Reproductive Aging of Neuroendocrine Systems

Abstract

The neural transition of perimenopause is a midlife transition state in the female that occurs in the context of a fully functioning neurological system and results in reproductive senescence. While viewed as a reproductive transition, the symptoms of the perimenopause are largely neurological in nature. Neurological symptoms that emerge during the perimenopause are indicative of disruption in multiple estrogen-regulated systems including thermoregulation, sleep and circadian rhythms, sensory processing, affect and multiple domains of cognitive function. Through the estrogen receptor (ER) network, estrogen functions as a master regulator to ensure that the brain effectively responds at rapid, intermediate, and long time scales to coordinate signaling and transcriptional pathways that regulate energy metabolism in brain. The ER network becomes uncoupled from the bioenergetic system during the perimenopausal transition and, as a corollary, a hypometabolic state associated with neurological dysfunction emerges. For some women this may increase risk for late-life neurodegenerative disease. Conversely, the perimenopause represents a window of opportunity to prevent age-related neurological disease. This chapter considers the significance of perimenopausal neurological symptoms, their relationship to the estrogenic receptor network control of brain metabolism, and the parallels between the perimenopause and transition state dynamics. Further, gaps in mechanistic and clinical understanding of the perimenopause are considered. The perimenopause fulfills criteria for a ‘critical period’ in the neuroadaptive landscape of aging in the female brain. For some, this critical transition period can be a tipping point for the emergence of neurological disease in later life.