Cognitive performance of women during menopause

Continuing research into the causes of declining cognitive performance in women during menopause may provide clinicians with insights into more effective therapies.^1,2 “Given the aging population, maintaining intact memory function is one of the primary public health challenges of our time,” said Jill M. Goldstein, PhD, MPH, professor of psychiatry and medicine at Harvard Medical School in Boston, Massachusetts. “Men and women age differently, particularly in early midlife when reproductive age during menopause is more critical than chronologic age for women, whereas chronologic age is key for men.”

Goldstein noted that menopause is marked by a decline in ovarian hormone production; notably, estradiol, which works in the brain. “Two decades of rodent and nonhuman primate studies have established that memory circuitry regions in the brain and their connections are significantly impacted by gonadal hormones like estradiol,” she said in an interview with Contemporary OB/GYN.

Goldstein’s team, as well as others, have shown that estradiol directly affects changes in memory performance and can reorganize memory circuitry in the brain. “It is critical to understand the impact of menopause on the brain to allow for development of strategies to prevent memory loss in women,” Goldstein said.

Sex differences in memory performance, particularly verbal material, emerge post puberty and are retained into adulthood, according to Goldstein. “Although women’s performance attenuates with menopause, a small female advantage is maintained in the healthy aging brain through midlife and old age,” she said. “Despite these findings, however, less is known about memory changes in women during the menopausal transition compared with age-matched men, or sex differences in specific memory domains early in midlife.”

Although all women eventually undergo menopause, there is a large age range for when it begins, ranging from the 40s to the 60s. “There is also substantial variation in women’s experience of the impact of menopause,” Goldstein said. “For example, many, but not all, women experience increased forgetfulness and so-called brain fog during the menopausal transition.”

Menopause also lowers the level of glucose in the brain (the primary fuel used by brain cells). “Fortunately, the brain eventually adapts to a new hormonal environment in order to maintain functioning,” said Goldstein, who is founder and executive director of the Innovation Center on Sex Differences in Medicine and the Helen T. Moerschner Endowed MGH Research Institute Chair in Women’s Health at Massachusetts General Hospital.

Although knowledge about the normative changes that occur in the middle-aged brain is rapidly expanding, “there are many questions that remain,” she said. For example, because some evidence exists that women are at a higher risk for memory disorders than men later in life, “applying a sex differences lens to the study of memory circuitry aging may help identify early antecedents of future memory decline,” Goldstein said. “Moreover, studying adults early in the aging process, as women transition into menopause, may reveal sex-dependent characteristics underlying aging of the memory circuitry in the middle decades of life.”

Cognitive complaints are more prevalent as women near menopause, according to a literature review published recently in the International Journal of Molecular Sciences.¹ A premature reduction in estrogen also increases a woman’s risk of cognitive disorders and dementia, including Alzheimer disease (AD), the authors noted.

“Menopausal hormone therapy from menopause to the age of 60 years may provide a ‘window of opportunity’ to reduce the risk of mild cognitive impairment and AD in later life,” the authors wrote. “Women with earlier menopause should be taken care of by various specialists such as gynecologists, endocrinologists, neurologists, and psychiatrists in order to maintain their mental health at the highest possible level.”¹

Hormone replacement therapy (HRT) is linked to improved cognition and larger brain volumes in at-risk APOE4 genotype women, according to results from the European Prevention of Alzheimer’s Dementia Consortium cohort, as reported recently in Alzheimer’s Research & Therapy.² HRT “may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup,” the authors wrote.

Marcia E. Klein-Patel, MD, PhD, system chair of the Women’s Institute at Allegheny Health Network in Pittsburgh, Pennsylvania, agreed with Goldstein that many women report symptoms of brain fog during perimenopause. “Recent data suggests, though, that some women may experience a temporary and limited word-finding difficulty, specifically for nouns,” she said.

Other symptoms related to this brain fog are most likely a result of menopausal symptoms that to lead to poor sleep, such as vasomotor symptoms and mood changes, according to Klein-Patel.

Clinicians can help patients navigate these cognitive challenges by focusing on behavioral basics such as eating well, sleeping well, having good relationships, and exercising. “If these strategies fail to improve symptoms, consider other management techniques, including medications and cognitive behavioral therapy,” Klein-Patel said.

Klein-Patel noted the recent heightened attention on menopausal concerns “can only help increase our opportunities to discuss wellness and to support continued research.”

Goldstein added that clinicians need to be aware when women are undergoing menopause and ask them about their experience. “This will have important implications for treatment, given that initiation of HRT in early post menopause or in perimenopause, which occurs approximately 5 to 10 years prior to menopause, has been shown to have positive effects on memory performance, cardiovascular function, and maintaining bone density,” she said.

By contrast, initiation of HRT in late menopause has demonstrated adverse effects in women, including increased risk of stroke and Alzheimer disease, according to Goldstein. “Women themselves can help maintain their intact memory function through 3 activities: effortful cognitive activity, effortful physical activity, and social contact,” she said.

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Goldstein is on the scientific advisory board and has some equity interest in Cala Health.

Klein-Patel reported no relevant financial disclosures.

References

1. Sochocka M, Karska J, Pszczołowska M, et al. Cognitive decline in early and premature menopause. Int J Mol Sci. 2023;24(7):6566. doi:10.3390/ijms24076566
2. Saleh RNM, Hornberger M, Ritchie CW, Minihane AM. Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort. Alzheimers Res Ther. 2023;915(1):10. doi:10.1186/s13195-022-01121-5