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January/February 2023
Women’s Health: Menopause and Brain Health The most publicized symptoms of menopause are typically hot flushes (or flashes), insomnia, and weight gain, with numerous supplements and medications marketed to address them. “Brain fog,” another common occurrence in menopause, is less publicized. Menopause brain fog is defined as a “constellation of cognitive symptoms experienced by women … which most frequently manifest in memory and attention difficulties and involve such symptoms as difficulty encoding and recalling words, names, stories, or numbers; difficulty maintaining a train of thought; distractibility; forgetting intentions (reason for coming into a specific room); and difficulty switching between tasks.”1 In most women, the transition through menopause occurs without long-term adverse effects, and hot flushes, insomnia, and cognitive issues eventually resolve in the postmenopausal years. According to the Alzheimer’s Association, two-thirds of Americans living with Alzheimer’s disease are women. Estimated lifetime risk of developing the disease for women aged 65 years is 1 in 5—more than the 1 in 8 women who are estimated to develop breast cancer. The Alzheimer’s Association notes that women in their 60s are twice as likely to develop the disease as they are breast cancer. These statistics—and their link to endocrine aging—are catalyzing research into whether menopausal changes with aging contribute to Alzheimer’s disease and other neurodegenerative disorders. Clinically, perimenopause and menopause are defined by changes in the reproductive system; however, most menopause-related symptoms are neurological due to the presence of estrogen receptors in the central nervous system and the effects of estrogen on brain glucose metabolism. During menopause, sex hormone production (estrogen and progesterone) declines substantially—up to 90%—resulting in dramatic physiological changes throughout the body, including the brain.2 “Sex hormones serve as master regulators of many physiologic processes. Menopause is associated with alterations in brain structure and function as well as metabolic processes, mood, sleep disturbance, and cognitive dysfunction,” says Laura Pritschet, a doctoral candidate in the department of psychological and brain sciences at the University of California, Santa Barbara. Her dissertation work uses noninvasive brain imaging to investigate the impact of menopause on brain structure, function, and cognition in women aged 45 to 55 years. Pritschet is advised by Emily Jacobs, PhD, a cognitive neuroscientist; associate professor of neuroscience at the University of California, Santa Barbara; and leading researcher in the field of neuroendocrine aging to explore the neural changes associated with menopause. Jacobs’ research over the last decade has established that endocrine aging results in changes to memory circuitry decades before the age (>65 years) typically targeted in studies of brain aging. In a 2016 study, Jacobs and her colleagues conducted functional MRI in 200 women aged 45 to 55 years in varying stages of endocrine decline.3 Women performed a verbal memory task while undergoing the MRI scan. “Brain activity differed by menopausal state. Despite minimal differences in chronological age, women with lower estrogen concentrations showed more pronounced alterations in brain connectivity and performed worse on the memory task,” Pritschet summarizes. In a follow-up functional MRI study of men and women, Jacobs and her colleagues found the memory task responses in the dorsolateral prefrontal cortex and hippocampus differed depending on the women’s reproductive stage.4 As estrogen and progesterone levels declined, the magnitude of hippocampal disengagement or deactivation decreased. “And midlife women outperformed age-matched men across several different memory assessments until postmenopause, when the female advantage was attenuated,” Pritschet explains. A 2021 neuroimaging study by a different group of researchers found similar brain changes related to menopause. Brain gray matter volume in the inferior temporal gyrus was lower after menopause; brain glucose use in the temporal lobes and white matter volume in multiple brain regions was also decreased from premenopause to postmenopause. However, the researchers found that postmenopausal women’s brains partially compensated for the decline by increasing cerebral blood flow and certain metabolic processes in the areas where brain matter volume was affected, allowing cognitive performance to be preserved. The researchers concluded that their findings “show that human menopause is a dynamic neurological transition that reshapes the neural landscape of the female brain during midlife endocrine aging, and provide preliminary evidence for an adaptive process serving the transition into late life.”5 This study also used positron emission tomography to detect amyloid-beta plaque deposition in the brain, which has been linked to the development of Alzheimer’s disease. In perimenopausal and postmenopausal women who also had a genetic risk factor for late-onset Alzheimer’s disease (apolipoprotein- E-4 genotype), amyloid-beta deposition was more