Illustration: Marina Muun/Knowable
- Perimenopause is the time in most women’s lives when menstrual cycles become irregular and fertility wanes.
- During this transition, many women experience a suite of changes, including hot flashes, disrupted sleep and mood swings.
- Women with a history of depression are more vulnerable: during perimenopause, they are twice as likely to experience debilitating depressive disorder than women who haven’t had past episodes.
- As researchers probe for reasons why some women fall prey to depression at this time and others don’t, a leading candidate has emerged: fluctuating levels of estrogen.
In May of 2018, Tabitha Bird spent a memorable day with her eldest son at a comic book convention in London. Later that evening, after she made sure that her two younger kids were safely tucked up in bed, Bird gathered every sleeping tablet, antidepressant, anti-anxiety med and ibuprofen pill she could find and walked out of the house. She drove to a nearby store where she bought a big bottle of water and some acetaminophen. Then she stopped in an empty industrial park and began to take the lot.
Bird woke up from a coma four days later. The 47-year-old, from a town in West Sussex in the UK, now attributes her suicide attempt and the depression leading up to it to perimenopause – the time in most women’s lives when menstrual cycles become irregular and fertility wanes.
During this transition, many women experience a suite of changes, including hot flashes, disrupted sleep and mood swings. Some breeze through perimenopause with little difficulty, but many – about 45% to 68% – experience depression, symptoms of which can include low mood, a loss of interest in things and even thoughts of suicide. Women with a history of depression, like Bird – who also suffered with it while pregnant – are the most vulnerable. During perimenopause, they are twice as likely to experience debilitating full-blown depressive disorder than women who haven’t had past episodes.
As researchers probe for reasons why some women fall prey to depression at this time and others don’t, a leading candidate has emerged: widely fluctuating levels of the sex hormone estrogen. Estrogen directs fertility, but mounting research shows that it also holds sway on parts of the brain involved in regulating emotion and stress.
“There is quite strong evidence that there is a special kind of depression linked to the hormonal changes,” says Pauline Maki, a researcher in the neuropsychiatry of women’s health at the University of Illinois at Chicago.
The good news is that women don’t have to just grin and bear it. Over the past decade, several large studies have shown that perimenopausal depression can be effectively treated. Antidepressants and psychotherapy work for many women. And a body of research finds that hormone therapy – in which patients take a low dose of estrogen or other hormones to supplement what the body makes – can treat or even prevent depression symptoms.
But many doctors are reluctant to prescribe hormone therapy amid concerns that it could raise the risk of heart attacks and breast cancer, a finding from a decades-old study that focused on post-menopausal women. Science has since clarified instances in which the treatment’s benefits outweigh the risks, yet these lingering fears have stymied both research and women’s use of hormone therapy in treating depression, says Maki.
And medical education often skips over menopause, producing doctors who don’t know how to recognise the menopause transition, let alone connect it to episodes of depression, researchers say. Consequently, many people suffer because their mental health symptoms are missed, dismissed or ineffectively treated.
Bird was one such patient. She had experienced a plethora of symptoms that included hot flashes, disturbed sleep and changes in mood and menstrual flow in the lead-up to her suicide attempt. “Looking back now, I can see this was the beginning of my perimenopause,” she says. But her doctor, she adds, doubted that it was linked to her depression.
Maki says it is all too common for health-care workers to overlook symptoms of the menopause transition. “The major problem in women’s midlife health right now is that providers just aren’t trained. It’s quite appalling.”
Estrogen and the brain
Many women are accustomed to the emotional ups and downs that can accompany the run-up to menstruation. These monthly mood swings coincide with fluxes of a suite of hormones. These include progesterone, which is made in the ovaries and encourages the uterus lining to thicken, and other hormones regulating ovulation that are secreted from the brain’s pituitary gland and hypothalamus.
But of all the reproductive hormones, estrogen is the most formidable. It’s produced in the ovaries, and its levels rise and fall over the typical 28-day menstrual cycle to direct local tasks such as helping to spark ovulation and preparing the lining of the uterus for fertilisation. Estrogen also orchestrates an array of activities in the brain.
