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Menopause is a period of significant physiological change that is largely related to estrogen depletion and subsequent cessation of ovarian function. During menopause period, women tend to gain weight and fat mass. It is not clear whether the increase in adiposity is a consequence of the decline in endogenous estrogen. Cardiovascular disease incidence increases with age in women as well as in men, but in women there is an additional increase due to the menopause. Many researches were conducted to assess the contribution of factors such as estrogen depletion, REE decline, and aging to weight gain. An increase in orexin-A plasma levels, paralleling lower estrogen levels, was found during menopause. The goal of this review is to provide insight into the biological mechanism governing orexin’s role in energy expenditure; autonomic nervous system and cardiovascular risk discuss its significance in the context of menopause. Orexins are hypothalamic neuropeptides recently discovered, involved in the regulation of feeding behaviour, sleepwakefulness rhythm, and neuroendocrine homeostasis. Orexins might offer the missing link between postmenopausal hypoestrogenism and other manifestations of the menopausal syndrome, including appetite and weight changes and increase in cardiovascular risk.