EXECUTIVE SUMMARY
More research is needed to learn how hormonal contraceptives affect the brain — both cognition and depression. Recent studies suggest some actions that may be beneficial.
- Major depression among users of the oral contraceptive pill (OCP) was 4.6%, compared to 11.4% of women who used to take the pill, one study finds.
- Other research reports that daily emotions, recorded in an online survey over 75 days, did not vary between men and women or women using OCP and those with natural cycles.
- Lower estradiol activities seem to be related to improved 3D spatial skills, another study shows.
Reproductive health clinicians need to know more about recent research into how hormonal contraception affects the brain, both cognitively and related to depression and behavior, new research suggests.1,2
Studies offer an intriguing glimpse at possible effects on cognition and suggest much more research is needed to better understand whether and how oral contraceptive pills may alter mood and depression.
“Hormonal contraceptives are not all created equal. Different hormonal contraceptives have different contraceptive mechanisms, and that relates directly or indirectly to how exogenous hormones can impact behavior,” says Adriene Beltz, PhD, lead study author and an associate professor of psychology at the University of Michigan in Ann Arbor. “Basically, the different hormones in hormonal contraceptives, and the ways they work in the body, differ across forms.”
The authors of a separate study found the prevalence of major depression among women using oral contraceptive pills may be lower than in former users of oral contraceptive pills.3
“We found that former pill users were more likely to report depression compared to women using the pill currently,” says Julia Gawronska, PhD, a postdoctoral research fellow at The Center for Health, Performance and Wellbeing at Anglia Ruskin University in Cambridge, England.
Common Misconception
There is a common misconception about the oral contraceptive pill (OCP) causing depression, Gawronska notes. Women who worry about depression and choose not to use effective contraceptive methods put themselves at risk of unintended pregnancies.
“Overall, the prevalence of major depression among users of the oral contraceptive pill was 4.6%, compared to 11.4% of women who used to take the pill,” Gawronska says. “We found statistical significance.”
Gawronska and colleagues concluded that estimates of women experiencing depressive symptoms while taking OCP may be misleadingly low, partly because women who experience depression may discontinue OCP use.3 “We are not saying the pill is improving depression or helping women,” Gawronska explains. “We’re thinking the findings are the result of the fact that the women who stop taking the pill are in a group that is more likely to experience depressive symptoms.”
Demographic factors may play a role in women’s experience with depressive symptoms. For instance, women who are divorced or separated, current smokers, earn low incomes, and have high body mass index are more likely to report experiencing depression.3
In an earlier study, Beltz and colleagues hypothesized that non-OCP users with a natural menstrual cycle would experience more mood cycling than pill users.4
“We looked at the positive and negative aspects of emotion,” Beltz says. “We looked at how emotion varied across days — the emotional ups and downs.”
Study participants included OCP users, naturally cycling women, and men. OCP users took one of three pill formulations for at least three months. Everyone reported daily emotions via a nightly 20-minute online survey over a 75-day period. Beltz and colleagues found that gender did not matter in emotions. Men and women reported similar levels of affective variability. Also, both women using OCP and those with natural cycles reported similar emotional findings.4
“If hormones mattered most for emotion, then the oral contraceptive pill users would be a bit more stable emotionally than non-pill users, but that’s not what we found at all,” Beltz says. “That represents the complexity of emotion and the fact that it’s influenced by many different things throughout the day and many different scenarios and stressors. Hormones might matter somewhat for some people, but they don’t drive emotions for everyone.”
Effects on Spatial Cognition
Another interesting new finding involves spatial cognition. “One area where we see these differences is in my work and some other recent work that has tracked the exogenous or external estradiol that pills with lower doses or lower estradiol activities seem to be related to improved spatial skills — particularly 3D spatial skills,” Beltz says.
It is a standard test of spatial cognition to ask people to look at 2D space and imagine what it looks like in 3D space. People who take hormonal oral contraception show better spatial cognition on these tests. Studies show that oral contraception formulations with androgenic progestins facilitate 3D mental rotations performance.1,5-7
“Possible effects on cognitive and perceptual processes have received only limited research attention to date,” says Elizabeth Hampson, PhD, a professor in the department of psychology and core member of the graduate program in neuroscience at Western University in London, Canada. Hampson answered questions via email. (For more information, see the Q&A on OC research in this issue.) “What makes such effects plausible, however, is that the human CNS [central nervous system] contains receptors for both estrogens and progesterone — and androgens, too, which are regionally expressed throughout the brain. The regions where receptors are present include parts of the cerebral cortex and limbic system.”
These are regions known to be important in cognitive processing and regulation of mood. “Interestingly, recent studies using functional magnetic resonance imaging — a brain imaging technique used to detect changes in the activity and connectivity of brain regions — have shown changes in brain activation of these same regions in oral contraceptive users compared with non-users,” Hampson says. “Whether this translates into any detectable changes in cognition function has not been established yet.”
