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Perimenopause as a neurological transition state

This article has been updated

Key Points

  • The clinical definition of perimenopause focuses on functional changes in the reproductive system; however, the symptoms of the perimenopause are largely neurological in nature

  • Most women transition through perimenopause without long-term adverse effects; however, a substantial proportion of women emerge from this transition with an increased risk of neurological decline

  • Estrogen functions as a master regulator to ensure the brain responds appropriately to coordinate signalling and transcriptional pathways that regulate energy metabolism

  • The estrogen receptor network becomes uncoupled from the bioenergetic system during the perimenopausal transition and a hypometabolic state associated with neurological dysfunction emerges

  • In neurological transition states, indicators of dysfunction at the limits of those normally seen can signal tipping points for neurological diseases

  • The presence, variability, intensity and duration of neurological perimenopausal symptoms could be warning signs for increased risk of neurodegenerative diseases later in life

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.

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Figure 1: Symptoms during perimenopause.
Figure 2: Neurological functions affected by the perimenopausal transition.
Figure 3: Estrogen receptor network.
Figure 4: Estrogen-mediated regulation of the bioenergetic system.

Change history

  • 08 June 2015

    In the version of this article initially published online there was an error in one of the headings, 'Adaptation in perimenopause' was incorrectly written as 'Adaption in perimenopause'. Also GLUT3 was incorrectly labelled as GLUT10 in Figure 4. Both errors have been corrected for the print, HTML and PDF versions of the article.

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Acknowledgements

R.D.B. would like to acknowledge the support of grants from the National Institute on Aging (P01AG026572 and R01-AG032236).

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R.D.B. researched data for the article and wrote the manuscript. All authors provided substantial contributions to the discussion of content, generation of figures and reviewed/edited the manuscript before submission.

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Correspondence to Roberta D. Brinton.

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Brinton, R., Yao, J., Yin, F. et al. Perimenopause as a neurological transition state. Nat Rev Endocrinol 11, 393–405 (2015). https://doi.org/10.1038/nrendo.2015.82

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