Are orexin antagonists capable of improving both insomnia and vasomotor symptoms in menopausal women?

The menopausal period in women is characterized by neuroendocrine alterations, which is in part mediated by the reduction in circulating estrogen. During this transition, many perimenopausal and menopausal women experience sleep disturbances and increased susceptibility to sleep-related disorders. Sleep disruptions are partially attributed to nighttime vasomotor symptoms (VMS), which exacerbates the insomnia risk in the menopausal woman. Converging data implicate the orexin system in the pathophysiology of insomnia and VMS, particularly through regulation of arousal, thermoregulation, and sympathetic outputs. Estrogen decline due to menopause is postulated to modulate orexin signaling, thereby heightening sympathetic drive and thermoregulatory instability. Given this potential mechanistic framework, orexin receptor antagonists, notably dual orexin receptor antagonists (DORAs), have been proposed as alternative menopausal therapeutics. Herein, we aim to examine preclinical, translation, and clinical literature assessing the therapeutic potentials of DORAs as a nonhormonal intervention for the mitigation of insomnia and VMS in midlife women.