Oral contraceptives (OCs) are the most popular form of birth control in the United States and in European countries (King et al., 2021, United Nations, 2019). Worldwide over 150 million women are prescribed OCs (Christin-Maitre, 2013, United Nations, 2019). OCs, commonly known as the “pill,” provide an effective option for contraception and safe family planning (McKenna and Fogleman, 2021, Osayande and Mehulic, 2014). They are increasingly used by adolescent and young women not only to control fertility but for a number of other treatments (Upadhya et al., 2017), including for symptomatic endometriosis, irregular cycles, heavy menstrual bleeding, menstrual period pain, premenstrual syndrome, and polycystic ovary syndrome (PCOS; Schindler, 2013), as well as so-called life style products to prevent acne or hair loss (Eichenfield et al., 2021, Williams et al., 2021). Hence, the effects of OCs go beyond their original purpose of contraception. However, the rate of women on OCs has been declining in the past 20 years. In 2010, close to 46% of women insured under a statutory insurance plan in Germany were using prescribed OCs. In 2020, however, it was only 35% (AOK-Bundesverband, 2021). In the Netherlands, in young women under that age of 25 years the use of OCs decreased from 88 to 76% between 2005 to 2017 (Marra et al., 2020). In Spain, the percentage of adolescents and young women using OCs decreased by 4% from 2006 to 2012 (Carrasco-Garrido et al., 2016).

Given the lack of research on this topic, we can only assume that the decline in the use of OCs is likely the result of switching to alternative contraception methods such as hormonal intrauterine devices (IUDs), hormone-free copper-based IUDs (Marra et al., 2020), and/or a rising awareness regarding potential side effects (Rosenberg et al., 1995), such as the risk of venous thrombosis (Khialani et al., 2020), depression, anxiety, and associated suicide attempts (Robakis et al., 2019), with the highest risk in adolescent women (Skovlund et al., 2018). Depression and suicidal behavior are strongly associated with alterations throughout the brain (Bani-Fatemi et al., 2018, Korgaonkar et al., 2011). However little is known about the extent OCs affect the brain’s function and morphology, although it is known that endogenous sex hormones do shape the brain across the life span in terms of both functional and organizational aspects (Arnold, 2009, Juraska et al., 2013, Phoenix et al., 1959). Thus, investigating the underlying effect of OCs on the brain is important as its use may influence women’s health.

In the following chapters, we review the current literature in neuroimaging methods and discuss to what extent neuroimaging can help us understand brain changes across the female menstrual cycle and how OCs might affect the brain’s structure. We wrote this review to facilitate the understanding of the sMRI and dMRI methods and its application in neuroimaging research on OCs and their effect on the brain. Our idea was to give these researchers a hands-on review on the latest and state-of-the-art imaging methods and its applications. First, we provide information about how sex hormones shape the human brain during development and maturation and how OCs containing synthetic hormones suppress the endogenous hormones in the body. Second, we review psychiatric conditions associated with OCs use. Third, we review neuroimaging findings in individuals using OCs. Given the fact, that there are some reviews on functional neuroimaging studies on OCs (e.g. Brønnick et al., 2020, Montoya and Bos, 2017), we focused on imaging methods sensitive to structural changes of gray and white matter, namely structural magnetic resonance imaging (sMRI) and diffusion magnetic resonance imaging (dMRI). Following this, we introduce neuroimaging methods developed in recent years that are suitable to be applied to OCs-related studies. We conclude with suggestions for future research directions to understand the female brain on oral contraceptives.