New research provides evidence that women using birth control pills experience different stress and inflammation responses compared to those not using these contraceptives. The findings, published in Brain, Behavior, and Immunity, shed light on the complex ways in which hormonal contraceptives can influence the body’s psychophysiological reactions.
For years, hormonal contraceptives, commonly known as birth control pills, have been an important part of many women’s lives. Over 300 million women worldwide use them. While these pills are well-studied for their safety and effectiveness in preventing pregnancy, researchers are still uncovering how they might affect other aspects of health. A small but growing body of research has suggested that these contraceptives might have unintended effects on women’s bodies, particularly in how they react to stress and inflammation.
Central to understanding these effects is the hypothalamic-pituitary-adrenal (HPA) axis, a major part of the body’s stress response system. This axis involves a complex set of interactions among the hypothalamus, the pituitary gland, and the adrenal glands, leading to the release of cortisol, a key stress hormone. It’s known that hormonal contraceptives can influence the functioning of the HPA axis, but the specifics of this interaction and its implications for stress and inflammation in women remain an area of active research.
“Women make up half the world’s population, however, we know very little about stress-related biology in women, due to an historic lack of inclusion of women and female animals in clinical and preclinical research until the early 90s,” said study author Summer Mengelkoch, a postdoctoral fellow in the Laboratory for Stress Assessment and Research at UCLA.
“In 1992, researchers found that men exhibit elevated cortisol reactivity following stress compared to naturally cycling women, who exhibit higher cortisol reactivity following stress compared to women using hormonal contraceptives.”
“Although hormonal mechanisms were suggested, they were not assessed. Thirty years later, researchers have yet to determine why or how sex differences in stress reactivity reliably occur, nor how, mechanistically, hormonal contraceptive use blunts cortisol reactivity. Understanding the mechanisms underlying female-specific hypothalamic-pituitary-adrenal (HPA) axis reactivity is important, as HPA axis dysregulation is a strong predictor of depression and anxiety disorders.”
For their study, the researchers recruited 75 women who were not using hormonal contraceptives (referred to as naturally cycling women) and 78 women who were current users of combined oral contraceptive pills. To ensure accurate comparisons, the study carefully selected participants based on their health status and contraceptive use history. The researchers scheduled their participation during specific times in their menstrual cycles to account for natural hormonal fluctuations.
The heart of the study was the Trier Social Stress Test, a well-established method for inducing stress in a laboratory setting. Participants were asked to prepare and deliver a speech, followed by a mental arithmetic task, both performed under the watchful eye of a researcher. This setup was designed to mimic real-life stressful situations. The researchers measured participants’ stress and mood levels at various points during the study, as well as collected saliva samples to analyze biological markers of stress and inflammation.
The findings revealed several key differences between the two groups of women. Women using hormonal contraceptives reported higher levels of subjective stress throughout the study. Biologically, they showed a more significant increase in cortisol levels in response to stress.
Furthermore, increases in cortisol were associated with more negative mood changes after the stressor in women using contraceptives. This association was not seen in women not using contraceptives.
In addition, women using hormonal contraceptives exhibited a decrease in certain inflammatory markers (like IL-1β) following stress, a pattern not observed in naturally cycling women. Interestingly, no significant changes were seen in another inflammatory marker, IL-6, in response to stress in either group.
Women using hormonal contraceptives also exhibited higher levels of tumor necrosis factor-alpha (TNF-α) across time points. TNF-α is another marker involved in inflammation, and its elevated levels in hormonal contraceptive users suggest a different pattern of inflammatory response.
“I was expecting to find hormonal contraceptive users to have a blunted cortisol and exaggerated inflammatory response to an acute psychosocial stressor,” Mengelkoch told PsyPost. “Instead, I found mixed patterns of inflammatory responses. Although hormonal contraceptive users did differ from naturally cycling women in their inflammatory responses to stress, the findings were not as straightforward as I had predicted.”
These findings suggest that birth control pills might influence how the body responds to stress, both psychologically and biologically, particularly in the context of inflammatory responses.
“For women, being able to control their own fertility is revolutionary, and for most women, the potential unintended consequences of hormonal contraceptive use are likely worth these benefits during at least some periods of their lives,” Mengelkoch said. “However, some types of hormonal contraceptive use, for some women, alter HPA axis reactivity and increase their risk of developing mood related disorders. This study provides the first evidence that beyond impacting cortisol responses to stress, hormonal contraceptive use also impacts inflammatory responses to stress.”
While the study provides important insights, the study — like all research — includes some limitations. For instance, the study didn’t include a control group of women who weren’t subjected to stress, which could have provided additional context for the findings. Additionally, the study was conducted during a global pandemic, a time of heightened stress for many, which may have influenced the results.
Future research should aim to replicate these findings in different settings and include a broader range of hormonal contraceptives. Understanding the full scope of how birth control pills affect women’s health beyond contraception is vital for informed healthcare choices.
“This is the first empirical study to test how hormonal contraceptive use impacts women’s inflammatory responses to stress in vivo,” Mengelkoch said. “The study was also conducted during the COVID-19 pandemic, and high levels of chronic stress during the study period may have impacted stress reactivity. In replications, I hope to explore how hormonal contraceptive use onset impacts stress-related gene expression, to get a better mechanistic understanding of the biological pathways through which hormonal contraceptive use impacts stress reactivity and inflammatory processes that have far reaching health consequences.”
“This work will also help me to pinpoint what components of hormonal contraceptives are having the largest effects on stress reactivity, as there are hundreds of formulations of hormonal contraceptives on the market today, which likely have different effects on stress reactivity and inflammation. I limited my current investigation to 1st-3rd generation oral hormonal contraceptive pills, however, even within these, there are quite a few variations (e.g., combo pills vs progestin only pills, different types of progestins, different dosages).”
“To do this work ethically, I would like to stress that hormonal contraceptive use is safe and effective,” Mengelkoch added. “However, we don’t know enough about the potential downstream side effects of their use to appropriately weigh the costs and benefits for individual women throughout their lives. For women or adolescent girls at a high risk of developing mood-related disorders, there might be some hormonal contraceptive formulations that are going to increase this risk, and other formulations that are going to decrease this risk.”
“I hope that my work will advance a precision medicine approach to hormonal contraceptive recommendations, so that each woman can make a truly informed decision with her doctor about her contraceptive use. To do this, we need funding for basic science research to investigate how endogenous and exogenous sex steroid hormones impact stress, inflammation, and risk for mood-related disorders.”
The study, “Hormonal contraceptive use is associated with differences in women’s inflammatory and psychological reactivity to an acute social stressor“, was authored by Summer Mengelkoch, Jeffrey Gassen, George M. Slavich, and Sarah E. Hill.
