Hormonal contraceptives (HCs) are used for birth control by millions of women worldwide. A recent survey from the United Nations revealed that more than 18% of women between the ages of 15 and 49 in North America and Europe (approximately 44 million) and more than 8% worldwide (approximately 151 million) are current HC users (United Nations, 2019). These compounds contain synthetically derived estrogens and/or progestins suppressing the natural fluctuation of sex hormones orchestrated by the hypothalamus-pituitary gonadal (HPG) axis (e.g., estradiol and progesterone; Montoya and Bos, 2017). Given the prevalence and length of HC usage it is surprising how little information is available regarding its impact on how women respond to stress and how HCs interact with stress to influence cognitive and emotional processes in turn. This is particularly remarkable since many stress-related mental disorders are more prevalent in women. For instance, women compared to men have a higher lifetime prevalence of posttraumatic stress disorder, major depression and several anxiety disorders, whereas men have a higher prevalence for alcoholism and autism (Cover et al., 2014, Kessler et al., 2005). Accumulating evidence further indicates that sex hormones and HCs critically alter behavior and brain function underlying proper cognitive and emotional processing (Brønnick et al., 2020, Lewis et al., 2019, Montoya and Bos, 2017, Rehbein et al., 2021). Yet, despite its broad relevance for women’s mental health very little is known about the association between HC usage and the vulnerability for mental disorders (Lewis et al., 2019, Raeder et al., 2019, Sundström Poromaa et al., 2020) as well as the underlying cognitive-emotional mechanisms that may pave the way to aberrant behaviors in the first place.

Our selective review will illustrate how HC usage influences the effects of stress hormones on cognition and emotion. As examples stimulated by our own work and others, we will focus on stress hormone effects on emotional learning and memory processes exemplified with episodic memory and fear conditioning as well as cognitive emotion regulation. Finally, we will outline important open questions and possible next steps for basic, translational and clinical research.

Stress hormone release in response to (potential) threats is essential for the adaptation to critical life events and ongoing, every-day challenging situations (McEwen, 2004). While the acute stress response is mostly adaptive, repeated or chronic stress constitutes a major risk factor for the development and maintenance of a whole range of mental and physical disorders (Cohen et al., 2016, McEwen, 2004, McEwen and Akil, 2020, Sanacora et al., 2022). In humans, uncontrollable situations containing a threat to the social self, represent potent stressors (Dickerson and Kemeny, 2004). This can be realized in the laboratory in order to test the impact of stress on subsequent cognitive and emotional processes (see Box 1 for an overview of some of the human stress induction paradigms relevant for the current review). A broader and in-depth review of different laboratory and online stressors is given by Pfeifer et al. (2021).

The endocrine system responds to a stressor by activating two major stress systems: the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. The SNS initiates a rapid response mediated by (nor)adrenaline released by the adrenal medulla, resulting in rapid increases in blood pressure and heart rate. This first stress response has been conceptualized as the fight-or-flight response (Cannon, 1932). The second and somewhat slower response comprises the release of glucocorticoids (mainly cortisol in humans). Glucocorticoid secretion is orchestrated by the HPA axis releasing corticotropin-releasing hormone from the hypothalamus to initiate the secretion of adrenocorticotropic hormone from the anterior pituitary into the bloodstream. Adrenocorticotropic hormone in turn stimulates glucocorticoid release from the adrenal cortex. Glucocorticoids can easily cross the blood-brain-barrier and target many brain structures expressing mineralocorticoid and glucocorticoid receptors. In particular, glucocorticoids influence regions critically involved in emotional learning and memory as well as emotion regulation processes such as the medial temporal lobe (hippocampus and amygdala) and prefrontal areas (Arnsten, 2009, Joëls and Baram, 2009, Rodrigues et al., 2009, Roozendaal et al., 2009).

In general, men and women differ in endocrine and behavioral stress responses (Kudielka and Kirschbaum, 2005, Taylor et al., 2000). The close and bidirectional interaction between one of the major stress systems (the HPA axis) and the sex hormone system (the HPG axis) is, at least in part, responsible for these sex differences. To create an even greater challenge, there is ample evidence that stress responsiveness of the HPA axis changes over the course of the menstrual cycle. A more pronounced glucocorticoid release can be observed during the luteal phase (compared to the follicular phase; Kajantie and Phillips, 2006, Kudielka and Kirschbaum, 2005) characterized by elevated estradiol and progesterone concentrations. Of special importance for the current review is the observation that HCs substantially influence the response of the HPA axis to stress (see Gervasio et al., 2022 for a recent meta-analysis; Kirschbaum et al., 1999). Typically, HCs dampen the free (unbound, biologically active) cortisol stress response by increasing cortisol-binding globulin levels and changing the proportion of total to free cortisol (Hellhammer et al., 2009, Kirschbaum et al., 1999, van der Vange et al., 1990). Thus, while total cortisol concentrations are increased in HC women which might have effects on HPA targeted systems throughout the body (see Hertel et al., 2017) their free cortisol concentrations are typically not elevated and their free cortisol response to a stressor is, in fact, blunted (Gervasio et al., 2022, Hellhammer et al., 2009). In contrast, other stress systems (e.g., the SNS) appear to be less influenced by HC usage (Kirschbaum et al., 1999).

Importantly, the bidirectional interaction between the HPA and HPG axes might underlie the different vulnerabilities for distinct stress-associated mental disorders as outlined before.

The influence of HCs on stress effects on cognitive and emotional processes might be caused by at least two possible mechanisms: First, the impact of HCs might occur due to differences in the endocrine response to a stressor. As mentioned above, HC usage causes a blunted free cortisol response to acute stress (Gervasio et al., 2022, Kirschbaum et al., 1999), which in turn might reduce or even reverse the cognitive and emotional stress effects in these women. Second, and not mutually exclusive to the first explanation, HC effects might occur due to a different responsiveness of the female brain under HC usage to the same neuroendocrine stress signals. In support of this hypothesis we observed that the same pharmacological administration of the stress hormone cortisol caused different and in part opposing effects on neural networks involved in fear learning (Merz et al., 2012; cf. 3.1) and emotion regulation (Jentsch et al., 2019; cf. 4).

The goal of this manuscript is to review experimental studies in humans, which have investigated the potential influence of HC usage on stress effects on episodic memory, fear conditioning and cognitive emotion regulation. We therefore focused on experiments that specifically tested HC women and compared the stress effects with men and/or naturally cycling (NC) women. Combined oral contraceptives containing an ethinylestradiol and a gestagenic component are the most frequently prescribed type of HCs (Burkman et al., 2011, Christin-Maitre, 2013) and therefore predominantly represented in the studies discussed here.

After a general introduction to episodic memory and the typical paradigms used to probe memory, we briefly outline potential factors mediating or influencing stress and HC effects on episodic memory. Thereafter, we selectively review experimental studies illustrating the impact of HCs on stress effects on episodic memory with a particular focus on memory encoding, memory consolidation, and memory retrieval.