Open this photo in gallery PhD candidate Laura Gravelsins, one of the reachers at University of Toronto's Einstein Lab who is studying the effects of hormonal contraceptives on the brain, poses for a portrait at in a testing room at the University in Toronto, March 29, 2019. Cole Burston

A new Canadian study on how the birth control pill affects a woman’s ability to think is the latest to address a decades-old knowledge gap researchers say needs to be fixed: How oral contraceptives impact the brain.

The study aims to test the working memory of around 60 young women who use oral contraceptives, says researcher Laura Gravelsins, a PhD student with the Einstein Lab on cognitive neuroscience, gender and health at the University of Toronto.

Gravelsins is among a number of researchers exploring an area that has historically been overlooked. Since the introduction of the pill in the 1960s, hormonal contraceptives – which contain estrogen, progestin, or a combination of both – have become a preferred option for many women. Yet, due, in part, to past assumptions that the brain operates separately from the rest of body and a general lack of research into women’s health, scientists are only now investigating how they may influence mood and cognition.

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Another area that needs exploration is how sex hormones, including those naturally produced by the body, influence developing brains. At the University of British Columbia, researchers are currently recruiting 300 girls, ages 13 to 15, to study what role sex hormones may play in their emotional development.

“We need more research,” says Dr. Gillian Einstein, a professor of psychology at University of Toronto and the Wilfred and Joyce Posluns Chair in Women’s Brain Health and Aging. “Women should demand more research on this.”

According to a 2015 Statistics Canada report, an estimated 1.3 million, or 16 per cent of non-pregnant women, ages 15 to 49, used oral contraceptives in the previous month. The prevalence was highest among girls, ages 15 to 19, with nearly 30 per cent reporting they used them.

More recent data from the Society of Obstetricians and Gynaecologists of Canada show oral contraceptive pills have plummeted in popularity among teens, ages 15 to 19, from 69 per cent in 2006 to 32 per cent in 2016. (Condoms were most frequently used.) However, other types of hormonal contraceptives may be gaining favour. In 2018, the Canadian Paediatric Society recommended long-acting reversible contraceptives, including hormone-releasing intrauterine devices, as a first-line option for young Canadians.

While hormonal contraceptives have been studied for decades, researchers and doctors have focused on the physical health risks related to their use, such as osteoporosis or blood clots, Gravelsins says. Much less attention has been paid to potential mood swings or how they may affect learning and memory, since the body and the brain have long been thought of as separate systems.

The existing literature provides a contradictory and incomplete picture of their effects on mood and cognition. In a 2016 countrywide study, for instance, researchers in Denmark found the use of hormonal contraceptives, including pills, patches, vaginal ring and hormone-releasing uterine devices, was tied to a higher risk of depression. However, other studies, including a 2013 U.S. study, have found they actually reduced symptoms of depression in women.

Not only does this mean scientists have little knowledge of how hormonal contraceptives may affect the brains of young women, including the developing brains of adolescents, it is also unknown how or whether they change the brain over the long-term, says Einstein, whose research is supported in part by the Women’s Brain Health Initiative.

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“The question becomes if you’re taking oral contraception for 20 years, might that have effects? And I don’t think we know that answer at all,” she says.

This knowledge gap is part of a broader historical lack of research into women’s health in general, says Dr. Amy Miller, chief executive officer of the non-profit Society for Women’s Health Research, based in Washington.

Until about 30 years ago, women were actively excluded in all kinds of medical clinical trials, since researchers were worried about the potential for harming undetected pregnancies and assumed that hormonal fluctuations made the female body too complicated to study, Miller explains.

“The consequence is, unfortunately, making health care decisions with the best available evidence, which is often lacking,” Miller says.

In recent years, however, due, in part, to the advocacy of organizations such as Miller’s and to advances in the study of how other types of hormones affect the brain, research into the potential mood and cognitive effects of hormonal contraceptives has taken off.

While mood changes were once dismissed as a coincidence, likely unrelated to the use of oral contraceptives, “I think we’re moving to a place now where we can say that is not the case – that there are women who are going to have a negative response because of the pill,” says Dr. Nicole Petersen, a postdoctoral fellow at the Semel Institute for Neuroscience and Behaviour at the University of California, Los Angeles.

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Still, she adds, not all women react the same way, and it’s yet unknown why.

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Petersen has conducted several brain-imaging studies that have found differences in the brain structure and activity between women who used oral contraceptives and those who didn’t. For example, one study showed oral contraceptive users had a thinner cortex in two regions of the brain.

However, she emphasizes it’s difficult to interpret what these differences in brain imaging mean in terms of how women actually experience the world. She also noted her studies compared women who were on oral contraceptives with those who weren’t – two groups that may be fundamentally very different from one another.

To address some of these study limitations, she is now conducting a randomized controlled trial that compares women against themselves to examine any changes in their mood and emotional regulation when they are given either a placebo or an oral contraceptive.

At the University of Toronto, Gravelsins is testing women’s working memory, or the ability to simultaneously retain and manipulate information, such as when performing complex math problems, an hour or two after they take an oral contraceptive, when hormone levels spike. She is testing them again around 24 hours afterward, when hormone levels decline, to see if and how their performance changes as the hormones are metabolized throughout the day.

Meanwhile, Dr. Frances Chen, an assistant professor of psychology who is leading the UBC study, explains that hormonal contraceptives have traditionally been designed for use by adult women. But researchers have yet to understand whether and how these medications interact with hormones naturally produced during puberty to influence girls’ emotions, behaviour and mental health.