New research provides evidence that women who use birth control pills experience different stress and inflammatory responses than women 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 responses.
Hormonal contraceptives, commonly known as birth control pills, have been an important part of many women’s lives for years. More than 300 million women worldwide use them. Although these pills have been well studied for their safety and effectiveness in preventing pregnancy, researchers are still discovering how they may affect other aspects of health. A small but growing body of research has suggested that these contraceptives may have unintended effects on women’s bodies, especially in the way they respond to stress and inflammation.
Central 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, an important stress hormone. It is 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 of the world’s population, yet we know very little about stress-related biology in women, due to a historical lack of involvement of women and female animals in clinical and preclinical research until the early 1990s,” says study author Summer. Mengelkoch, a postdoctoral researcher at the Laboratory for Stress Assessment and Research at UCLA.
“In 1992, researchers found that men show increased cortisol reactivity after stress compared to women undergoing natural cycling, who show higher cortisol reactivity after stress compared to women using hormonal contraceptives.”
“Although hormonal mechanisms were suggested, these were not assessed. Thirty years later, researchers have yet to determine why or how sex differences in stress reactivity reliably occur, nor how hormonal contraceptive use mechanistically blunts cortisol reactivity. Understanding the mechanisms underlying female-specific reactivity of the hypothalamic-pituitary-adrenal (HPA) axis is important because 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 (also called natural 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 scheduled their participation at specific times in their menstrual cycle to account for natural hormonal fluctuations.
The core of the study was the Trier Social Stress Test, a proven method for inducing stress in a laboratory environment. 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 is designed to mimic real-life stressful situations. The researchers measured participants’ stress and mood levels at various points during the study, and collected saliva samples to analyze biological markers of stress and inflammation.
The findings revealed some important differences between the two groups of women. Women who used hormonal contraceptives reported higher levels of subjective stress during 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 swings after the stressor in women who used contraceptives. This association was not seen in women who did not use contraceptives.
In addition, women taking hormonal contraceptives showed a decrease in certain inflammatory markers (such as IL-1β) after stress, a pattern not seen in naturally cycling women. Interestingly, no significant changes in another inflammatory marker, IL-6, were observed in response to stress in either group.
Women taking hormonal contraceptives also showed higher levels of tumor necrosis factor alpha (TNF-α) at different times. TNF-α is another marker involved in inflammation, and its elevated levels in hormonal contraceptive users indicate a different pattern of inflammatory responses.
“I expected that hormonal contraceptive users would experience blunted cortisol levels and an exaggerated inflammatory response to an acute psychosocial stressor,” Mengelkoch told PsyPost. “Instead, I discovered 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 clear-cut as I predicted.”
These findings suggest that birth control pills may influence how the body responds to stress, both psychologically and biologically, especially 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 using hormonal contraceptives are likely worth these benefits for at least some periods of their lives,” Mengelkoch said. “However, some forms of hormonal contraceptive use alter the reactivity of the HPA axis in some women and increase the risk of developing mood-related disorders. This study provides the first evidence that hormonal contraceptive use affects not only cortisol responses to stress, but also inflammatory responses to stress.”
Although the research provides important insights, the study – like any research – has some limitations. For example, the study did not include a control group of women who were not exposed to 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 affected 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 critical to informed health care choices.
“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 investigate how the onset of hormonal contraceptive use influences stress-related gene expression, to gain a better mechanistic understanding of the biological pathways through which hormonal contraceptive use influences stress reactivity and inflammatory processes that have far-reaching health consequences to have.’
“This work will also help me determine which components of hormonal contraceptives have the greatest 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 have limited my current research to first through third generation oral hormonal contraceptive pills, but even within those there are quite a few variations (e.g., combination versus progestin-only pills, different types of progestins, different dosages).”
“To do this work ethically, I would like to emphasize that the use of hormonal contraceptives is safe and effective,” Mengelkoch added. “However, we don’t know enough about the potential side effects of its use to properly weigh the costs and benefits for individual women across their lives. For women or adolescent girls who are at high risk for developing mood-related disorders, there may be certain hormonal contraceptive formulations that are going to increase this risk, and other formulations that are going to decrease this risk.”
“I hope my work will advance a precision medicine approach to hormonal contraceptive recommendations so that every woman can make an informed decision about her contraceptive use together with her doctor. To do this, we need funding for basic science research to investigate how endogenous and exogenous sex hormones influence 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.