What happen When Depression Sneaks up on Menopause?

 

 •Perimenopause is the period in most women's lives when their menstrual cycles become irregular and their fertility begins to decline.
•Many women experience a variety of changes during this time, including hot flashes, disrupted sleep, and mood swings.
•Women with a history of depression are more vulnerable: during perimenopause, they are twice as likely as women without a history of depression to experience debilitating depressive disorder.
•As researchers investigate why some women experience depression at this time of year while others do not, a leading candidate has emerged: fluctuating oestrogen levels.

 

Tabitha Bird spent a memorable day with her eldest son at a comic book convention in London in May of 2018. Bird walked out of the house later that evening, after making sure her two younger children were safely tucked up in bed. She gathered every sleeping tablet, antidepressant, anti-anxiety medication, and ibuprofen pill she could find. She drove to a nearby store and purchased a large bottle of water as well as some acetaminophen. Then she came to a halt in the middle of an empty industrial park and began to take the lot.

 

Four days later, Bird awoke from a coma. The 47-year-old from West Sussex, UK, now blames her suicide attempt and the depression that preceded it on perimenopause – the period in most women's lives when menstrual cycles become irregular and fertility declines.

 

Many women experience a variety of changes during this time, including hot flashes, disrupted sleep, and mood swings. Some women breeze through perimenopause with ease, but many – approximately 45 percent to 68 percent – experience depression, with symptoms including low mood, loss of interest in things, and even suicidal ideation. Women with a history of depression, such as Bird, who also suffered from it while pregnant, are especially vulnerable. They are twice as likely to experience debilitating full-blown depressive disorder during perimenopause as women who haven't had previous episodes.

 

As researchers investigate why some women experience depression at this time of year while others do not, a leading candidate has emerged: widely fluctuating levels of the sex hormone oestrogen. Estrogen regulates fertility, but new research indicates that it also has an impact on parts of the brain that regulate emotion and stress.

"There is quite strong evidence that there is a special kind of depression linked to hormonal changes," says Pauline Maki, a University of Illinois at Chicago researcher in the neuropsychiatry of women's health.

 

The good news is that women are not forced to grin and bear it. Several large studies over the last decade have shown that perimenopausal depression can be effectively treated. Many women benefit from antidepressants and psychotherapy. And a growing body of evidence suggests that hormone therapy – in which patients receive a low dose of oestrogen or other hormones to supplement what the body produces – can treat or even prevent depression symptoms.

 

However, many doctors are hesitant to prescribe hormone therapy due to concerns that it may increase the risk of heart attacks and breast cancer, according to a decades-old study of postmenopausal women. Despite the fact that science has since clarified instances in which the treatment's benefits outweigh the risks, these lingering concerns have stymied both research and women's use of hormone therapy in treating depression, according to Maki.

 

According to the researchers, medical education frequently skips over menopause, producing doctors who don't know how to recognise the menopause transition, let alone connect it to episodes of depression. As a result, many people suffer because their mental health symptoms are overlooked, dismissed, or treated ineffectively.
 
Bird was one of these patients. She had a slew of symptoms leading up to her suicide attempt, including hot flashes, insomnia, mood swings, and changes in menstrual flow. "Looking back, I can see that this was the start of my perimenopause," she says. Her doctor, she adds, was sceptical that it was related to her depression.
 
According to Maki, it is all too common for health-care workers to ignore symptoms of menopause transition. "The main issue in women's midlife health right now is that providers are simply untrained." It's truly horrifying."

 

Oestrogen and the brain

Many women are used to the emotional ups and downs that come with the menstrual cycle. These monthly mood swings correspond to changes in a number of hormones. These include progesterone, which is produced in the ovaries and encourages the uterine lining to thicken, as well as other ovulation-regulating hormones secreted by the pituitary gland and hypothalamus in the brain.
 
However, oestrogen is the most potent of the reproductive hormones. It is produced in the ovaries, and its levels rise and fall during the typical 28-day menstrual cycle to direct local tasks such as assisting in the initiation of ovulation and preparing the uterine lining for fertilisation. Oestrogen also orchestrates a variety of brain activities.
 
