Hormonal contraceptives (HCs) are one of the most important health and economic developments in the 20th century, used by at least 85% of women in western countries for 5 or more years at some point in their lives. Of all HCs – including oral contraceptives or “The Pill”, implants (e.g., Norplant), cervical rings, injections (e.g., Depo-Provera), and some intrauterine devices (IUDs, e.g., Mirena) – oral contraceptives remain the most accessible and commonly used. Approximately 15% of married women and 26% of unmarried menstruators of reproductive age use oral contraceptives (United Nations, Department of Economic, United Nations Department of Economic and Social Affairs Population Division. Contraceptive Use by Method, 2019), translating to more than 151 million people worldwide using oral contraceptives, 74 million an injectable, 23 million implants, and 159 million IUDs (either hormonal or copper) at any given time. This makes HCs one of the most widely used classes of drugs worldwide (Chadwick et al., 2012). By allowing unprecedented control over reproduction, HCs have resulted in health benefits that extend well beyond family planning and expanded financial independence for individuals and families. Common health benefits include menstruation-related alleviating premenstrual symptoms and premenstrual dysphoric disorder (PMDD), dysmenorrhea, endometriosis, and polycystic ovarian syndrome (PCOS) (Chadwick et al., 2012, Wong et al., 2009, Brown et al., 2018, Hewitt and Cromer, 2000). HCs also substantially reduce the risk of some forms of cancer including ovarian, endometrial, and colon cancers by up to 50% (Chadwick et al., 2012, Murphy et al., 2017, Luan et al., 2015, Havrilesky et al., 2013, Michels et al., 2018, Iversen et al., 2017). In addition, regulatory effects of HCs are the primary reason for many individuals being on HCs, especially during adolescence: these include regulating periods, decreasing acne, and alleviating premenstrual symptoms (Hewitt and Cromer, 2000, Lahoti et al., 2021).

HCs also broadly benefit mental health. Most individuals using HCs experience either improved mood and decreased risk for depression and panic disorder (Keyes et al., 2013, Cheslack-Postava et al., 2015), or have no noticeable impact on mood or depression (Scheuringer et al., 2020). Nevertheless, for a subset of individuals – approximately 4-10% of users – HCs come with serious side effects including increased risk for depression and suicidality (Porcu et al., 2019, Poromaa and Segebladh, 2012, Skovlund et al., 2016, Skovlund et al., 2018, Edwards et al., 2020. 2020., Schaffir et al., 2016, Worly et al., 2018, Anderl et al., 2021;epub, Anderl et al., 2020). This equates to around 30 million people worldwide that experience anxiety or depression as a consequence of HC use at any given time.

Balancing known risks with known benefits for HCs is widely practiced when prescribing HCs. For example, HCs increase risk of blood clots and cardiovascular disease in patients that smoke (Petitti, 2003, Frye, 2006); and there is a small, temporarily increased risk of breast and cervical cancers with increasing duration of use (Mørch et al., 2017, Appleby et al., 2007). For most individuals, these risks are balanced against long-term reduction of other cancers, including ovarian and colorectal cancers (Chadwick et al., 2012, Murphy et al., 2017, Luan et al., 2015, Havrilesky et al., 2013, Michels et al., 2018, Iversen et al., 2017). Androgenic formulations of HCs are preferentially prescribed to adolescents for their beneficial effects on bone development (Hewitt and Cromer, 2000, Lahoti et al., 2021, Frye, 2006). Predicting who will benefit from HCs and who is at risk of deleterious side effects, and delineating strategies to optimize outcomes for all HC users is an important factor in reproductive health medicine. To extend this consideration to mental health benefits for HCs, we first need to understand how HCs impact the brain (Pletzer and Kerschbaum, 2014, Taylor et al., 2021) and psychological processes (Cobey and Buunk, 2012); and identify specific risk factors for adverse mood effects.

In this review, we make a case for the need for well-designed rodent models of HC-exposure, in concert with studies of human-HC users, to understand the mechanisms by which HCs interact with a variety of biological and environmental factors to modify mental health. Animal models are uniquely suited to begin to address this gap in knowledge. Well-designed experiments will provide a basis to understand the molecular, circuit, and systems level impacts of HC formulations on stress-responsiveness, and on a range of psychological processes including depression-like behaviors, reward, motivation, and anxiety. By understanding the processes modulated by HCs and how they interact with individual risk factors, we can begin to apply a personalized medicine approach in which we aim to identify individuals that will benefit from specific HC formulations or strategies.

Studying HCs in the people that use them is essential for identifying the impact on people’s life, mood, brains, and general health. To date, this work has defined various ways, reviewed below, by which HCs influence the brain. And yet individual differences in experience, genetics, stress exposure, age, and duration of HC use, as well as vulnerability to mood and other psychiatric disorders, make studying specific effects of HCs on neural mechanisms and psychological processes extremely difficult in human-subjects research. This is particularly problematic when these side effects occur in only a subpopulation of HC users. When data is collapsed into averages, and we assume the results represent “the average user”, important effects that occur in a relatively small proportion of people are often obscured (Foster and Beltz, 2018).

