Hormonal Contraception Linked to Increased Risk of Depression

In 2010, Nancy Gibbs, writing for Time magazine on the 50^th anniversary of the Food and Drug Administration’s approval of the birth control pill, described what was, to date, one of the largest studies looking at the long term effects of the use of hormonal contraception. She wrote that the study demonstrated that women taking the birth control pill significantly reduced their risk of premature death, yet “many women still question whether the health risks outweigh the benefits.” Every packet of birth control pills comes with a comprehensive list of possible side effects, from nausea to increased risk of blood clots. Some studies have also suggested that the use of hormonal contraception may be linked to mood disturbances—though the evidence has been somewhat contradictory. Now, a large-scale study out of the University of Copenhagen in Denmark suggests that use of hormonal contraception like the birth control pill is associated with a first diagnosis of depression.

Hormones, contraception, and mood

Changing levels of cycling hormones like estrogen and progestin govern a woman’s monthly menstrual cycle, including triggering ovulation, or the release of an egg from the ovary, and the preparation of the uterus for implantation of a potentially fertilized egg. Hormonal contraception like the birth control pill, the patch, or the vaginal ring contain synthetic forms of these female sex hormones to even out levels over the course of the menstrual cycle, inhibiting ovulation and implantation in the process. It is one of the most reliable forms of birth control available to women.

“Virtually all women of reproductive age who have ever been sexually active have used at least one contraceptive method at some point in their life—that’s about 99 percent of all American women. The most recent national data suggest that about 62 percent of women in the US are currently using some form of birth control,” says Megan Kavanaugh, a senior research scientist at the Guttmacher Institute. “The three most common methods used are oral contraceptive pills—about 26 percent of that 62 percent are using those—with the second most common being sterilization followed third by condoms. And there’s a reason why so many women use the pill. It works quite well for preventing pregnancy, which has a number of social and economic benefits to the individual. But use of the pill can also have other benefits including regulation of the menstrual cycle, treating of premenstrual syndrome (PMS) and premenstrual dysmorphic disorder (PMDD), and the decreased risk of certain cancers.”

Converging evidence suggests that the same hormones that regulate fertility also influence mental health (See “Sex Differences and the Brain”). Emily Jacobs, a neuroscientist at the University of California Santa Barbara, says that it’s now known that persistent maladaptive responses to stressors can lead to mood disorders—and many of the brain regions that regulate stress response are densely populated with estrogen receptors.

“It’s possible that dampening the natural fluctuations of sex steroid hormones with chronic oral contraceptive use could dysregulate activity in stress circuitry and, in turn, increase risk for mood disorders,” she says.

Øjvind Lidegaard, a gynecologist at the University of Copenhagen, says that many women do report feelings of diminished mood after being prescribed the pill.

“This is something that many women report after commencing use of oral contraception—and more women than you would expect just by the general occurrence of depression,” he says. “So it was something we felt that we needed to take a more systematic look at.”

A health registry of millions

In Denmark, approximately 40 percent of women use hormonal contraception, says Lidegaard. Because Denmark is unique in its administration of a national health service register that collects medical and mental health data from all people living in the country, he and his colleagues could look for a potential link between hormonal contraception use and later depression in a large patient sample. They looked at more than one million females between the ages of 15 and 34 who had no major psychiatric diagnosis and had not redeemed any prescription for antidepressant medication when they had been prescribed hormonal contraception; the researchers then traced the women’s medical history over the next few years. The results were published in JAMA Psychiatry on Sept. 28, 2016.

“Even after only six months of use, we saw 40 percent more use of antidepressants in women taking hormonal contraception than those who did not,” says Lidegaard. “We were even more surprised to see that in teenagers, women aged 15 to 19, the increase was closer to 80 percent. Perhaps I should not have been so surprised as many parents I know with teenage daughters say they can be very sensitive at this time. But this suggests the teenage years may be a very vulnerable period of time for women to take exogenous hormones.” The absolute risk of getting depression in women 15-19 years old is about 1 percent per year; if they took hormonal contraceptive products the risk rose to 1.8 percent per year, and was cumulative: If they were on for five years, their absolute risk would be 9 percent, Lidegaard said.

He and colleagues controlled for environmental factors such as smoking, social class, body mass index, and polycystic ovarian syndrome in their analysis—and still saw the same increased risk. And while he says it cannot definitively prove causation, he believes it shows a strong association that needs to be considered.

“Even when we controlled for these factors, the risk estimate didn’t change,” he says. “So when I’m asked if there might be other explanations for why these women are getting depressed outside of the use of oral contraception, we did not see any evidence for what that other thing could be.”

Moving forward

Kavanaugh says that the results of this study are striking but that we, as a society, should be careful about how they might be applied.

“We certainly don’t want to discount these findings—but we need to take this study in light of the broader literature that is available to us. There are other studies that suggest that women in their mid-20s may show a decreased risk of depression when they use hormonal contraception,” she says. “Hormonal contraception has a whole host of positive benefits for women. So we really need more research to tease out what this link really is so that patients can have the information they need to make an informed decision when weighing those risks and benefits.”

Lidegaard agrees. He would like to see this study replicated and a more open discussion of risks with women before birth control pills are prescribed. One thing he does not want to see is an outright ban on hormonal contraception.

“I still recommend hormonal contraception. And here in Denmark we have one of the highest percentages of use of hormonal contraception in the world,” he says. “So we are not against hormonal contraception, but we think it is important that women get the right information about the benefits and the risks so they can make an informed decision. And I also think that doctors need to be more careful about taking good medical histories in terms of previous depression so we do not prescribe products that can worsen a patient’s condition.”

Jacobs’s lab will soon launch a new study to look at the effects of long-term oral contraceptive use on brain structure and function.

“We need studies like these to shed light on potential issues. Women have been taking birth control pills for a long time and we don’t have the answers to a lot of our questions about what they may be doing,” she says. “So we need more and more good science around these things—when it comes to women’s health and the brain, there’s a lot of catch-up we need to do.”