As women transition toward menopause, these hormonal fluxes become extreme. Estrogen, in particular, can ebb and flow wildly – soaring to levels three times that of younger women or dipping to post-menopausal lows. The brain feels the impact of these fluctuations as much as five years before the rest of the body does, says Jayashri Kulkarni, a psychiatrist specialising in women’s mental health at Monash University in Australia.
“The brain is the first organ that starts to register the menopausal process. It’s happening before the hot flashes, before the menstrual cycle starts to change,” Kulkarni says.
In the past decade, a clearer picture has emerged of estrogen’s role in the brain. Estrogen receptors are present in the hippocampus, amygdala and hypothalamus, regions that are important to cognition, emotional processing and stress responses. Before perimenopause hits, the hormone, in the form of circulating estradiol, helps keep these systems running smoothly, says Paul Newhouse, who investigates cognitive and neuropsychiatric disorders at Vanderbilt University in Nashville, Tennessee.
Estrogen’s buffering effect plays out in a number of ways. The hormone can influence mood by way of its positive effect on serotonin, the mood-regulating neurotransmitter, for example. Animal studies show that estrogen increases the density of serotonin receptors in rats’ brains, potentially helping buoy mood. It also seems to enhance the antidepressant effects of selective serotonin-reuptake inhibitors (SSRIs) in women.
Estrogen also helps to balance activity between areas of the brain that traffic in emotions: The hippocampus and the amygdala are both involved in recognising, assessing and responding to emotional information. Neuroimaging studies show that when estrogen levels dip, the amygdala becomes more active. This may make negative information seem more important and can prolong the body’s response to stress. When estrogen levels are higher, images show that the hippocampus is more active, helping to regulate the amygdala and creating a more balanced emotional and cognitive response. Overall, estrogen appears to temper women’s response to negative and stressful information, helping them react with a more positive outlook.
“High estrogen levels essentially ‘protect’ the activity of these regulatory structures” in the brain, says Newhouse, coauthor of an overview on estrogen’s role in depression in the 2019 Annual Review of Clinical Psychology.
But during the transition to menopause, that changes, he says. Women who are already vulnerable to depression may plunge back into it when they lose the buffering effects of estrogen. This includes women who experience severe depression and anxiety during their menstrual cycle, who may also be more likely to experience depression due to the sudden hormonal shifts of pregnancy and childbirth. Similarly, it is these women who are more likely to be struck by perimenopausal depression.
Bird falls into this group. She suffered sudden crippling bouts of depression and anger while pregnant with her two youngest children. Usually she is very easygoing, she says. But one day, while carrying her daughter, she stepped out in front of a bus with the intension of ending her own life. And while pregnant with her youngest son, she felt so angry that she threw a cup of coffee at her husband.
“I’m not that type of person,” she says. “It does completely change your personality.”
A landmark study published in JAMA Psychiatry in 2015 demonstrated that women with a history of depression are more sensitive to changing levels of estrogen and that those fluctuations can trigger severe depression. Healthy postmenopausal women, some with a history of depression and some without, were given estradiol through a skin patch. After three weeks, some women from each group got a placebo instead of the estradiol. Roughly 80% of the women who had suffered with severe depression in the past experienced a recurrence when estrogen was withdrawn and they were switched to the placebo, the National Institutes of Health study found. But those with no history of depression were fine when the estrogen was taken away.
Maki says that this “very important study” clearly suggested a link between loss of estrogen and depression and that there is a category of women who are sensitive to estrogen withdrawal.
More recent studies support the link between depression and estrogen during perimenopause. Researchers from Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues, measured estrogen levels in blood serum of 50 women, ages 35 to 56, over a period of eight weeks. The most variable estrogen levels were linked to greater depressive symptoms, the team reported in the Journal of Clinical Endocrinology & Metabolism in 2020. A follow-up study found that feelings of irritability are common among mildly depressed perimenopausal women.
