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Summary

The menopause transition (MT) is a neuro-endocrine process that impacts the aging trajectories of multiple organ and systems including the brain. The MT occurs over time and is characterized by clinically defined stages with specific neurological symptoms. However, the way this process impacts the human brain remains unclear. Recently Mosconi et al. [1] reported a multi-modality neuroimaging study that indicates substantial differences in brain structure, connectivity, and energy metabolism across MT stages (pre-, peri- and post-menopause). These effects involved brain regions sub-serving higher-order cognitive processes and were specific to menopausal endocrine aging rather than chronological aging, as determined by comparison to age-matched males. Brain biomarkers largely stabilized during postmenopause, and gray matter volume (GMV) recovered in key brain regions for cognitive aging. Notably, GMV recovery and in vivo brain mitochondria ATP production correlated with preservation of cognitive performance in the postmenopausal stage, suggesting adaptive compensatory processes. In parallel to the adaptive process, amyloid-β deposition was more pronounced in peri- and postmenopausal women carrying the apolipoprotein E-4 (APOE-4) genotype, the major genetic risk factor for late-onset Alzheimer’s disease (AD), relative to genotype-matched males.

Commentary

All women undergo the menopause either through the natural endocrine aging process or medical intervention [1]. The climacteric is not only a reproductive transition state but also a neurological one [2]. Neurological symptoms include changes in thermoregulation, mood, sleep, and cognitive performance which highlight the importance of estradiol for the brain function [3]. Estradiol is the “master regulator of the female brain” due to its effects on neuronal structure and function. Its neuroprotective role is of particular relevance for cognitive aging and AD, which affects nearly twice more women than men [4].

During the MT, estradiol declines affecting synaptogenesis, neuronal number and morphology, and glucose metabolic rates. Additionally, estrogen depletion is linked to amyloid-beta (Aβ) accumulation, a hallmark of AD [5].

Clinical studies indicate that during the perimenopause there is a dip in cognitive performance, mostly verbal memory, possibly followed by a rebound in the postmenopause as Mosconi et al. [1] demonstrated through biomarker stabilization or recovery in the late postmenopause [1]. Surgically induced menopause at an early age is also associated with a higher risk of AD, which is mitigated by menopausal hormone therapy (MHT) [3]. In fact, neurological symptoms may be particularly intense in cases of iatrogenic premature ovarian insufficiency (POI), affecting woman’s quality of life.  In Argentina, an interhospital network found that 5.96% of POI cases result from gynecological surgeries due to benign pathology; thus, stressing the importance of maintaining a conservative approach regarding ovarian resection [6]. The possible benefits of MHT on the female brain including stress reduction, cognitive performance improvement, and a delay in the onset of AD are still being evaluated [7].

Although MHT may alleviate early cognitive symptoms, currently it is not indicated for the prevention of AD. Despite this, some argue that MHT given to healthy perimenopausal women may be recommended to support cognitive function with careful consideration of other risks [3].

Sandra C. Demayo, MD
Past President of the Argentinian Society of Gynecological and Reproductive Endocrinology (SAEGRE)
Chair of the Gynecological Endocrinology Area, Argerich Hospital, Buenos Aires, Argentina
Fellow of the American College of Obstetricians and Gynecologists

References

  1. Mosconi L, Berti V, Dyke J, et al. Menopause impacts human brain structure, connectivity, energy metabolism, and amyloid-beta deposition. Sci Rep. 2021;11(1):10867.
    https://pubmed.ncbi.nlm.nih.gov/34108509/
  2. Monteleone P, Mascagni G, Giannini A, Genazzani AR, Simoncini T. Symptoms of menopause – global prevalence, physiology and implications. Nat Rev Endocrinol. 2018;14(4):199-215.
    https://pubmed.ncbi.nlm.nih.gov/29393299/
  3. Jett S, Schelbaum E, Jang G, et al. Ovarian steroid hormones: A long overlooked but critical contributor to brain aging and Alzheimer’s disease. Front Aging Neurosci. 2022;14:948219.
    https://pubmed.ncbi.nlm.nih.gov/35928995/
  4. Rettberg JR, Yao J, Brinton RD. Estrogen: a master regulator of bioenergetic systems in the brain and body. Front Neuroendocrinol. 2014;35(1):8–30.
    https://pubmed.ncbi.nlm.nih.gov/23994581/
  5. Zhang S, Fan W, Hu H, et al. Subcortical Volume Changes in Early Menopausal Women and Correlation With Neuropsychological Tests. Front Aging Neurosci. 2021;13:738679.
    https://pubmed.ncbi.nlm.nih.gov/34955807/
  6. Demayo S, Giannone L, Monastero A, et al. Reality of premature ovarian failure in Argentina. Rev Assoc Med Bras (1992). 2019;65(3):419-423.
    https://pubmed.ncbi.nlm.nih.gov/30994842/
  7. Boyle CP, Raji CA, Erickson KI, et al. Estrogen, brain structure, and cognition in postmenopausal women. Hum Brain Mapp. 2021;42(1):24-35.
    https://pubmed.ncbi.nlm.nih.gov/32910516/

 


If you would like to add a comment or contribute to a discussion based on this issue, please contact Menopause Live Editor, Peter Chedraui, at  peter.chedraui@cu.ucsg.edu.ec.

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