The first sign something was amiss was the tiredness. Then I started forgetting where I had left my phone or keys, only to find them in the fridge or kitchen cupboard. The breaking point came when I went to make a cup of tea before an important interview, only to return 45 minutes later to a string of increasingly irritated emails asking why I wasn’t on the call. I had been potting houseplants instead.
As a woman in my early 40s, I was aware of this thing called perimenopause looming. But were my symptoms related to this, or just a product of getting older, or simply down to the mental load of juggling work, family and social demands?
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Teasing out what is perimenopause and what is just life is difficult, but the run-up to menopause can bring some alarming symptoms – not least cognitive ones, such as difficulty recalling names, trouble concentrating and putting keys in the fridge.
“We now know that up to 62 per cent of all perimenopausal and postmenopausal women report these [cognitive symptoms], which can be so severe as to spark fears around early-onset dementia,” says , director of the Women’s Brain Initiative at Weill Cornell Medicine in New York.
Though long ignored or dismissed as inevitable consequences of ageing, the neurological manifestations of menopause are finally drawing scientific interest. It is increasingly clear brain changes occur during this period – and that some can ultimately be positive. More than that, these changes demonstrate that menopause may offer a crucial window for protecting brain health. The question is how.
Your brain on hormones
Menopause occurs when a person with a uterus stops menstruating and their ovaries stop producing significant amounts of and , the two main sex hormones that regulate female reproduction. This usually happens between the ages of about 45 and 55, but it can also happen earlier, whether naturally or because of the removal or impairment of the ovaries. Perimenopause is the warm-up to this transition, beginning up to a decade before a woman’s final period.
The brain is closely connected to the ovaries via a network of glands, and many brain regions possess receptors for reproductive hormones, allowing those hormones to directly influence brain function, development and cognition. The most studied of these is oestradiol, the primary form of the oestrogen hormone that is produced during women’s reproductive years. In the brain, it protects neurons from damage, stimulates the growth of new ones and interacts with neurotransmitters involved in concentration, processing information and regulating emotions.
“During menopause we have this profound loss of oestradiol in particular, and these oestrogen receptors in the brain, they’re sort of starved for attention,” says , who studies sex hormones and cognition at the Centre for Addiction and Mental Health in Toronto, Canada.
However, these hormones don’t simply disappear overnight. “It’s a very volatile process where the system fails, then a kind of backup generator kicks in and works for a while, and then the system fails again, which is why you have these massive and very volatile hormonal fluctuations,” says , a neuroscientist at Diakonhjemmet Hospital in Oslo, Norway.
Hormonal roller-coaster
The brain doesn’t respond well to such fluctuations. “We don’t like hormonal surges, we don’t like hormonal withdrawal,” says , director of the Women’s Mental Health Research Program at the University of Illinois in Chicago. “That variability also likely contributes to the memory problems that many women experience during perimenopause.”
The “brain fog” that many women report during perimenopause is real: studies consistently demonstrate that there is a small but measurable decline in the ability to learn, and to recall both new information, such as recently made appointments, and previously known information, such as your spouse’s name. While cognitive performance remains within normal limits for most women during this phase – and on par with men of the same age – around 1 in 10 experience . The transition is also accompanied by structural changes in the brain. “We and others have found alterations in brain structure, metabolism, connectivity and biochemistry in many parts of the brain, including regions vulnerable to Alzheimer’s,” says Mosconi.
But are the symptoms of cognitive impairment, as well as the structural changes to the brain, temporary, or could they have longer-term consequences? Answering this question has taken decades, in part because of the chronic lack of funding for research into women’s health. “People will say, ‘It’s a niche area; it’s not important to study because it only happens to a subset of the population’,” says Galea. “Which is hilarious, because we are 50 per cent of the population.”
The field also experienced a significant setback in the early 2000s, after a major trial exploring the effects of hormone replacement therapy (HRT) nearly brought research into the menopausal brain to a standstill.
Investigating HRT
For women going through menopause, HRT involves taking a combination of oestrogen and progestogen, a hormone that mimics progesterone and reduces the risk of uterine cancers; because oestrogen can, over time, encourage the problematic build-up of the uterine lining and increase cancer risk, is only offered to women who have had their uterus removed. Through the 1980s and 90s, small studies indicated that and reduced anxiety in menopausal women; suggested HRT might be protective against Alzheimer’s disease, which is and tends to result in more severe symptoms. In 2000, Maki and her colleague Susan Resnik found that in areas of the brain associated with memory performance, more so than in women not taking exogenous oestrogen; this was, she says, the first direct evidence linking sex hormones and memory function in women.