Researchers are also learning more about the group of women whose mood is susceptible to estrogen fluctuations. A recent study suggests that estrogen-sensitive women fall into three groups: those whose mood slumps when estrogen declines, those who feel low when estrogen rises high and those who are sensitive to large shifts in either direction. The study could help explain other conflicting results concerning whether sensitivity to high versus low estrogen levels plays a role in perimenopausal depression.
The reasons for the differences between women’s response to estrogen aren’t clear, says Newhouse. But some researchers suggest it may be down to variations in the way enzymes biosynthesise estradiol or the hormone’s role in protein production.
Of course, estrogen isn’t the only factor tipping people over the edge to a depression in midlife. For some, the perimenopausal years can feel like life is piling on. Hot flashes and poor sleep can worsen mood. Careers near their peak, and children fly the nest, or parents grow older, requiring more care. These challenges can drag people down, says Maki. Women who don’t have a partner or are in unhappy relationships are also more likely to feel low during the menopause transition. Some evidence suggests that women of color are more at risk, as are those with less formal education or who are financially hard-up, research shows.
While estrogen clearly can play a critical role in whether someone sinks into perimenopausal depression, for others a mix of shifting hormones, changes in social circumstances and physiological issues like hot flashes, may tip the scales, says Kulkarni. Doctors need to be aware of these interacting factors to recognise and treat depression during the menopause transition, she says.
Beating the blues
As scientists learn more about who is susceptible to perimenopausal blues, they are also coming to grips with how best to help people beat it.
For those who are affected by estrogen withdrawal, topping up estrogen can help. Several small but strong studies demonstrate that replenishing the body’s estrogen – alone and in combination with progestin, a synthetic hormone with properties similar to progesterone – is effective at treating depressive symptoms experienced during the transition to menopause. For example, a trial of 50 perimenopausal women with depression found that 68% felt their symptoms improve with estradiol, a team reported in JAMA Psychiatry in 2001.
Other research shows estrogen can boost or speed up the mood-enhancing effects of antidepressants. A small study of 17 women between the ages of 40 and 60 years who were taking antidepressants for major depression found that estrogen significantly improved their mood compared with a placebo. A larger study of 293 depressed post-menopausal women found that mood improved in nearly 84% of those who used an antidepressant and hormone therapy compared with 63% of those who just used antidepressants.
Hormone therapy may even help prevent the onset of depression. Research has found that a regimen of estrogen administered as a skin patch, along with a pill containing a synthetic hormone with an identical structure to progesterone, is better than a placebo at preventing depression in 172 women in their perimenopausal and early postmenopausal years. Just 17% of women on the hormone therapy developed depression compared with 32% taking the placebo.
Estrogen therapy also boosts low mood following a hysterectomy that removes both ovaries, known as surgical menopause. It is even helpful in treating post-traumatic stress, research suggests. A study found that women who had been sexually assaulted were less likely to experience intrusive flashbacks of the trauma if they took emergency contraceptive containing estrogen and progestin compared to progestin only or none at all.
“This is a genius study,” says Newhouse. “It suggests that estradiol levels can impact how the brain responds to, organises and maybe even remembers extremely stressful events.”
Despite estrogen’s clear mood-enhancing effects, its use in treating depression is still controversial, partly because a large, highly publicised study from nearly 20 years ago found that hormone therapy raised the risk of breast cancer, heart attacks and stroke. Since then, research has clarified that the increased cardiovascular risks are mainly in cases of older women who re-started combined estrogen and progestin therapy after menopause.
Research is also working to clarify the connection between hormone therapy and breast cancer. Most menopause specialists’ interpretation of the data is that hormone therapy is linked to a small increase in breast cancer risk, raising the risk to a level slightly above that attributed to drinking one glass of wine per day (annually, one additional case of breast cancer for every 1,000 users).