These hormonal fluctuations become more pronounced as women approach menopause. Oestrogen, in particular, can fluctuate wildly, reaching levels three times those of younger women or plummeting to post-menopausal lows. According to Jayashri Kulkarni, a psychiatrist specialising in women's mental health at Monash University in Australia, the brain feels the effects of these fluctuations up to five years before the rest of the body.
 
"The brain is the first organ to detect the menopausal process." "It happens before the hot flashes, before the menstrual cycle changes," Kulkarni explains.
 
Over the last decade, a clearer picture of oestrogen’s role in the brain has emerged. Oestrogen receptors are found in the hippocampus, amygdala, and hypothalamus, all of which are involved in cognition, emotional processing, and stress responses. According to Paul Newhouse, a cognitive and neuropsychiatric disorders researcher at Vanderbilt University in Nashville, Tennessee, the hormone, in the form of circulating estradiol, helps keep these systems running smoothly before perimenopause.
 
Oestrogen’s buffering effect manifests itself in a variety of ways. For example, the hormone can influence mood by positively affecting serotonin, a mood-regulating neurotransmitter. According to animal studies, oestrogen increases the density of serotonin receptors in rats' brains, potentially helping to lift mood. In addition, it appears to boost the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) in women.
Oestrogen also helps to balance activity in brain areas that deal with emotions, such as the hippocampus and the amygdala, which are both involved in recognising, assessing, and responding to emotional information. According to neuroimaging studies, when oestrogen levels fall, the amygdala becomes more active. This can make negative information appear more significant and prolong the body's response to stress. Images show that when oestrogen levels are higher, the hippocampus becomes more active, assisting in the regulation of the amygdala and creating a more balanced emotional and cognitive response. Overall, oestrogen appears to moderate women's reactions to negative and stressful information, allowing them to respond with a more positive outlook.
 
"High oestrogen levels essentially 'protect' the activity of these regulatory structures" in the brain, according to Newhouse, co-author of an overview on oestrogen’s role in depression published in the 2019 Annual Review of Clinical Psychology.
 
That changes, he says, during the menopause transition. Women who are already predisposed to depression may relapse once the protective effects of oestrogen wear off. This includes women who experience severe depression and anxiety during their menstrual cycle, as well as women who are more likely to experience depression as a result of the abrupt hormonal shifts associated with pregnancy and childbirth. Similarly, these women are more likely to suffer from perimenopausal depression.

 

This category includes birds. During her two youngest children's pregnancies, she experienced crippling bouts of depression and rage. She describes herself as "usually very easygoing." But one day, while carrying her daughter, she stepped out in front of a bus, intending to commit suicide. And, while pregnant with her third child, she became so enraged that she threw a cup of coffee at her husband.

 

"I'm not that kind of person," she explains. "It completely alters your personality."

 

 

Oestrogen receptors in the brain

A seminal study published in JAMA Psychiatry in 2015 found that women with a history of depression are more sensitive to changes in oestrogen levels, and that these fluctuations can lead to severe depression. Estradiol was administered via skin patch to healthy postmenopausal women, some of whom had a history of depression and others who did not. After three weeks, some women in each group were given a placebo instead of oestradiol. According to the National Institutes of Health study, when oestrogen was removed and the women were switched to a placebo, roughly 80% of the women who had previously suffered from severe depression experienced a recurrence. Those who had no history of depression, on the other hand, were fine when the oestrogen was removed.
 
According to Maki, this "very important study" clearly suggested a link between oestrogen deficiency and depression, and that there is a subset of women who are sensitive to oestrogen withdrawal.
 
Recent research backs up the link between depression and oestrogen during perimenopause. Over an eight-week period, researchers from Brigham and Women's Hospital and Harvard Medical School in Boston and colleagues measured oestrogen levels in the blood serum of 50 women ranging in age from 35 to 56. The team reported in the Journal of Clinical Endocrinology & Metabolism in 2020 that the most variable oestrogen levels were associated with more depressive symptoms. A follow-up study discovered that irritability is common among mildly depressed perimenopausal women.
 
