Pathophysiology
Clinical meaning
Vasomotor symptoms (VMS) — hot flashes and night sweats — are the hallmark clinical manifestation of menopause, affecting approximately 75% of women and significantly impairing quality of life in 25-30%. The pathophysiology centers on dysfunction of the hypothalamic thermoregulatory center caused by estrogen withdrawal. In the arcuate nucleus of the hypothalamus, KNDy neurons (coexpressing kisspeptin, neurokinin B, and dynorphin) modulate the thermoneutral zone — the range of core body temperature within which neither sweating nor shivering is triggered. Estrogen normally suppresses neurokinin B signaling; when estrogen declines, neurokinin B activity increases, dramatically narrowing the thermoneutral zone so that minor fluctuations in core temperature trigger inappropriate heat dissipation responses (cutaneous vasodilation, flushing, diaphoresis). This mechanism is the pharmacological target of NK3 receptor antagonists (fezolinetant). Pharmacotherapy is stratified by mechanism: systemic estrogen therapy (oral or transdermal) directly restores estrogen-mediated suppression of KNDy neuron hyperactivity, providing 50-80% reduction in VMS frequency and is the most effective treatment; transdermal delivery bypasses hepatic first-pass metabolism, avoiding triglyceride elevation and reducing VTE risk compared to oral formulations. SSRIs and SNRIs (paroxetine, venlafaxine) modulate serotonergic and noradrenergic...