palpitations and go from doctor to doctor before anyone recognizes a hot flash. 'This was me in 2015,' she said.
How estrogen swings and KNDy neurons may trigger hot flashes
Low estrogen alone does not explain hot flashes, she said, because women in perimenopause have them while their estrogen levels swing widely. These swings from high to low are the likely trigger. Before menopause, estrogen keeps a wide buffer zone for body temperature. As that zone narrows, even a small rise in core temperature can set off sweating and flushing. The driver sits in kisspeptin-neurokinin B-dynorphin (KNDy) neurons in the hypothalamus. Without estrogen to restrain them, these neurons enlarge, release too much neurokinin B (NKB), and stimulate themselves. 'When mom's not home, what do the kids do? They misbehave,' Dr. Neal-Perry joked.
Studies in mice, in the brains of postmenopausal women, in genetic data, and in a trial where NKB infusion brought on hot flashes in young women all pointed to NKB as the culprit. That basic science made the NKB pathway a treatment target. 'Without this, we would not be where we are today,' she said.
What fezolinetant and elinzanetant may offer women with hot flashes
Blocking the neurokinin 3 (NK3) receptor gives back the balance that estrogen once provided, Dr. Neal-Perry explained. Fezolinetant blocks only the NK3 receptor, while elinzanetant blocks both the NK3 and the neurokinin 1 (NK1) receptor. The NK1 receptor responds to substance P and, unlike NK3, also acts outside the brain.
No head-to-head trials have compared the two drugs, she cautioned, and the trials were designed differently. 'You just need to make sure you understand how the study was designed when you're interpreting it,' she said. She praised both programs for including women with obesity. 'Most often, obese women are excluded from studies, and then the data is just extrapolated.' The trials also enrolled more Black and Latina women, 'which again is not that common.'
Both drugs reduced hot flashes within a week. 'There are very few interventions that actually do that,' Dr. Neal-Perry noted. On liver safety, 'there is a lot of misinformation out there,' she said. Neither drug showed liver toxicity in the trials, but fezolinetant raised liver enzymes in some women, so liver tests are needed before starting either drug.
Long-term efficacy is still unknown, Dr. Neal-Perry concluded, because the receptors these drugs target can become less responsive over time. Real-world studies, she said, will be essential.
KNDy, kisspeptin-neurokinin B-dynorphin; NKB, neurokinin B; NK3, neurokinin 3; NK1, neurokinin 1.