Researchers are also learning more about the subset of women whose moods are influenced by oestrogen fluctuations. According to a recent study, oestrogen-sensitive women are divided into three groups: those who experience mood swings when oestrogen levels fall, those who experience mood swings when oestrogen levels rise, and those who are sensitive to large changes in either direction. The findings could help to explain other contradictory findings about whether sensitivity to high versus low oestrogen levels plays a role in perimenopausal depression.
 
According to Newhouse, the reasons for the differences in women's oestrogen responses are unclear. However, some researchers believe it could be due to differences in the way enzymes biosynthesise oestradiol or the hormone's role in protein production.

 

As oestrogen levels changes, women’s response vary

Of course, oestrogen isn't the only factor that pushes people into midlife depression. For some, the perimenopausal years can feel like a never-ending stream of events. Hot flashes and lack of sleep can both have a negative impact on mood. Careers are nearing the pinnacle, children are leaving the nest, or parents are getting older and require more care. According to Maki, these difficulties can bring people down. Women who do not have a partner or are in an unhappy relationship are more likely to experience depression during the menopause transition. According to research, women of colour are more at risk, as are those with less formal education or who are financially disadvantaged.
 
While oestrogen clearly plays a role in whether someone develops perimenopausal depression, for others, a combination of shifting hormones, changes in social circumstances, and physiological issues such as hot flashes may tip the scales, according to Kulkarni. According to her, doctors must be aware of these interacting factors in order to recognise and treat depression during the menopause transition.

 

Beating the blues

Scientists are learning more about who is susceptible to perimenopausal blues and how to best help people overcome it.
 
Top-up oestrogen can help those suffering from oestrogen withdrawal. Several small but significant studies show that replenishing the body's oestrogen – both alone and in combination with progestin, a synthetic hormone with properties similar to progesterone – is effective in treating depressive symptoms associated with the menopause transition. For example, a team reported in JAMA Psychiatry in 2001 that in a trial of 50 perimenopausal women with depression, 68 percent felt their symptoms improved with oestradiol.
 
Other research indicates that oestrogen can enhance or hasten the mood-enhancing effects of antidepressants. A small study of 17 women aged 40 to 60 who were taking antidepressants for major depression discovered that oestrogen significantly improved their mood when compared to a placebo. In a larger study of 293 depressed postmenopausal women, mood improved in nearly 84 percent of those who used an antidepressant and hormone therapy, compared to 63 percent of those who only used antidepressants.
 

Oestrogen improves mood in depressed women 

Hormone therapy may even aid in the prevention of depression. A skin patch regimen of oestrogen, combined with a pill containing a synthetic hormone with an identical structure to progesterone, was found to be more effective than a placebo in preventing depression in 172 women in their perimenopausal and early postmenopausal years. Only 17% of women receiving hormone therapy developed depression, compared to 32% of those receiving a placebo.
 
Oestrogen therapy also improves mood after a hysterectomy, which removes both ovaries, a condition known as surgical menopause. According to research, it can even help with the treatment of post-traumatic stress disorder. According to one study, women who had been sexually assaulted were less likely to have intrusive flashbacks of the trauma if they used an emergency contraceptive that contained both oestrogen and progestin, as opposed to progestin only or none at all.
 
"This is a brilliant study," Newhouse says. "It implies that oestradiol levels can influence how the brain responds to, organises, and possibly even remembers extremely stressful events."
 
Despite oestrogen’s obvious mood-enhancing effects, its use in treating depression remains controversial, in part because a large, widely publicised study conducted nearly 20 years ago discovered that hormone therapy increased the risk of breast cancer, heart attacks, and stroke. Since then, research has revealed that the increased cardiovascular risks occur primarily in older women who resumed combined oestrogen and progestin therapy after menopause.
 
In addition, research is being conducted to determine the relationship between hormone therapy and breast cancer. According to the majority of menopause specialists, hormone therapy is associated with a small increase in breast cancer risk, raising the risk to a level slightly higher than that associated with drinking one glass of wine per day (annually, one additional case of breast cancer for every 1,000 users).
 
