This might turn out to be a crucial window to try to prevent Alzheimer’s and other chronic diseases that often accompany older age.
During menopause, which marks the end of a woman’s menstrual cycles, her ovaries stop producing the hormones estrogen and progesterone, bringing an end to her natural childbearing years. But those hormones also regulate how the brain functions, and the brain governs their release — meaning that menopause is a neurological process as well. “Many of the symptoms of menopause cannot possibly be directly produced by the ovaries, if you think about the hot flashes, the night sweats, the anxiety, the depression, the insomnia, the brain fog,” says Lisa Mosconi, an associate professor of neurology at Weill Cornell Medicine and director of its Women’s Brain Initiative. “Those are brain symptoms, and we should look at the brain as something that is impacted by menopause at least as much as your ovaries are.”
In June, Mosconi and her colleagues published in the journal Scientific Reports one of the few studies to observe in detail what happens to the brain throughout the menopause transition, not just before and after. Using various neuroimaging techniques, they scanned the brains of more than 160 women between the ages of 40 and 65 who were in different stages of the transition to examine the organ’s structure, blood flow, metabolism and function; they did many of the same scans two years later. They also imaged the brains of men in the same age range. “What we found in women and not in men is that the brain changes quite a lot,” Mosconi says. “The transition of menopause really leads to a whole remodeling.”
On average, women in the United States enter the menopause transition — defined as the first 12 consecutive months without a period — at around 50; once diagnosed, they are in postmenopause. But they may begin to have hormonal fluctuations in their 40s. (For some women, this happens in their 30s, and surgical removal of the ovaries causes immediate menopause, as do some cancer treatments.) Those fluctuations cause irregular periods and potentially a wide variety of symptoms, including hot flashes, insomnia, mood swings, trouble concentrating and changes in sexual arousal. During this phase, known as perimenopause, which averages four years in length (but can last from several months to a decade), Mosconi and colleagues observed that their female subjects experienced a loss of both gray matter (the brain cells that process information) and white matter (the fibers that connect those cells). Postmenopause, however, that loss stopped, and in some cases brain volume increased, though not to its premenopausal size. The researchers also detected corresponding shifts in how the brain metabolized energy, but these did not affect performance on tests of memory, higher-order processing and language. This suggests that the female brain “goes through this process, and it recoups,” says Jill M. Goldstein, a professor of psychiatry and medicine at Harvard Medical School and founder and executive director of the Innovation Center on Sex Differences in Medicine at Massachusetts General Hospital. “It adapts to a new normal.”
Understanding what happens in the brain around the time of the menopause transition could inform when and how doctors treat a given woman’s symptoms. Hormone therapy — whether estrogen alone or in combination with a progestogen — is not ordinarily prescribed until postmenopause, and carries risks; on the other hand, it can help treat hot flashes, bone loss or undesirable urinary or vaginal changes for women under 60 (or who have begun menopause within the past 10 years), according to the North American Menopause Society. Some women who receive hormone therapy might also gain cognitive benefits, but more evidence is needed to identify who should be treated. Randomized control trials of postmenopausal women have tried to assess whether hormone therapy decreased the risk of Alzheimer’s disease or other cognitive declines, but these have returned mixed results so far.
Yet Mosconi and colleagues found that women in their study who had a particular genetic risk factor for Alzheimer’s disease began to develop amyloid plaques, which are linked to the disease, during perimenopause in their late 40s and early 50s — earlier than previously thought. If the brain changes significantly during perimenopause, that might turn out to be a crucial window during which to try to prevent Alzheimer’s and other chronic diseases that often accompany older age. (Because hormone therapy is not generally prescribed for perimenopausal women, clinical trials on its potential cognitive benefits have not been done for them.)
Several major chronic diseases, including Alzheimer’s, appear to afflict women disproportionately. As Goldstein and her colleagues noted in a January opinion column in JAMA Psychiatry, more than two-thirds of those diagnosed with Alzheimer’s are women (only in part because they live longer, and older people are at greater risk). Women, too, are at twice the risk of developing a major depressive disorder, and they do so in tandem with cardiovascular disease at twice the rate men do — a combination, the authors point out, that increases their risk of death from cardiovascular causes as much as fivefold. Heart disease is also a risk factor for Alzheimer’s.
Figuring out why those health disparities exist and what to do about them will require researchers to consider sex and gender specifically as variables, which science has been slow to do. Over the past 30 years, for example, researchers hoping to understand age-related cognitive decline have generally analyzed data from men and women collectively, obscuring differences between the sexes as far as when deficits tend to appear and how to diagnose them. “We need to think about designing studies from the outset in a way that’s relevant for women and men,” says Janine Austin Clayton, director of the Office of Research on Women’s Health at the National Institutes of Health. “Men and women both undergo chronological aging and reproductive aging, but in distinct ways,” she says. “Not looking at those separately masks findings and is a missed opportunity.”
Another challenge is separating the impacts on health caused by aging versus those caused by the hormonal changes that accompany menopause. Ideally, you would compare a large number of women who are experiencing them to women of the same age who are not. But by their 50s, most women have reached perimenopause; by their 60s, almost all are postmenopausal. Mosconi and her colleagues accounted for this by comparing women with age-matched men. But, as Stephanie Faubion, director of the Mayo Clinic Center for Women’s Health and medical director of the NAMS, points out, “Men’s brains are going to be different than women’s.”
The fact that women can experience significant brain changes around menopause also raises questions about how commonly this happens and the extent to which it affects women’s daily lives, says Pauline Maki, a professor of psychiatry, psychology and obstetrics & gynecology at the University of Illinois at Chicago College of Medicine. It’s crucial to note, she says, that women frequently report cognitive deficits around menopause, and that such symptoms are usually temporary. But her work has shown that they are more likely to have a lasting impact on low-income women of color — probably, she says, because those women have higher rates of stress, disrupted sleep and other mental-health burdens that “make the brain more vulnerable.”
Conversely, there are a number of possible preventive measures to protect cognitive health before and after the menopause transition. Abstaining from tobacco, being physically active, eating a plant-rich diet, reducing stress and getting enough sleep — these are all ways to support brain function. “Menopause is a critical window, when a woman might begin to develop the first signs of chronic disease,” Clayton says. As such, it’s an important time for her to check in with her health care provider and discuss her reproductive history and menopause status, each of which can influence her disease risk and treatment options. In turn, providers of all kinds need to be prepared to care for women throughout their transition: “It’s not just in the realm of gynecology,” Faubion says, “and we have to stop thinking of it that way.”
Kim Tingley is a contributing writer for the magazine.
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