A number of approaches have been used to reduce inter-individual variability and understand the impact of HCs on mental health. One effective approach has been to recruit people who have previously experienced adverse mood symptoms (e.g, (Poromaa and Segebladh, 2012, Petersen et al., 2021, Gingnell et al., 2013); another to focus on younger people using HCs for the first time (e.g. (Skovlund et al., 2016, Skovlund et al., 2018), or to use sophisticated, daily behavioral assessments and repeated imaging to assess HC effects on individuals mood and cognition over time (Foster and Beltz, 2018, Beltz and Moser, 2020, Kelly et al., 2020). These approaches have demonstrated more consistent results, yet it remains difficult to assess how different factors, including age, duration of use, and prior stress contribute to vulnerability to adverse consequences of HCs, and under what circumstances HCs confer protection against mood disturbances.

A second sticking point for understanding the effects of HCs in the brain and on mental health, is that we do not yet know which mechanisms of HCs mediate these effects. HCs cause direct effects in the brain via high-affinity synthetic hormones that mimic increased levels of estradiol or progesterone and, conversely, chronic suppression of circulating estradiol, progesterone, and testosterone (Porcu et al., 2019, Graham and Milad, 2013, Graham et al., 2018, Porcu et al., 2012, Simone et al., 2015, Fleischman et al., 2010). HCs also exert “off-target” effects including androgenicity or anti-androgenicity (Fuhrmann et al., 1996, Sitruk-Ware and Nath, 2010, Schindler et al., 2003, Fedotcheva, 2021, Africander et al., 2011, Phillips et al., 1990) of synthetic progestins, regulation of the HPA axis and stress responses (e.g., (Hertel et al., 2017, Kirschbaum et al., 1995) as well as interactions with glucocorticoid and mineralocorticoid receptors (GR, MR, respectively) (Fuhrmann et al., 1996, Sitruk-Ware and Nath, 2010, Africander et al., 2011, Carr, 1998) (See Table 1). Because HC users have access to a wide variety of HC types, doses, and formulations, and many people have used several types or formulations to find works best for them and their particular circumstances, most studies of HC use also reflect this heterogeneity. This means that most studies include multiple types of HCs, formulations, and doses; albeit with a bias towards oral contraceptives, as the most commonly used HC type. This heterogeneity in many studies further complicates interpretation of what mechanisms are exerting which effects on brain and behavior.

To understand the complex interactions between HCs, stress, and precise systems, circuit, cellular, and molecular mechanisms by which HCs confer increased vulnerability – or resilience – to depression, we need to be able to experimentally control and manipulate more variables. Due to ethicality and individual variability, this is incredibly difficult in human subjects’ research. Instead, we need complementary laboratory animal models of contraceptive hormone exposure that mimic the beneficial and adverse effects observed in people to identify how HCs affect the brain, determine risk factors for adverse effects, and predict which HC formulations are most beneficial for individuals.

Rat and mouse models are essential for identifying detailed molecular, cellular, and circuit-level mechanisms of hormonal action on the brain and behavior (Anker and Carroll, 2011, Oberlander and Woolley, 2016, McEwen and Milner, 2017, Song et al., 2018). In laboratory animals, we can systematically vary history of stress exposure, age of onset of HC exposure, interactions of stress during HC use, and HC formulations. Specific genotypes, including different strains and transgenic animals can identify the role of individual differences in stress or hormone responsivity (McKenna and Simon, 1993, Brinks et al., 2007, Cazares et al., 2019. 2019.). Behavioral models of anxiety- and depression-like behavior (e.g., anhedonia, (Planchez et al., 2019, Heinzmann et al., 2014) and cognitive functions (e.g., memory and visuospatial navigation (Tronson and Keiser, 2019;xx.) allow us to examine the impact of HCs on psychological processes. In laboratory animals, we can also directly measure stress hormone levels (Porcu et al., 2019), and conduct pharmacological manipulations, invasive surgical, molecular and imaging techniques to determine the precise causal mechanisms by which HCs affect the brain. Animal models of HC exposure can thus provide a way to determine which effects of HCs – direct effects on estrogen and progesterone receptors, indirect effects of reduced hormone levels, or off-target effects of synthetic hormones – mediate the various changes in affective, cognitive, and stress-related functions.

Importantly, animal models of HC exposure are not a replacement for human studies. Rather, animal models are “reverse-translational” extension of this research, whereby we design models to mimic known human states, answer questions arising from human subjects’ research, and develop new hypotheses to be tested in human HC users. Animal models, when well-integrated with data from human studies, will be essential for filling-in gaps in knowledge, advancing our understanding of how HCs affect the brain, and will be instrumental in maximizing benefits and minimizing mental health risks of HCs in healthcare settings.

In this review, we will outline what we know about HC effects on the brain and define the questions arising from human studies that animal models can answer. We will end by describing existing models, discussing future directions and alternative models moving forward.