Towards a more comprehensive neuroscience of hormonal contraceptives.

Neuroscientists have the opportunity to assist in that calculus by empowering users with high-fidelity information about the biopsychological effects of HC use. We offer two particularly exciting ways to approach this in future research. First, research can ‘zoom out’ to detect mean- or even population-level trends in large studies. Current studies are hampered by small sample sizes with limited representation and poor HC measurement. The field would benefit from harmonized large-scale consortia, randomized controlled trials, and ultimately meta- or mega-analyses of diverse users. The ways in which HC-related changes in brain structure and function may be systematically tied to behavior are not yet known. Nevertheless, a reasonable starting point for largescale neuroimaging efforts is to leverage the trends found in behavioral studies in order to home in on circuitry that is likely to be impacted by HCs, and to consider individual differences that are likely to matter for the detection of effects (for example, age, duration of use, and HC type and formulation). Large-scale efforts could also be modelled on approaches used during other phases of human steroid hormone transition during the lifespan 13 . For example, the neuroscience of menopause was propelled forward by societies and workshops that led to standardized definitions and measurements 14 , which do not yet exist for HCs. Second, future research can ‘zoom in’ to clarify the extent to which the effects of HCs on the brain and behavior apply to individual users. In order to detect population-level trends, largescale efforts must collapse across all users (or subsets of users), and thus risk obfuscating the effects of HCs on individuals. It is already clear that individual differences matter for the effects of HCs, HC users differ from one another, and neural and behavioral phenotypes are multifactorial. So the decision to use HCs must be a personalized one, and it must be informed by a personalized science. Precision imaging and intensive longitudinal behavioral studies provide a promising path forward. They generate time series from many biological or psychological assessments that can be powerfully used in individual descriptive and predictive modelling analyses. Converging evidence generated by consortia data and meta-analyses as well as medical records with indices of hormone sensitivity (for example, premenstrual dysphoric disorder) may ultimately inform a precision medicine approach to HC prescriptions. In other words, such studies could reveal diagnostic markers that prospectively identify how an individual is likely to respond to a certain HC formulation — avoiding long periods of trial and error, and promoting physical and mental wellbeing.

The extant literature does not offer unilateral consensus on the potential neural effects of HCs. This is not unexpected for a relatively new field, especially one that has been financially and socially under-supported. Indeed, given the groundswell of evidence that sex steroid hormones regulate the structure and function of the mammalian brain, it is discouraging that few rigorous human neuroimaging studies of HCs have been conducted (33 studies in total as of a 2020 systematic review 1 ). The studies that do exist focus primarily on oral contraceptives, which are the most widely used and studied HCs in the United States and Europe. In longitudinal studies, effects of oral HCs on the medial temporal lobe have been observed, including reduced grey matter volumes within the left amygdala, parahippocampal cortex 2 , and hippocampal subfield CA2/3 (ref. 3 ). In women who had previously experienced mood deterioration in response to HCs, small randomized trials revealed decreased cortical thickness 4 and lower task-related brain activation 5 in prefrontal regions. The findings of resting-state functional connectivity studies have been mixed, with reports of higher, lower, or equivalent connectivity in individuals using and not using oral contraceptives 6 . This stands somewhat in contrast to a more coherent picture emerging from the extant behavioral literature on HCs, especially with respect to cognition and psychopathology 7 . Systematic reviews report that verbal memory differs between oral contraceptive users and non-users, and that visuospatial effects depend on the specific hormonal formulation of the pill 8 . Furthermore, motivation for seeking out and engaging with potential romantic partners, willingness to engage and persist in competitions, and financial choices involving risk may differ between HC users and non-users (reviewed elsewhere 9 ). The magnitude of these effects appears small, and these findings require replication. Last, there are some reports of links between HC use and changes in mental health, including increases in anxiety and depression 10 , but these effects seem to depend largely upon individual differences, including user age at initiation and duration of use 7 , 11 . Thus, the behavioral literature makes it increasingly clear that the effects of HCs are complex. Timing, pre-existing conditions, and route of administration (for example, oral, transdermal, insertable, or injectable) and hormone formulation are critical. Although this kind of nuance is common in burgeoning areas of research, it is easily lost in translation to the public. In a world of black and white messaging, the neuroscience of HCs is firmly in the grey. So, let us try to provide some clarity: the brain is a highly plastic, endocrine organ, and HCs are one among many factors to which it reacts and adapts; this occurs within the unique time-varying biopsychosocial backgrounds of individual users. This means that some users may experience negative side effects, others may experience positive outcomes, and still others may have benign experiences. Benefits and adverse symptoms can even occur simultaneously in the same person, or change within a user over time. Therefore, alarmist or overly simplistic claims of universal neural or psychological danger are empirically unsupported. Indeed, previous ‘pill scares’ have had unintended consequences, including increases in teenage pregnancies and unplanned childbirth 12 . Important physiological side effects can and do occur in some users, including cardiovascular problems (especially venous thromboembolism), nausea, breast tenderness, headaches, and mood disturbance. However, undesirable physiological and biopsychological side effects cannot be easily disentangled from the potential benefits of HCs. It is vital to remember that HCs are approved by national and international drug regulation agencies, and that they reduce the risk of unintended pregnancies. They can also be effective tools for managing common but devasting menstrual conditions such as heavy bleeding, dysmenorrhea, and endometriosis, and may have non-menstrual benefits, such as lowering the risks of ovarian and endometrial cancers. Given this complexity, only individuals — together with their trusted health professionals — can possibly do the complex calculus required to determine whether to use HCs.

The human brain demonstrates tremendous plasticity in response to various experiences — learning, parenting, sleeping, eating, bonding — and the list continues. Steroid hormones, including those contained in or modulated by HCs, are just one of the many internal and external factors that affect neural architecture and functioning. Certainly, it is normal for brains to change when hormones do (consider stress, the menstrual cycle 15 , 16 , and pregnancy 17 , 18 ); and individuals can have very real and very different responses to those hormones. This reality provides vital context for the neuroscience of hormonal contraception, as there is concern, disdain, and confusion surrounding the scant empirical literature. Although some consensus is emerging concerning links between HCs and behavior – highlighting the importance of individual differences and experiences – the current state of knowledge regarding HCs and the brain is much too limited to draw definitive conclusions. Further large-scale research (for example, consortia) is needed to understand the effects of specific HC types and formulations in diverse populations. Individualized research (for example, precision imaging and intensive longitudinal studies) is needed to personalize contraceptive approaches that reduce risk and maximize benefits. Women’s health research has been historically under-supported in the biomedical sciences, including neuroscience. Now is the time to correct course: investigating the neuroscience of hormonal contraception is a necessary and urgent scientific endeavour with wide-reaching implications for society and public health.