Neurokinin Antagonists to Treat Vasomotor Symptoms—Possible Implications for Long-Term Health and Disease

In women in post-menopause, the presence of severe vasomotor symptoms is associated with sleep disorders and a depressive mood. Vasomotor symptoms, sleep disorders, and a depressive mood are all related to an increased risk of cardiovascular events and bone fractures. The association is still elusive, but some mechanisms may sustain a hypothetical causal relation. During flush, the heart rate increases, augmenting blood turbulence and possibly posing a risk for endothelial damage. Altered sleep is associated with a reduced nocturnal blood pressure decline, which represents a risk factor for cardiovascular disease. Cortisol levels rise during each flush but also following sleep deprivation or in individuals with depression. Increased cortisol was found in women with menopausal symptoms and can induce insulin resistance, metabolic syndrome, cardiovascular disease, and bone demineralization. An elevated oxidative state is associated with vasomotor symptoms, sleep disturbances, and depression and increases the risk of cardiovascular events and osteoporosis. The use of non-hormonal remedies for symptom management leads to a decrease in blood pressure and a reduction of 24 h urinary cortisol, contingent upon the extent of symptom alleviation. Recent evidence indicates that fezolinetant, a neurokinin-3 receptor antagonist and elinzanetant, a neurokinin-1-3 receptor antagonist, diminish the frequency and severity of vasomotor symptoms. As the secondary endpoint of these studies, some amelioration of patients reported that sleep disturbance was observed during fezolinetant and more consistently during elinzanetant. Some improvement in the quality of life and depressive mood were also observed during elinzanetant. The causal relation of symptoms with cortisol levels and oxidative stress, and the reduction in cortisol and blood pressure by symptom improvements, support the possibility that neurokinin antagonists may decrease those factors linking menopausal symptoms with cardiovascular disease and osteoporosis. Dedicated studies are needed to test the hypothetical possibility that neurokinin receptor antagonists contribute to reduce the long-term burden of cardiovascular disease and osteoporosis of symptomatic women in post-menopause unwilling or with contraindication to the use of menopause hormone therapy.