New research provides evidence that women who use birth control pills experience different stress and inflammation responses compared to those who do not use these contraceptives. The findings, published in Brain, behavior and immunityshed 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. More than 300 million women around the world use them. While these pills are well-studied for their safety and effectiveness in preventing pregnancy, researchers are still discovering how they might affect other aspects of health. A small but growing body of research has suggested that these contraceptives could have unwanted effects on women’s bodies, particularly on how they react to stress and inflammation.
Critical to understanding these effects is the hypothalamic-pituitary-adrenal (HPA) axis, an important part of the body’s stress response system. This axis involves a complex set of interactions between the hypothalamus, pituitary gland, and adrenal glands, leading to the release of cortisol, a key stress hormone. It is known that hormonal contraceptives can influence the functioning of the HPA axis, but the details of this interaction and its implications for stress and inflammation in women remain an area of active research.
“Women make up half of the world’s population, yet we know very little about the biology related to stress in women, due to a historical lack of inclusion of women and female animals in clinical and preclinical research until the early 1920s. 90s,” said study author Summer. Mengelkoch, a postdoctoral fellow at the UCLA Stress Assessment and Research Laboratory.
“In 1992, researchers found that men exhibit greater cortisol reactivity after stress compared to women who cycle naturally, who exhibit greater cortisol reactivity after stress compared to women who use hormonal contraceptives.”
“Although hormonal mechanisms were suggested, they were not evaluated. Thirty years later, researchers have yet to determine why or how sex differences in stress reactivity reliably occur, nor how, mechanistically, hormonal contraceptive use mitigates 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 (known 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 history of contraceptive use. The researchers timed 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 of inducing stress in a laboratory. Participants were asked to prepare and deliver a speech, followed by a mental calculation task, both performed under the watchful eye of a researcher. This setup was designed to mimic stressful real-life situations. The researchers measured participants’ stress levels and mood at various points during the study, in addition to collecting 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.
Additionally, increases in cortisol were associated with more negative mood changes following the stressor in women using contraceptives. This association was not observed in women who did not use contraception.
Additionally, women who used hormonal contraceptives showed a decrease in certain inflammatory markers (such as IL-1β) after stress, a pattern not seen in women who cycle naturally. Interestingly, no significant changes in another inflammatory marker, IL-6, were observed in response to stress in either group.
Women using hormonal contraceptives also exhibited higher levels of tumor necrosis factor alpha (TNF-α) at all 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 expected to find that hormonal contraceptive users would have reduced cortisol and an exaggerated inflammatory response to an acute psychosocial stressor,” Mengelkoch told PsyPost. “Instead, I found mixed patterns of inflammatory responses. Although hormonal contraceptive users differed from naturally cycling women in their inflammatory responses to stress, the findings were not as straightforward as she had predicted.”
These findings suggest that birth control pills could influence the way 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 probably justify these benefits during at least some periods of their lives,” Mengelkoch said. “However, some types of hormonal contraceptives, in some women, alter the reactivity of the HPA axis and increase the risk of developing mood-related disorders. “This study provides the first evidence that beyond affecting cortisol responses to stress, hormonal contraceptive use also affects inflammatory responses to stress.”
Although the study provides important information, like all research, it includes some limitations. For example, the study did not include a control group of women who were not under stress, which could have provided additional context for the findings. Additionally, the study was conducted during a global pandemic, a time of increased stress for many, which may have influenced the results.
Future research should attempt 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 to making informed healthcare decisions.
“This is the first empirical study to test how hormonal contraceptive use affects 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 affected stress reactivity. In replications, I hope to explore how the initiation of hormonal contraceptive use impacts stress-related gene expression, to gain a better mechanistic understanding of the biological pathways through which hormonal contraceptive use impacts stress reactivity and outcomes. inflammatory processes that have far-reaching consequences for health.”
“This work will also help me identify which components of hormonal contraceptives have the greatest effects on stress reactivity, as there are hundreds of hormonal contraceptive formulations on the market today, which likely have different effects on stress reactivity. and inflammation. I limited my current research to first and third generation oral hormonal contraceptive pills; However, even within these, there are quite a few variations (e.g., combination pills versus progestin-only pills, different types of progestins, different doses).”
“To do this work ethically, I would like to emphasize that the use of hormonal contraceptives is safe and effective,” Mengelkoch added. “However, we do not know enough about the possible side effects of its use to adequately weigh the costs and benefits for each woman throughout her life. For women or adolescents at high risk of developing mood-related disorders, there may be some hormonal contraceptive formulations that will increase this risk and other formulations that will decrease this risk.”
“I hope my work advances a precision medicine approach to hormonal contraceptive recommendations, so that every woman can make a truly informed decision with her doctor about her contraceptive use. To do this, we need funding for basic science research that investigates how endogenous and exogenous sex steroid hormones impact stress, inflammation, and the risk of 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.