pronounced than for men of the same age with the same genotype. Although estrogen depletion has been linked to increased amyloid-beta plaque in female animals, the links in human females and the future development of Alzheimer’s disease are still being researched.5 According to Pritschet, research into the aging brain during the middle decades of life has the power to identify early markers of future memory decline. She notes that Jacobs’ past and ongoing research demonstrates the benefits of applying a “sex-dependent lens” to aging. Jacobs’ work shows that menopause may lead to a change in activation in the brain that can still accompany minimal differences in cognitive performance; that is, differences in brain activity across groups are not always detrimental, Pritschet says. “For example, when Jacobs and her colleagues looked closer at postmenopause women, those with higher estrogen levels performed more like pre- and perimenopausal women. Therefore, careful investigations like this may help identify and target a subset of women who may be the most at risk for cognitive decline in postreproductive years,” she says. Guidance for Geriatric Health Professionals As women approach menopause, they may be unaware that hormonal changes are responsible for their cognitive symptoms and may be concerned that they may be progressing toward dementia. “When I chat with women about their experiences throughout menopause, I’m always taken aback by how little they were prepped on what to expect. We need to destigmatize menopause and encourage open discussions about this neurological transition state early in women’s lives,” Pritschet recommends. She emphasizes the importance of open discussions with health care providers about the array of menopausal symptoms that may occur. “It is critical that geriatric professionals have a discussion with women about the expectations of the menopausal transition, preferably very early in the aging process,” she emphasizes. She adds that each woman’s threshold for tolerating symptoms is different, and encouraging women to track changes in mood, sleep, pain, cognitive issues, sexual desire, and other symptoms can help health professionals determine when the severity and duration of symptoms warrants interventions to improve quality of life. A 2022 white paper by the International Menopause Society provides guidance for health care professionals working with women going through menopause and experiencing related brain fog. The authors encourage health providers to normalize the menopause experience and reassure women that cognitive changes associated with menopause should not be confused with early-onset dementia, as dementia before age 64 is very rare. Research findings indicate that cognitive changes generally begin in perimenopause but may mostly resolve in postmenopause.1 Pritschet notes that some women can mitigate menopause symptoms, such as brain fog, with lifestyle modifications like regular exercise, good sleep hygiene, and an improved diet. For some women, hormonal therapy may help minimize cognitive symptoms. “There is evidence to suggest that hormone therapy can reverse some of the brain changes that stem from the loss of hormones in midlife. However, it is important to note that the beneficial effects of hormone therapy depend heavily on the timing of administration as well as dosage and formulation,” Pritschet says. The International Menopause Society states that current guidelines do not recommend hormonal therapy at any age to treat cognitive issues related to menopause or prevent cognitive decline or dementia due to a lack of evidence. However, estrogen therapy in women with early menopause may be helpful in maintaining cognitive function and decreasing dementia risk. The society also notes that hormonal therapy early in postmenopause appears to be safe for addressing cognitive function and that estrogen therapy even later in postmenopause appears to be safe for cognitive function.1 Research into the effects of different formulations and timing of hormonal therapy is ongoing, as is neuroscientific research into the aging female brain. Historically, research into aging brains has focused on older men and postmenopausal women. The effects of sex hormones and interactions with brain aging have only recently emerged as a research focus. Ongoing research from Jacobs, Pritschet, and other researchers is expected to help clarify the effects of the menopausal transition on the female aging brain. Visit https://jacobs.psych.ucsb.edu/research for more information. — Jennifer Van Pelt, MA, is a freelance writer and health care researcher located in the Lancaster, Pennsylvania, area.
References 2. Brinton RD, Yao J, Yin F, Mack WJ, Cadenas E. Perimenopause as a neurological transition state. Nat Rev Endocrinol. 2015;11(7):393-405. 3. Jacobs EG, Weiss BK, Makris N, et al. Impact of sex and menopausal status on episodic memory circuitry in early midlife. J Neurosci. 2016;36(39):10163-10173. 4. Jacobs EG, Weiss B, Makris N, et al. Reorganization of functional networks in verbal working memory circuitry in early midlife: the impact of sex and menopausal status. Cereb Cortex. 2017;27(5):2857-2870. 5. 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. |
