In this Virtual Special Issue (VSI), we asked the questions what do we know about how hormonal contraceptives (HCs) modulate cognition, emotion, behavior, and the brain; and how can translational approaches help us better understand the benefits, risks, and neutral effects of HCs on the brain? Understanding the impact of HCs on the brain is a topic experiencing a surge of interest, in part, due to the recent rise in sex- and gender-related variables being studied in neuroscience as driven by initiatives such as the study of sex as a biological variable (SABV, NIH) and the study of sex-and gender-based analyses (SGBA, CIHR) (Clayton, 2016, Government of Canada, 2018). Most people who menstruate or have uteri (women+) use HCs at some point in their lives, and many use them for an extended period (United Nations, Department of Economic and United Nations Department of Economic and Social Affairs Population Division, 2019). This VSI brings together leaders in the field to synthesize what we know about HCs and their effect on the brain and behavior. The result is a collection that proposes new directions forward, including integrating existing and new rodent models with research on human subjects to better understand the complex effects of HCs on the brain and behavior. As such, a theme emerging through this VSI is the need to understand the mechanisms by which HC formulations interact with individual differences to modulate stress, cognition, brain structure and function, emotion, and mental health.

Studies of cognition and behavior have demonstrated nuanced effects of HCs –not gross improvements or disruptions, but rather subtle changes across a range of domains. Gurvich and colleagues (2023) provide a systematic overview of oral contraceptives and cognition, laying the basis for detailed analyses of specific effects of HCs on cognition. Griksiene, Monciunskaite, and Ruksenas (2022) demonstrate that predicting outcomes requires consideration of the uniqueness of the synthetic progestins used in each HC formulation. This idea is extended by Pletzer, Winkler-Crepaz, and Hillerer (2023) who describe the specific roles of progestins and their metabolites, and specific methods for future clinical and preclinical studies. Hampson (2022) emphasizes that HCs are not simply endogenous hormones, and thus pharmacological factors need to be considered when studying the effects of HCs on psychological variables; and Beltz (2022) argues that the effects of HC must be analyzed in context of their route of administration as well as their organizational and activational effects. Concas, Serra, and Porcu (2022) explain that HCs alter neurochemical processes that ultimately influence social and sexual behaviors, a theme extended by Arthur, Casto, and Blake (2022) who compare how HCs modify competition for reproductive, social, and financial resources.

Changes in behavior, cognition, and emotion are key components of mental health disorders. Translational research integrating questions and approaches from both humans and animal models will be key to understanding the underlying mechanisms by which HCs may alter risks for mental health disorders. In this VSI, Graham (2022) identify pathways by which HCs may interfere with normal exposure/extinction and interact with anxiety treatments integrating data from both clinical studies in humans and preclinical models in rats. Jentsch and colleagues (2022) identify the interactions between HCs and stress effects on memory, cognition, and emotion as key aspects for future preclinical research; and Hilz and Lee (2023) suggest that given the role of ovarian hormones in motivation and reward, HCs may also be an important consideration for the development and treatment of substance use disorders. Extending this broader picture of likely HC effects, Kheloui, Smith, and Ismail (2023) highlight the critical role of gut microbiota in mediating HC effects on stress and the brain and the need to investigate developmental effects of HCs on the brain.

HCs also affect structure, activation, and functional connectivity of the brain, yet the precise patterns of differences in HC users are not consistent across studies. Heller and colleagues (2022) reconcile the literature examining the effects of HCs on brain structure, whereas Song and colleagues (2023) review of magnetic resonance imaging (MRI) and functional MRI (fMRI) studies to examine the effects of HCs on the human brain. Both papers highlight methodological differences that contribute to discrepancies in the literature and suggest guidelines for future studies to enable better comparisons and interpretations of HC-effects on the brain. Casto, Jordan, and Petersen (2022) delve deeper into the significance and functionality of observed differences in resting-state functional connectivity observed between those taking HC and those who do not.

The complex and contradictory nature of findings on HC-effects on brain, behavior, and mental health, as described throughout this VSI, highlights the importance of integrating individual differences in our studies of HCs. This raises questions including: what contributes to the likelihood of beneficial effects versus risk of negative outcomes in different individuals? And how can we, as a field, move towards understanding individual differences in HC effects on brain and behavior? And in health and disease? The first of these questions can be addressed by directly targeting individual differences in genetics. For example, Gravelsins, Zhao, and Einstein (2023) directly address how genetics influence endogenous hormone levels and fluctuations and how these contribute to individual differences in HC effects on cognition. Similarly, Klump and Di Dio (2022) interrogate the gene x hormone interactions that accompany links between HC use and binge eating disorder. The second question requires new and emerging analytical techniques, and Hill and Mengelkoch (2022) discuss moving towards person-based approaches to leverage individual differences, rather than average-based analyses. This approach is particularly suited to longitudinal designs in human HC studies. These person-specific interactions, and individualistic analyses are also highlighted by Reddy and colleages (2022) as critical for identifying HC-modulation of risks and severity of stroke. Understanding the role of individual differences – due to genetics or experiences – in HC effects will be critical to understand precise effects of HCs, and to move towards personalized approach to HC prescriptions.

Whereas human studies clearly show that HCs affect the brain and behavior, it is difficult to study the underlying mechanisms; and as noted above, experiments with humans are limited by their heterogeneity in genetics and experiences. Well-designed animal models of HC exposure will provide tractable ways to address the “how” questions arising from human-subject studies. Tronson and Schuh (2022) stress the importance of animal models for uncovering the molecular, cellular, and circuit level underpinnings of HCs impact on the brain and behavior. Methodological considerations involved in designing translational animal models are described in two reviews. Hilz (2022) identifies brain-region-specific targets for future studies of HC using animal models, and the framework presented by Lacasse, Gomez-Perales, and Brake (2022) outline at least six different approaches to testing HC in rodents, and their merits for focusing on different questions and different mechanisms. To advance HC research, animal models are essential for defining the precise mechanisms underlying HC effects on emotion, cognition, behavior and the brain.

This VSI highlights several key themes. Notably the need to understand the distinct roles of the estrogenic component versus various progestins in modulation of brain structure and function, mood, and behavior; and the necessity of accounting for individual differences to understand outcomes of HC use. Most importantly, this collection of papers emphasizes the importance of an integrative approach : we need to account for reproductive system control, HPA-axis, gut-brain axis, and endocrine systems, and interactions with individual differences across genetic, experiential, mental health status to fully understand HC-effects on the brain. Together, these papers illustrate an under-studied area and a field poised for exponential growth, with avenues for well-designed translational studies to define precise mechanistic effects, and paths towards multiple converging methods in both humans and animal models to identify HC modulation of brain and behavior. In the future, this work will be critical for including HCs – a rarely considered, but ubiquitous sex and gender-related variable – as a factor in studies aiming to understand sex- and gender- differences in risk and resilience to physical, neurological, and mental health disorders.