Meanwhile, the trials, a large-scale effort to establish whether HRT was beneficial for long-term health, were under way. Maki, who was involved with this work, expected these studies to confirm the beneficial effects of hormone therapy. Instead, in July 2000, WHI investigators announced that they were stopping the main trial three years early: data suggested that HRT was associated with in the risk of cardiovascular disease and breast cancer, while in the risk of dementia and cognitive decline.
“This wasn’t just a study of a few people – it was thousands of people, billions of dollars, published in a high-impact journal. So it was big news,” says , a consultant psychiatrist at the National Female Hormone Clinic at the Maudsley Hospital in London. The effect was immediate: “Overnight, everyone came off HRT, and the funding for this area disappeared.”
Though the failed trials set HRT research back, they did reveal important nuances in how sex hormones work in the brain. We now know that the type of oestrogen matters significantly. That used in the WHI trials was derived from the urine of pregnant horses and mostly consisted of oestrone, a relatively weak form of the hormone. Galea’s research has since shown that giving oestrone to rats that had their ovaries removed to mimic menopause reduced the number of new neurons in the hippocampus, an area of the brain involved in memory-making, learning and emotional regulation. Giving oestradiol, which binds more strongly to oestrogen receptors than other forms of the hormone, however, . show that administering progestogen alongside oestradiol inhibits that neuronal growth – painting a complex picture of both the effect of sex hormones on the brain and how to manipulate that effect.
The WHI study also demonstrated that the timing of HRT is significant. When the study launched, most women started the therapy in their early 50s. But most of the trial participants, who hadn’t previously been on HRT, were in their 60s and 70s, sometimes decades past their last period. This was largely for statistical reasons: if you want to establish whether HRT prevents age-related conditions such as Alzheimer’s and cardiovascular disease, you will be waiting a long time to find out if your participants are only just starting to go through menopause at the time of their recruitment.
A critical window
More recent evidence indicates, however, that there might be a “window of opportunity” for preventing dementia, and that some HRT is beneficial if started at the onset of menopause symptoms or soon after. examining data from 51 studies found that women who started oestrogen-only therapy within 10 years of their final menstruation were at significantly decreased risk of Alzheimer’s later in life, compared with women who didn’t have HRT.
“The theory is that during this period, the brain may be more receptive to the positive effects of exogenous oestrogen on brain health, potentially slowing cognitive decline,” says Mosconi, the senior study author. “Starting hormone therapy much later, specifically more than a decade after menopause, does not seem to provide the same cognitive benefits and could carry higher risks.”
In the decades since the end of the WHI trials, a tide of evidence has swept away many of the concerns about the safety of HRT – particularly for modern formulations – while menopause awareness campaigns and celebrity endorsements have encouraged greater discussion about the risks and benefits of the therapy. has underscored that HRT, especially in women starting the therapy before age 65, is unlikely to increase dementia or cognitive impairment risks, and that other health risks of HRT should be weighed against its overall benefits. And though research into HRT’s , many women report that the therapy gave them back their sense of self.
However, the idea of prescribing HRT for dementia prevention alone isn’t yet recommended – not least because it is unclear who would benefit. For one thing, oestrogen-only therapy, which seems to carry the most protective benefits, is recommended solely for women who have had a hysterectomy. And though around two-thirds of women who go through menopause experience cognitive challenges during that time, only around . In most cases, the memory deficits many women experience during the menopause transition .
“Obviously in the moment, it sucks for the woman who is having a hard time adjusting, but after it’s done, the brain should be able to recover,” says , a neuroscientist at the University of Groningen in the Netherlands.
Who is at risk – and how to help them
But for some women – particularly those whose brains might be more vulnerable to the menopausal drop in oestradiol – recovering from what should be temporary challenges might be more difficult. Identifying these women will help researchers determine who may be at a higher risk of developing dementia and investigate whether targeted interventions, including HRT, could help.