Hormonal contraception’s positive effect on 3D spatial skills is small, and it depends on the type of pill. “Lower doses of ethinyl estradiol are related to better spatial skills. Estradiol is one component of pills, and the other component is progestin,” Beltz explains. “The particular progestins that facilitate better spatial skills are those with levonorgestrel and norethindrone acetate.”
Research with those pills provides a clear picture. “If the pills are working like they should, they basically shut down the ovaries,” Beltz says.
What researchers have not yet found is any difference in oral contraceptive users’ personalities and gender self-concept when compared with non-users. “We have not found differences in folks who used the pills from those who don’t, and we wouldn’t expect to,” Beltz says. “We interpret this as there’s not different types of folks who are using the pill, and that hormone influences from the pill do not change our behavior wholesale or our personality.”
Oral contraceptive pills do not change who someone is, but they appear to have more focused influences — persistent, small effects — on spatial skills.
“If cognitive side effects do exist in oral contraceptive users, they are likely to be mild and likely to be highly selective effects,” Hampson says. “We wouldn’t expect to find any across-the-board effects on cognition.”
For instance, researchers suggested that combined oral contraceptives might positively affect verbal fluency, Hampson adds. This would mean a facility in generating appropriate words, sentences, or phrases when speaking. However, the finding is tentative because the evidence is preliminary. Any effects may depend on the dosage of the contraceptives used or which variety of progestins they contain.
What is more important to contraceptive care and counseling is for prescribers to screen women for depression and inform them about potential mood effects, offering them alternative contraception options depending on their individual needs.
“Even if women do not have depression at initiation, they should still be told about potential mood effects,” Gawronska says. “Those likely to experience depressive symptoms experience them at the beginning of taking the contraceptive pill.”
Other women might experience depressive symptoms later in life, so all women should be informed. “Contraception is a crucial component of preventive healthcare, and most women tolerate oral contraceptive pills without experiencing depressive symptoms,” Gawronska says. “However, there is a subset of vulnerable women who may experience adverse mood side effects and even develop depression while using OCP, and the reasons are not entirely clear.”
What clinicians should know is that this group of women is likely to discontinue OCP use. Providers need to be ready to help them find another method of their choice.
“Our study has found that former users of the OCP are significantly more likely to report major depression compared to women currently using the pill,” she adds. “We think the significantly lower prevalence of depression amongst the group using the OCP is likely to be due to survivor bias, with women who experience symptoms of depression more likely to discontinue taking it.”
Gawronska’s study is cross-sectional. Women were measured for depression at one point in their lives, so investigators cannot say whether the pill causes depression.
“Some studies have shown us that once folks have been using a hormonal contraceptive for a while — up to four or five years — their depression risk actually decreases,” Beltz says.
The research paints a picture of how starting new hormonal contraceptives, especially for adolescents, might lead to an increased risk of depression. But over time, it might lower depressive risk for some people, Beltz adds.
“We need a longitudinal study,” Gawronska says. “In this paper, we looked at whether there is a difference between current users, former users, and never users. We didn’t find a [statistical] difference in depression between current users and never users.”
Women seeking OCP should be screened routinely for depression and offered alternative contraception if they indicate a desire to stop taking OCP.
“Only the individual, in collaboration with the healthcare provider, can do the complex calculus involved in assessing risk,” Beltz says.
Robert A. Hatcher, MD, MPH, chairman of the Contraceptive Technology Update editorial board, notes, “Many factors may be affecting the health and happiness of women we see in family planning clinics: the right of individual women to terminate an unwanted pregnancy, COVID, antisemitism, international unrest, political chaos in our own country, and loneliness afflicting all age groups in our society. All these contribute to depression in our land. Our society as a whole and each individual must work alone and with groups to address these issues that threaten personal and societal peace and happiness.”
REFERENCES
- Beltz AM. Hormonal contraceptive influences on cognition and psychopathology: Past methods, present inferences, and future directions. Front Neuroendocrinol 2022;67:101037.
- Beltz AM, Hampson E, Berenbaum SA. Oral contraceptives and cognition: A role for ethinyl estradiol. Horm Behav 2015;74: 209-217.
- Gawronska J, Meads C, Smith L, et al. Association of oral contraceptive pill use and depression among US women. J Affect Disord 2024;344:132-140.
- Weigard A, Loviska AM, Beltz AM. Little evidence for sex or ovarian hormone influences on affective variability. Sci Rep 2021;11:20925.
- Beltz AM, Moser JS. Ovarian hormones: A long overlooked but critical contributor to cognitive brain structures and function. Ann N Y Acad Sci 2020;1464:156-180.
- Laird S, Ney LJ, Felmingham KL, Gogos A. Hormonal contraception and the brain: Examining cognition and psychiatric disorders. Curr Psychiatry Res Rev 2019;15:116-131.
- Pletzer BA, Kerschbaum HH. 50 years of hormonal contraception: Time to find out, what it does to our brain. Front Neurosci 2014;8:256.
More research is needed to learn how hormonal contraceptives affect the brain — both cognition and depression. Recent studies suggest some actions that may be beneficial.
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