Effects of hormonal contraceptives on brain function and behavior: advancing mechanistic and translational understanding

Hormonal contraceptives (HCs) are among the most widely prescribed medications worldwide, used by more than 300 million women, often continuously for years and frequently initiated during adolescence. While their contraceptive efficacy and overall safety profile are well characterized, their long-term effects on brain function, motivated behavior, and neural circuitry remain incompletely understood. Importantly, HCs should not be considered a homogeneous exposure: synthetic estrogens and progestins differ substantially in their pharmacological properties, receptor selectivity, androgenicity, and metabolic profiles. By suppressing endogenous ovarian steroidogenesis and altering progesterone-derived neuroactive steroids, including allopregnanolone, HCs can modulate neurobiological systems involved in reward processing, motivation, stress responsiveness, affective regulation, cognition, and social behavior through effects on GABAergic, dopaminergic, neuroendocrine, and other signaling systems.Recent advances have shifted the field from primarily characterizing associations toward identifying the biological mechanisms through which synthetic contraceptive steroids influence brain and behavior. Experimental studies demonstrate that contraceptive steroids can influence reward sensitivity, reinforcement learning, motivational behavior, anxiety-like behavior, social interactions, feeding, and synaptic plasticity, while clinical and neuroimaging studies have identified associations between HC use and alterations in stress reactivity, mood regulation, cognitive function, and brain structure and connectivity. A major challenge now is to determine how pharmacologically distinct contraceptive exposures act across molecular, cellular, and neural circuit levels to produce these behavioral outcomes, and why their effects vary across individuals and developmental stages.Important translational challenges also remain. Animal and human studies often differ in formulations, dosing regimens, outcome measures, and reporting standards, and HCs continue to be treated as a homogeneous exposure despite considerable pharmacological diversity. Greater integration across behavioral neuroscience, neuroendocrinology, neuropharmacology, and clinical research is needed to identify formulation-specific mechanisms, establish causal links between biological and behavioral effects, and improve translational relevance.This Research Topic aims to advance mechanistic understanding of how pharmacologically distinct HCs influence brain function, motivation, reward-related processes, and behavior across the lifespan. We particularly welcome contributions that move beyond HC use as a binary exposure and bridge levels of analysis, from contraceptive pharmacology and molecular or cellular mechanisms to neural circuitry and behavior. Studies integrating preclinical and clinical neuroscience are encouraged to help identify the biological mechanisms underlying individual variability, persistence or recovery following HC exposure, and longer-term consequences for brain health.Potential topics include:• Hormonal contraceptive pharmacology and neuroactive steroid signaling, including formulation-specific effects, receptor pharmacology, androgenicity, suppression of endogenous steroidogenesis, allopregnanolone, GABA-A receptor modulation, and affective regulation.• Hormonal contraceptives and reward circuitry, including dopaminergic signaling, reinforcement learning, psychostimulant responsiveness and substance use vulnerability, and motivated behavior.• Natural reward processing, including feeding behavior, energy balance, social and sexual motivation, effort-based decision-making, and goal-directed versus habitual behavior.• Learning, memory, cognition, and neuroplasticity, including hippocampal-striatal interactions, executive function, synaptic plasticity, neurotrophic signaling, and epigenetic mechanisms.• Adolescence and other sensitive developmental windows, including the potential for HC exposure to influence corticolimbic maturation, stress responsivity, emotional behavior, and persistent neurobiological outcomes.• Stress neurobiology and individual susceptibility, including HPA-axis function, biological vulnerability and resilience, sex differences, endocrine determinants of behavioral outcomes, and interactions between HC exposure and environmental stress.• Emerging neurobiological mechanisms, including neuroimmune signaling, neuroactive steroid systems, mitochondrial function, and gut-brain interactions relevant to motivation, reward, and behavior.• Individual variability and precision neuroendocrinology, including formulation-specific effects, androgenicity, age at initiation, duration of use, genetic and endocrine susceptibility, prior exposure history, and biological mechanisms underlying differential responses to HCs.• Metabolic mechanisms, persistence, and long-term brain health, including cerebral energy and lipid metabolism, interactions between HCs and vascular or lifestyle risk factors, mechanisms supporting persistence or recovery of neurobiological and behavioral effects following discontinuation, and consequences of HC exposure across aging and the lifespan.• Improving mechanistic and translational rigor, including standardized reporting of contraceptive formulation, dose and route of administration; pharmacologically informed experimental design; harmonization of preclinical and clinical approaches; and studies linking molecular, cellular, circuit-level, and behavioral outcomes.We welcome Original Research, Brief Research Reports, Reviews, Mini Reviews, Perspectives, Opinion, and Methods articles that advance understanding of the neurobiological and behavioral effects of hormonal contraceptives through rigorous basic, translational, and clinical research. Topic editors: Patrizia Porcu, Ami P Raval, Jesse M. Lacasse, Nafissa Ismail Source: https://www.frontiersin.org/research-topics/86248/effects-of-hormonal-contraceptives-on-brain-function-and-behavior-advancing-mechanistic-and-translational-understanding