Perimenopause as a neurological transition state

Abstract

Perimenopause is a midlife transition state experienced by women that occurs in the context of a fully functioning neurological system and results in reproductive senescence. Although primarily viewed as a reproductive transition, the symptoms of perimenopause are largely neurological in nature. Neurological symptoms that emerge during perimenopause are indicative of disruption in multiple estrogen-regulated systems (including thermoregulation, sleep, circadian rhythms and sensory processing) and affect multiple domains of cognitive function. Estrogen is a master regulator that functions through a network of estrogen receptors to ensure that the brain effectively responds at rapid, intermediate and long timescales to regulate energy metabolism in the brain via coordinated signalling and transcriptional pathways. The estrogen receptor network becomes uncoupled from the bioenergetic system during the perimenopausal transition and, as a corollary, a hypometabolic state associated with neurological dysfunction can develop. For some women, this hypometabolic state might increase the risk of developing neurodegenerative diseases later in life. The perimenopausal transition might also represent a window of opportunity to prevent age-related neurological diseases. This Review considers the importance of neurological symptoms in perimenopause in the context of their relationship to the network of estrogen receptors that control metabolism in the brain.

A trip down memory lane about sex differences in the brain

“…Female rodents experience stages of life similar to perimenopause and menopause in women, during which their responses to learning and stress can change rather dramatically [26,74]. Obviously, women in perimenopause experience substantial changes as they transition into a stage of life associated with reproductive senescence [75]. These examples notwithstanding, I am not suggesting that researchers investigate all stages of female life in laboratory studies or that we only study nonvirgins, but rather that we simply appreciate the dynamic nature of the female brain.…”

Reproductive Aging: Perimenopause and Psychopathological Symptoms

“…In the perimenopausal brain, there is an increased risk for some women of developing neurodegenerative diseases later in life [42,43]. Neurodegeneration is the progressive loss of functional activity and trophic degeneration of nerve axons and their terminal arborizations following the destruction of their cells of origin or interruption of their continuity with these cells, and it occurs in Alzheimer's disease, Parkinson's disease, progressive supranuclear paralysis, frontotemporal dementia, corticobasal degeneration, Huntington's disease, prion diseases, amyotrophical lateral sclerosis, spinocerebellar ataxia, and multiple sclerosis [44][45][46][47].…”

“…Perimenopause is primarily viewed as a reproductive transition; however, the symptoms of perimenopause are not just largely neurological in nature, but are also indicative of disruption in multiple estrogen-regulated systems (including thermoregulation, sleep, circadian rhythms, sensory processing, and several domains of cognitive function) [1,42].…”

Neuroprotection in Perimenopausal Women

“…It was demonstrated how during reproductive ages the estrogen-induced signaling pathways in hippocampal and cortical neurons converge upon the mitochondria to enhance aerobic glycolysis coupled to the citric acid cycle, mitochondrial respiration, and ATP generation, and in senescence when estrogens are missing, it is a chronic oxidative stress due to the shift from an aerobic glycolytic to a ketogenic profile/phenotype/ [35,60], and this shift is preceded by the early, already mentioned decline in glucose transport and metabolism [46]. In mouse model, the mitochondrial bioenergetic deficit precedes AD [92].…”

“…As it is shown in the Table 1, the hazard ratios reached statistical significance in cases with bilateral oophorectomy: at the age < 34 years for dementia and <38 years for PD. Perimenopause is a "fragile" period in woman's life, comparable to the fragility of the adolescence, if we speak about "hormonal storms," but the hormonal pyramid is upside down, and more than these, the North American neurologists are considering perimenopause as a neurological transition state [35], because the characteristic symptoms regarding thermoregulation, sleep, circadian rhythms, and sensory processing are of neurological nature, besides the changes of cognitive function [36].…”