Hormonal contraceptives, including oral contraceptives (OCs, “the pill”), IUDs (e.g., Mirena), implants (e.g., Nexplanon), and the vaginal ring, are a critical part of healthcare, providing an unprecedented level of reproductive control and, in turn, economic and educational benefits for families. In addition, because OCs blunt ovarian cycles, they also exert health benefits, including alleviation of menstrual symptoms and treating premenstrual dysphoric disorder, controlling acne, and reducing the risk of ovarian, epithelial, and endometrial cancers (Havrilesky et al., 2013; Michels et al., 2018; Murphy et al., 2017; Schindler, 2013). Despite the myriad of benefits for many users, hormonal contraceptives have some side effects, and adverse effects on mood, remains the most common reason for cessation of use (Lewis et al., 2019; Sanders et al., 2001). At least 4–10 % of users – or up to 30 million individuals at any given time – experience increased risk for mood disorders (Poromaa and Segebladh, 2012).

Whereas OCs increase depression and anxiety for some users, others experience beneficial effects on mood (Keyes et al., 2013; Porcu et al., 2019; Poromaa and Segebladh, 2012; Tronson and Schuh, 2022). These conflicting findings are likely due to individual differences in mood-related risk factors, differences between OC formulations, and different inferences from analyses that focus on group averages versus those that assess individual risks or changes across time (Beltz, 2022). This raises the question of how to predict who is likely to experience beneficial effects and who is at risk for detrimental effects – but to do that we need to better understand how OCs affect the brain. Here, we begin to characterize a new mouse model with which to identify mechanisms by which OCs contribute to regulation of stress and risks for anxiety and depression.

Developing animal models is a necessary step towards understanding how OCs modulate the brain and behavior (Hilz, 2022; Tronson and Schuh, 2022). Previous studies in rodents have successfully modeled OC exposure in rodents using daily hormone injections, implants, or daily oral gavage protocols to model suppression of ovulation, extensions of fertility, modulation of social and affective behaviors, cognition, and changes in neurochemistry (Allaway et al., 2021; Carrington and Bailey, 1985; Isono et al., 2018; Lacasse et al., 2022; Porcu et al., 2012; Simone et al., 2015). Here, we build on these studies to design a mouse model specifically targeted to mimic OC exposure, their effects on the hypothalamic-pituitary-adrenal (HPA) axis, and subsequent changes in risk/resilience to depression- and anxiety-like processes.

Across studies and across individual OC users, one reliable physiological effect is the suppression of the acute stress response (Kirschbaum et al., 1995; Mordecai et al., 2017; Tronson and Schuh, 2022). Given that stress and dysregulated stress-related signaling play a key role in depression and anxiety, changes in the HPA axis as a consequence of OC use is particularly interesting for identifying how OCs influence risk and resilience to depression (Slattery and Cryan, 2017; Tafet and Nemeroff, 2016).

The main goal of this study was to determine whether translationally relevant doses of ethinyl estradiol + levonorgestrel (EE + LVNG) in mice mimic the suppression of HPA axis response to acute stress observed in humans, and thereby provide a basis for future mechanistic studies on the interactions of OCs, stress, and depression. Here, we assessed stress-coping, anhedonia-, anxiety-, and other depression-like behaviors. These mouse behaviors are sensitive to stress and dysregulation of HPA axis and have been used extensively to study behavioral, circuit, neurochemical, and molecular changes associated with stress- and depression-related phenotypes (Bangasser and Valentino, 2014; Commons et al., 2017; Kolber et al., 2008; McEwen, 2000; Serchov et al., 2016; Tafet and Nemeroff, 2016).

Based on previously observed effects in humans (Hertel et al., 2017; Kirschbaum et al., 1995; Merz et al., 2012) and rats (Allaway et al., 2021; Carrington and Bailey, 1985; Follesa et al., 2002; Lacasse et al., 2022; Porcu et al., 2012; Simone et al., 2015), we hypothesized that a translationally relevant dose of orally administered contraceptive hormones will suppress acute stress responses and trigger increases in anxiety- and, depression-like behaviors. Our main findings supported the suppression of corticosterone in response to stress, and showed a specific anhedonia-like effect, without broad depression-like or anxiety-like effects.