In 1960, the FDA approved hormonal contraceptives for use in the United States (Kao, 2000). Soon after, other nations’ governing bodies also approved use (Salles, 2020). Nearly all women in the United States have used some form of contraceptive in their lifetime, with 82% of these women choosing to take the oral contraceptive pill (OCP) (Daniels, 2013). OCPs are used to prevent pregnancy and to treat medical conditions such as polycystic ovary syndrome (PCOS), dysmenorrhea, endometriosis, uterine fibroids and other menstrual cycle or pelvic pain disorders (Allen, 2022). From a 2015-2017 CDC survey, approximately 5.9 million women in the United States alone currently use OCPs (Daniels, 2018); this number does not account for women who have used OCPs in the past. Hormonal contraceptives are well-studied -- a PubMed search for “birth control hormonal” yielded 23,999 unique results. Safety, efficacy and contraindications related to hormonal contraceptives are well-established (CDC, 2020).

Hormonal contraceptive preparations incorporate a progesterone-analog and in most cases an estrogen-analog. Mechanisms of action for their contraceptive effects have also been extensively studied, relating to impact on function of the pituitary and hypothalamus, as well as additional peripheral effects (Horvath et al., 2000). The progesterone-analog suppresses secretion of luteinizing hormone (LH), thereby preventing ovulation, and increases viscosity of cervical mucus, which inhibits sperm motility (Horvath et al., 2000). Progesterone analogs used in hormonal contraceptive preparations exhibit variable androgenic properties (Allen, 2022). The estrogen-analog also contributes to suppression of LH, suppresses secretion of follicle stimulating hormone (FSH) and alters the endometrium (Horvath et al., 2000).

The mechanistic basis of hormonal contraceptive effects on brain structure and function remains incompletely understood. However, mechanisms of endogenous estrogen and progesterone effects on the brain have been more extensively characterized. Estrogens and progesterone are produced in the ovaries and adrenal glands (Rettberg et al., 2014). Endogenous estrogens (ie. estrone, estradiol and estriol) and progesterone (including its downstream derivatives dihydroprogesterone and tetrahydroprogesterone) interact with nuclear estrogen receptor-alpha, nuclear estrogen receptor-beta, membrane bound G-protein-coupled estrogen receptor 1 (GPER), nuclear progesterone receptors and progesterone receptor membrane component 1 (PGRMC1) in the brain (Brinton et al., 2008, Rettberg et al., 2014). Estrogen receptors are in general, widely distributed and can be found in both neurons and glial cells, however, distribution of different isoforms vary (Rettberg et al., 2014). Estrogen receptor-alpha has been shown to be expressed in the hypothalamus, forebrain, hippocampus and amygdala in humans (Rettberg et al., 2014). Compared to estrogen receptor-alpha, estrogen receptor-beta is more narrowly distributed, with literature showing expression in hippocampus and cerebral cortex in rodents and humans (Rettberg et al., 2014). GPER is more recently discovered and has been shown to be expressed in the hippocampus, hypothalamus, and midbrain of rodents (Prossnitz & Barton, 2011). Nuclear progesterone receptor expression is also expressed widely across the brain (Guennoun, 2020, Schumacher et al., 2014). PGRMC1 expression has been described in rat cerebellum, cortical regions, hippocampus and hypothalamic nuclei (Toffoletto et al., 2014). Estrogen and progesterone receptors contribute to numerous downstream effects; for example, regulation of glucose transport, regulation of mitochondrial ATP production (Rettberg et al., 2014), and synapse formation (McEwen & Milner, 2017). Progesterone has also been attributed to neuroprotection and myelin repair (Guennoun, 2020).

Sex steroid effects on neurotransmitter pathways is a complex topic that requires further research to fully characterize the multilevel, interacting effects of sex steroids (Nguyen et al., 2017). Studies tentatively suggest estrogens increase serotonergic activity (Nguyen et al., 2017), however, this is only a tentative conclusion and, as other reviews have noted, many factors such as receptor type, region of the brain, and type and duration of estrogen treatment are at play (Barth et al., 2015). Additionally, estrogens are thought to modulate dopamine receptor activity; it has been shown to potentiate D1 receptors and antagonize D2 receptors (Nguyen et al., 2017). Studies also suggest progesterone can increase or decrease serotoninergic activity (Nguyen et al., 2017), suppress glutamate activity and potentiate GABA-A receptor activity (Barth et al., 2015). While literature supports the impact of sex steroids on serotonin, GABA, glutamate, and other neurotransmitter systems, there is no real consensus on the directionality (excitatory or inhibitory) and spatial localization of these effects. More research is needed on the effects of endogenous sex steroids on the brain (Barth et al., 2015, Nguyen et al., 2017). More pertinent in the context of this review, is that endogenous sex steroid effects may not extrapolate to exogenous sex steroids, such as OCPs. However, we can still refer to this information as we focus on the effects of exogenous estrogen analogs and progesterone analogs comprising hormonal contraceptive preparations in this review.

Previous reviews of human [e.g., Brønnick (Brønnick et al., 2020) and Taylor (Taylor et al., 2021)] and animal [e.g., (Porcu et al., 2019)] studies, have assessed the scientific literature and voiced the need for more research on brain effects of hormonal contraceptives. These reviews provide excellent summaries of the literature on human and animal effects of hormonal contraceptives, respectively, but they did not integrate findings across human and animal studies. The aim of this systematic review is to critically assess human and animal studies, with addition of many new studies that have not been previously reviewed, and to assess how the current literature provides insight into potential mechanisms of hormonal contraceptive effects on brain structure and function. While human studies are most clinically relevant, animal studies offer insight into underlying mechanisms, which can never be derived from in vivo human studies. Animal studies also allow for rigorous randomized experimental studies, which are challenging to conduct in humans. Combined assessment of animal and human studies can facilitate future translational studies to characterize clinically relevant mechanisms in humans.