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Abstract

Hot flashes (HF), transitory episodes of erythema, heat sensation, anxiety followed by chills, are described in carcinoid syndrome, mastocytosis, medullary thyroid cancer, hyperthyroidism, pheochromocytoma, alcohol consumption, side effects of drugs, and infections. They are pivotal among menopause-related vasomotor symptoms beside genitourinary syndrome in addition to sleep disturbances (40-60% of females), and metabolic changes. HF affect 70% of women (20% of them have a severe impairment of life quality); they last for 4-7 years, starting 4-6 years before last menstruation. The main HF cause is ovarian-derivate estrogen deprivation which activates complex endocrine and neuroendocrine mechanisms involving noradrenaline, 5-hydroxytriptamine (5-HT), calcitonin gen-related peptide, orexin, kisspeptin, neurokinin B, and epigenetic elements like modulation of tachykinin receptor 3, accelerated epigenetic aging (as found in Women's Health Initiative Observational Study), expression of central serotonin transporters. Estrogen deficiency uncouples the negative feedback with preoptic area of hypothalamus, responsible for thermoregulation by inducing an exacerbated vasodilatory response to a small increase of body temperature. TRPV1 (transient receptor potential vanilloid 1) in preoptic hypothalamic area may play a role by NE-α2ADR (norepinephrine-activated α2-adrenergic receptors) activation. Higher expression of serotonin transporter SLC6A4 causes a lack of 5-HT at synapsis which is a trigger for presynaptic 5-HT receptor feedback, thus a release of serotonin amount prevents hot flashes. Kisspeptin and neurokinin B which are co-expressed in infundibular nucleus of hypothalamus are involved in central thermoregulation and gonadotropin releasing hormone anomalies. The NKR3 (neurokinin 3 receptor) antagonist receptor improves HF. Understanding the pivotal role of central neurotransmitters in hot flashes is the basis of new therapeutically researches because otherwise estrogen replacement has a long list of side effects, and it is contraindicated in breast cancer-related hypogonadism.