But the type of hormone therapy can affect the risk. Studies have found that estrogen taken alone can protect against breast cancer. But estrogen is typically prescribed only to women who have undergone a hysterectomy as too much of the hormone can cause uterine cancer; women with an intact uterus take a combined therapy of estrogen and progestin or synthetic bioidentical progesterone. A recent large study of women with an average age of 63 years found that out of 8,506 women taking combined estrogen and progestin, some 584 developed breast cancer, compared to 447 cases among 8,102 women taking a placebo. But the study did not find that significantly more women died from breast cancer as a result of taking combined hormone therapy.
These findings are backed up by another recent study that shows an increase in rates of breast cancer in women taking estrogen and progestin. Both studies contradict earlier findings of a higher risk of breast cancer among all types of hormone therapy.
The stigma attached to hormone therapy has stuck around, Kulkarni says.
And there are still questions about how best to use estrogen to treat depression, says Jennifer Gordon, a clinical psychologist at the University of Regina in Saskatchewan, Canada, who studies how female reproductive hormones affect mood. For example, it’s not clear if estrogen works better when administered as a skin patch or orally, she says. The US Food and Drug Administration has not approved estrogen to treat low mood and depression. The North American Menopause Society suggests that estrogen can augment antidepressants but urges caution in the hormone’s use, advising doctors to limit prescription to people who have additional symptoms such as hot flashes.
Doctors reach for antidepressants first because most people who suffer with major depression during midlife have a history of the disease, says Maki, who helped write the society’s menopause guidelines.
This is Bird’s experience. She is now taking very strong antidepressants that worked for a while, though they made her feel numb. But recently, she adds, feelings of anger and irritability started to sometimes break through. Bird had come to accept that she will take antidepressants for the rest of her life but began to wonder whether hormone therapy could help too.
Kulkarni is concerned that a failure in care for women in midlife is contributing to high suicide rates in this age group. In Australia, the highest female suicide rate is among women aged 45–49. A similar trend is seen in the US and the UK. Kulkarni wants to see hormone therapy play a more prominent role for people like Bird and others with a similar psychological history. “If you recognise there’s a hormone factor that’s leading to depression, common sense says it needs to be a hormone solution,” she says.
But medication and hormones are not the only option, says Gordon. Her research shows that yoga and meditation can help to prevent depressive symptoms as the menstrual cycle wanes, even for people with a history of severe depression.
A push for more awareness
Despite a range of treatments available, many people in need are not reached. Stephanie Faubion, a clinical researcher specialising in menopause at the Mayo Clinic in Jacksonville, Florida and medical director of the North American Menopause Society, says that a major hurdle is that doctors of a broad array of specialties are not taught about menopause. Those specialties include psychiatry and gynecology. Consequently, a number of related midlife health issues are often overlooked, she says. “Depression is one of many symptoms that goes undiagnosed and untreated at this time.”
Some medical societies are now working together to increase awareness of changes common around menopause and to improve diagnosis and treatment of related problems, says Faubion. For example, the American Medical Women’s Association, which aims to support women working in medicine and women’s health issues, is advocating for clinicians to hold regular health visits for people as they approach menopause. The North American Menopause Society contributes to this initiative, and it also provides training for health-care practitioners. Faubion says the society has pushed for more menopause education in medical school curriculums and doctors’ residency programs but it has been a hard sell.
In the meantime, people may at least help themselves by seeking care when they are struggling with their mood, says Faubion. There are even technologies and apps that track reproductive changes that can help individuals understand their symptoms and make a case to their healthcare provider.
But if doctors dismiss concerns that low mood could be linked to perimenopause, people must not give up, says Bird. She says she was discouraged that her doctor didn’t do more for her – still, she persisted and has since seen a menopause specialist who prescribed hormone replacement therapy.
“You need to go back to the doctor,” she says. “Don’t let them fob you off.”
Natasha Gilbert is a freelance reporter based in Washington DC who covers the environment, agriculture and sustainability. She’s a good listener, a keen observer and a bit of a cynic. Check out her work at bynatashagilbert.com or @ngreports.
This article originally appeared in Knowable Magazine, an independent journalistic endeavor from Annual Reviews.