So far, studies suggest that may be associated with a higher risk of dementia, compared with women who experience it naturally in their 40s or 50s. Menopause can be induced surgically, by the removal of the ovaries, or medically, in the course of treating other conditions. “They also experience more severe menopause symptoms, probably because the brain experiences more of a shock,” says Gervais. Those carrying genetic risk factors for Alzheimer’s disease may also be less resilient during the time around menopause. For some women, and – whether as a result of the demands of life or associated with changes during this transition, or both – can also play a role in the development of dementia.
“Menopause offers a valuable opportunity to identify and address these vulnerabilities before the disease has a chance to take hold,” says Mosconi.
One promising approach could be to focus on specific symptoms. Hot flushes are a common menopause symptom thought to stem from the effects of declining oestrogen on the brain region that controls body temperature. Maki’s research suggests that more severe hot flushes, particularly if they continue for many years, are associated with poorer memory performance, tiny stroke-like lesions in the brain and the . This may imply that hot flushes directly impact memory circuits in the brain; treating hot flushes might affect the progression of cognitive decline.
Researchers are also investigating selective oestrogen receptor modulators (SERMs), drugs that mimic the effects of the hormone in some parts of the body, but not others. Mosconi is currently involved in trials of , which is designed to trigger oestrogen receptors in the brain without affecting those in the uterus. If effective, this could negate the need for women to take progesterone and raise the possibility of using oestrogen protectively.
Not just oestrogen and progesterone
Besides oestrogen, other hormones are also affected by the menopause transition, . FSH stimulates the ovaries to mature eggs each month and to produce oestrogen; as women’s supply of eggs dwindles and levels of oestrogen drop, FSH levels climb higher in response and remain elevated even once menopause is over. Animal studies have suggested that this hormonal shift could contribute to and , prompting efforts to develop an FSH-blocking antibody to improve bone health and reduce weight gain. However, FSH receptors are also abundant in the brain – implying that FSH also plays a role in cognitive function.
Over the past five years, at Icahn School of Medicine at Mount Sinai in New York and neuroscientist at Shenzhen Institute of Advanced Technology in China have been exploring whether FSH-blocking antibodies could also influence the development of Alzheimer’s in mice that are bred to be genetically prone to the disease. So far, . Zaidi and Ye’s studies in female mice that had their ovaries removed showed that FSH accelerated the buildup of amyloid beta plaques and tau tangles associated with Alzheimer’s in their brains, speeding up cognitive decline; in the mice.
“We’re not disputing that reduced oestrogen may contribute to memory loss, but high levels of FSH post-menopause may also play a direct role in memory loss, particularly spatial memory and recognition memory,” says Zaidi, who hopes to begin safety trials of the antibody in humans later this year.
Ye points out that there is a period during early perimenopause when oestrogen levels are relatively stable, but FSH is rising sharply: “During this period, there is a transient decline in cognitive performance, especially verbal memory,” he says. It is possible that FSH, rather than oestrogen, is to blame.
Most experts agree that conventional HRT, particularly when initiated at the start of menopausal symptoms, is an effective way of combating the short-term cognitive symptoms associated with perimenopause. Early initiation of HRT could also help keep FSH levels in check, says Ye.
Don’t fear the menopause
After my morning spent repotting plants and not on my work call, I started speaking with older female friends about the problems that I had been experiencing. They reassured me that it wasn’t, in fact, early-onset dementia; several suggested trying HRT. I have been taking oestrogen and progestogen for the past two years and I am pleased to report that I am feeling much more like my old self – and haven’t discovered any keys nested amongst the yoghurt pots for some time.
That said, HRT isn’t a solution for everyone, which is why exploring alternatives such as blocking FSH is important. There are also non-hormonal ways that women can reduce their risk of developing dementia, including eating more healthily, getting regular exercise, reducing stress and alcohol consumption, and not smoking. Helpfully, these same strategies can reduce many troublesome menopause symptoms.
However, despite its challenges, menopause isn’t some looming monster we should fear. In fact, the neuronal rewiring that occurs during this transition might even be beneficial, with women emerging from it enjoying a more stable mood and improved emotional well-being.
“Many experts, myself included, believe that menopause is actually a renovation project on the brain,” says Mosconi. “After menopause, all those neurons and connections between neurons that were needed to support ovulation and enable a pregnancy are no longer needed and can be discarded. It’s the brain’s chance to get ‘leaner and meaner’, if you will. This can lead to some glitches – but also has some advantages.”