However, the type of hormone therapy used can influence the risk. Breast cancer can be prevented by taking oestrogen alone, according to research. However, oestrogen is typically only prescribed to women who have had a hysterectomy because too much of the hormone can cause uterine cancer; women with an intact uterus receive combined oestrogen and progestin therapy or synthetic bioidentical progesterone. A recent large study of 8,506 women with an average age of 63 years found that 584 developed breast cancer among 8,506 women taking combined oestrogen and progestin, compared to 447 cases among 8,102 women taking a placebo. However, the study found that taking combined hormone therapy did not result in a significant increase in the number of women dying from breast cancer.
 
These findings are supported by a recent study that found an increase in breast cancer rates in women taking oestrogen and progestin. Both studies contradict previous findings that all types of hormone therapy increase the risk of breast cancer.
 
According to Kulkarni, the stigma associated with hormone therapy has persisted.
 
And, according to Jennifer Gordon, a clinical psychologist at the University of Regina in Saskatchewan, Canada, who studies how female reproductive hormones affect mood, there are still questions about how best to use oestrogen to treat depression. For example, it's unclear whether oestrogen works better when applied topically or orally, she says. The FDA has not approved oestrogen for the treatment of low mood and depression. The North American Menopause Society suggests that oestrogen can supplement antidepressants, but advises doctors to limit prescriptions to people who have additional symptoms such as hot flashes.

 

According to Maki, who helped write the society's menopause guidelines, doctors first turn to antidepressants because most people who suffer from major depression during midlife have a history of the disease.

 

This is Bird's perspective. She is now on very strong antidepressants, which worked for a while but made her numb. But, she adds, feelings of rage and irritability have recently begun to surface. Bird had accepted that she would have to take antidepressants for the rest of her life, but she began to wonder if hormone therapy could help as well.

 

Kulkarni is concerned that a lack of care for women in their forties is contributing to high suicide rates in this age group. Women aged 45–49 have the highest female suicide rate in Australia. A similar pattern can be seen in the United States and the United Kingdom. Kulkarni would like to see hormone therapy play a larger role in the lives of people like Bird and others with similar psychological histories. "If you recognise that there is a hormone factor that is causing depression, common sense dictates that there must be a hormone solution," she says.

 

Gordon, on the other hand, believes that medication and hormone therapy are not the only options. Her research shows that yoga and meditation, even in people with a history of severe depression, can help to prevent depressive symptoms as the menstrual cycle progresses.

 

A push for more awareness

Despite the availability of a variety of treatments, many people in need are not reached. According to Stephanie Faubion, a clinical researcher specialising in menopause at the Mayo Clinic in Jacksonville, Florida, and the medical director of the North American Menopause Society, a major barrier is that doctors from a wide range of specialties are not taught about menopause. Among these specialties are psychiatry and gynaecology. As a result, she claims, a number of related midlife health issues are frequently overlooked. "At the moment, depression is one of many symptoms that go undiagnosed and untreated."
 
According to Faubion, some medical societies are now collaborating to raise awareness of the changes that occur during menopause and to improve diagnosis and treatment of related problems. The American Medical Women's Association, for example, which aims to support women in medicine and women's health issues, is advocating for clinicians to conduct regular health visits for people approaching menopause. The North American Menopause Society contributes to this initiative and also provides health-care practitioners with training. According to Faubion, society has pushed for more menopause education in medical school curricula and doctor residency programmes, but it has been a difficult sell.
 
Meanwhile, people can help themselves by seeking help if they are struggling with their mood, according to Faubion. There are even technologies and apps that track reproductive changes, which can help people understand their symptoms and make a case to their doctor.
 
However, if doctors dismiss concerns that low mood may be linked to perimenopause, people should not give up, according to Bird. She was disappointed that her doctor didn't do more for her, but she persevered and has since seen a menopause specialist who prescribed hormone replacement therapy.
 
"You need to see the doctor again," she says. "Don't let them dupe you."