Oral contraceptives (OCs) are used by millions of adolescent and adult females across the globe, with common indications including prevention of pregnancy, acne, menorrhagia and premenstrual syndrome. Globally, 68% of partnered women use oral contraceptives (United Nations, Trends in Contraceptive Use Worldwide, 2015). OCs were introduced just over 60 years ago and much of the research has focussed on physical effects, however, there is growing recognition of the potential influence of OCs on brain structure and function (Bronnick et al., 2020), as well as mood, behaviour and cognition (Gogos, 2013, Warren et al., 2014, Lewis et al., 2019, Gamsakhurdashvili et al., 2021).Fig 1.

OCs contain an estrogen (typically ethinylestradiol) and a synthetic progestin (in combined OCs) or contain only a progestin. Combined OCs vary in the dose and type of the estrogen (ethinylestradiol or estradiol), the type and dose of the progestin component, as well as the regime (monophasic, biphasic, triphasic or quadriphasic) (De Leo et al., 2016). Combined OCs suppress ovarian hormone function and subsequently reduce endogenous levels of estradiol, progesterone and testosterone (Sahlberg et al., 1987). In addition, depending on the type of progestin, OCs have differing levels of androgenic, estrogenic, progestogenic, glucocorticoid or anti-glucocorticoid activity (De Leo et al., 2016). Both the suppression of endogenous steroid hormones as well as the introduction of exogenous synthetic hormones provide mechanisms by which OCs may influence cognitive processes.

A vast body of research demonstrates that endogenous sex hormones can impact cognition, with much of the existing literature focusing on the effects of estradiol (Beltz and Moser, 2020). Physiological fluctuations in endogenous levels of estrogen and progesterone, seen throughout the menstrual cycle, as well as at menopause and during pregnancy, have provided a base for research regarding cognitive impacts of sex hormones (for reviews see (Beltz and Moser, 2020, Bernal and Paolieri, 2022, Bimonte-Nelson et al., 2021). A recent review of the neuroimaging literature assessing the influence of OCs on the brain identified structural and functional changes in regions associated with affective and cognitive processing, including the amygdala, hippocampus, prefrontal cortex and cingulate gyrus (Bronnick et al., 2020).

The literature surrounding the influence of OCs on cognitive and emotion processing is rapidly expanding. Studies have variously reported that OCs affect different cognitive domains including attention (Gravelsins et al., 2021), working memory (Gravelsins et al., 2021), verbal memory (Mordecai et al., 2008), visual-spatial abilities (Wharton et al., 2008), emotional memory (Nielsen et al., 2013). However, findings are mixed and some of this heterogeneity has been attributed to different cognitive tasks and domains, pill type (particularly relating to whether the progestin component of the OC has androgenic or antiandrogenic effects (Wharton et al., 2008, Nielsen et al., 2013, Gurvich et al., 2020, Pletzer et al., 2015) and the influence of interacting factors such as stress (Herrera et al., 2020). The aim of this systematic review is to provide an update and synthesis on the literature relating to OC use and cognitive performance, including both neurocognitive domains as well as social-emotional cognition, as well as to identify factors that modulate the associations between OCs and cognitive performance.