Harnessing the science behind hot flashes

Brought to you by Astellas Pharma Canada Inc.When the Kisspeptin, Neurokinin B, and Dynorphin (KNDy) neurons were discovered in 2008, hot flashes became a cool topic – scientifically speaking. The discovery of KNDy neurons and their critical role in thermoregulation offered hope that novel targeted treatments aimed at addressing the physiology of vasomotor symptoms (VMS) could be identified and developed to diminish the immense burden of hot flashes. Indeed, up to 80% of women experience VMS during the menopause,1 and they not only impair daily functioning and quality of life,1 but unmanaged menopause symptoms are estimated to cost the Canadian economy a staggering $3.5 billion annually.2The burden of VMS may extend beyond physical, psychosocial and economic consequences. Associations have been reported among the persistence of untreated VMS and increased risks for cardiovascular disease, breast cancer and poorer cognition.3,4,5,6 These observations provide additional reasons to treat hot flashes beyond symptomatic relief.The science behind hot flashesWe now know that hot flashes are a thermoregulatory phenomenon associated with changes in how the reproductive and thermoregulatory systems interact in the nervous system.7 KNDy neurons in the hypothalamus express various receptors including the estrogen receptor-alpha (ERα), which exerts negative feedback on KNDy neurons to keep their activity in check.7 When circulating estradiol levels decline during menopause, this negative feedback loop between the brain and the reproductive system is lost, leading to increased binding of neurokinin B (NKB) via NK3 receptors. 7 This in turn causes KNDy neurons to become hypertrophied and hyperactive, which increases signaling to neurons in the thermoregulatory centre which themselves also bind NKB. 7 Heat dissipation mechanisms in the thermoregulatory centre then become hypersensitive and hyper-responsive, which is experienced by women as hot flashes. 7Targeting KNDy neurons to restore thermoregulatory balanceFezolinetant and elinzanetant are novel treatments that were designed to target the source of increased signaling by KDNy neurons to the thermoregulatory centre.8 Fezolinetant is a selective NK3 receptor antagonist that blocks the binding of NKB on KNDy neurons,9 thereby preventing increased signaling to the thermoregulatory centre.7 Elinzanetant works in a similar manner but in addition to blocking the NK3 receptor, it also blocks the NK1 receptor,10 which may improve sleep outcomes. In a nutshell, fezolinetant and elinzanetant selectively moderate neuronal activity in the thermoregulatory centre by binding to the NK3 receptor and blocking NKB, helping to restore balance and reducing the frequency and severity of hot flashes.Translating the science into practiceWe now have three Health Canada approved, evidence-based options that are specifically indicated (i.e., on-label) to reduce the frequency and severity of moderate to severe hot flashes: menopausal hormone therapy (MHT), fezolinetant and elinzanetant.9,10,11 Menopause management guidelines continue to recognize the role of MHT (i.e., estrogen + progestogen therapy or estrogen alone in women without an intact uterus) as the most effective treatment for VMS.11 Estrogen restores the negative feedback loop on KDNy neurons in the hypothalamus and prevents hypertrophy and increased signaling to the thermoregulatory centre.7,12 However, some women are not good candidates for MHT due to the presence of contraindications (~10% of women), comorbidities that may tip the risk-benefit ratio away from MHT (up to 70% of women) or have a personal preference to avoid hormone therapy (up to 56% of women in Europe and the U.S.).1 In women who are not suitable candidates for MHT, management guidelines recommend that nonhormonal therapies that are supported by evidence should be offered.13 Fezolinetant and elinzanetant are on-label nonhormonal options indicated for treatment of moderate to severe VMS .9,10,13 Having more options available will improve the lives of women living in Canada suffering from debilitating menopause-associated VMS.Managing hot flashes in 2025Discovery of the KNDy neuron has advanced our understanding of the science behind hot flashes and the important connections between the brain’s thermoregulatory centre and the reproductive system. Clinicians now have additional options to offer women suffering from bothersome moderate to severe hot flashes, including MHT and novel, evidence-based, and targeted nonhormonal therapies. Having more tools in the toolbox allows for more personalized management decisions that consider an individual woman’s goals of therapy and preferences. Understanding the science behind hot flashes will equip clinicians with the knowledge to confidently discuss the available therapies with women seeking treatment for hot flashes, thereby supporting shared decision-making, which remains an integral part of promoting women’s health during the menopause. We are hopeful that better treatment of VMS will translate to downstream positive health trajectories by reducing both short- and long-term outcomes for women in midlife and beyond.

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