Chill pill: the link between oral contraceptive and stress response

When someone says ‘stress’, many people connect it to negative effects and feelings; however, small amounts of stress are actually important for well-being. According to the World Health Organization (WHO), any type of change which causes physical, emotional, or psychological tension can be defined as stress (Stress, n.d.).  In other words, stress just means that something is biologically meaningful and therefore requires the body’s attention. Of course, prolonged chronic stress negatively affects the body, but so does no stress. Furthermore, there is growing evidence that hormones, specifically the ones used in oral contraceptives (the pill), may affect the way women respond to stress (Kirschbaum et al., 1996; Bouma et al., 2009). I was intrigued by this information as I have not heard about it until I read This Is Your Brain on Birth Control. Therefore, I decided to explore this topic and discuss this unspoken information.

Before I get into the research on this topic, let me begin by explaining how stress is regulated in the human body. The way in which our bodies deal with stress is through stress response (Seyle, 1956). Although the stress response may slightly differ depending on what is going on, it has a couple of common ingredients. The first common ingredient is that stress turns your sympathetic nervous system (SNS) on, its response then carries information through the release of epinephrine and norepinephrine, and is responsible for the “flight-or-fight” response (Foley & Kirschbaum, 2010). However, the SNS part of the stress response of women on the pill seems to stay completely intact (Kirschbaum et al., 1996). The second common ingredient of stress response is the activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is made up of 3 systems that work together: the hypothalamus, pituitary, and the adrenal glands. The hypothalamus releases a corticotropin-releasing hormone (CRH) that stimulates the pituitary gland which passes the information to the adrenal glands via the release of adrenocorticotropic hormone (ACTH) which then stimulates the adrenal glands, leading to the release of cortisol (the main stress hormone) into a bloodstream (Herman et al., 2016). When the HPA-axis is too active, it will go into a shutdown mode as a protective mechanism. This appears to also be true for the HPA-axis of women taking the pill (Kirschbaum et al., 1996; Bouma et al., 2009; Sharma et al., 2020; Gervasio et al., 2022).

Recent study by Sharma and colleagues (2020) explored how the pill affects the brain with regard to emotional working memory. Specifically, the researchers examined stress reactivity among brain structure and function using the Trier Social Stress Test (TSST) which is a common laboratory procedure used to study stress among human participants. The participants were split into three groups: adolescent-onset pill-takers, adult-onset pill-takers, and non-pill-takers. First, saliva samples were taken to examine estradiol and progesterone levels (two major female steroid hormones) among the groups. Second, a subset of participants were exposed to the TSST during which saliva samples for cortisol were collected to measure stress reactivity. Participants also underwent a memory task along with structural and functional magnetic resonance imaging (MRI).

The results revealed higher progesterone levels among non-pill-takers compared to pill-takers. This may be a useful thing during pregnancy as it prevents the uterus from contracting, therefore it makes sense that non-pill-takers demonstrate higher levels of it. In terms of stress reactivity, adolescent-onset pill-takers displayed a decrease in cortisol levels during the TSST compared to their adult-onset counterparts. This suggests that adult-onset pill-takers are more reactive to stress. In addition, pill-takers demonstrate region-specific differences in structural brain volumes and more brain activity during working memory for negative pictures compared to non-pill-takers. For example, the MRI analysis revealed that pill-taking women displayed smaller gray matter volume in the right putamen, which is important for learning and motor control upon other functions, compared to non-pill-takers. These women also displayed larger white matter volume in the left hippocampus, which is deeply involved in learning and memory, compared to the non-pill-takers. These brain differences may be a result of altered neurodevelopment by the pill use. It is fascinating to note that Sharma et al. ‘s (2020) study is among the first studies to examine the age-dependent effect of the pill on structure and function of the brain on stress reactivity.

Although the research on the effects of the pill on behavior and neurophysiology is at its infancy, it is important to pass this information about the effects of the pill on stress reactivity. Furthering the knowledge of the effects of the pill on stress will allow us to better understand women and their behavior.


Bouma, E. M. C., Riese, H., Ormel, J., Verhulst, F. C., & Oldehinkel, A. J. (2009). Adolescents’ cortisol responses to awakening and social stress; Effects of gender, menstrual phase and oral contraceptives. The TRAILS study. Psychoneuroendocrinology, 34(6), 884–893.

Foley, P., & Kirschbaum, C. (2010). Human hypothalamus–pituitary–adrenal axis responses to acute psychosocial stress in laboratory settings. Neuroscience & Biobehavioral Reviews, 35(1), 91–96.

Gervasio, J., Zheng, S., Skrotzki, C., & Pachete, A. (2022). The effect of oral contraceptive use on cortisol reactivity to the Trier Social Stress Test: A meta-analysis. Psychoneuroendocrinology, 136, 105626.

Herman, J. P., McKlveen, J. M., Ghosal, S., Kopp, B., Wulsin, A., Makinson, R., Scheimann, J., & Myers, B. (2016). Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response. Comprehensive Physiology, 6(2), 603–621.


Selye, H. (1956). The stress of life.

Sharma, R., Smith, S. A., Boukina, N., Dordari, A., Mistry, A., Taylor, B. C., Felix, N., Cameron, A., Fang, Z., Smith, A., & Ismail, N. (2020). Use of the birth control pill affects stress reactivity and brain structure and function. Hormones and Behavior, 124, 104783.

Stress. (n.d.).

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