Hormonal contraceptives and mental health: synthetic hormone influences on fear behavior, neurocircuitry, and the GUT microbiome

The National Institute of Mental Health (NIMH) awarded University of Massachusetts Boston a $406,073 Project Grant under the Mental Health Research Grants program (CFDA 93.242) beginning June 1, 2025, through May 31, 2028. This research project investigates the mechanisms by which hormonal contraceptives (HCs) affect fear-based mental health outcomes, specifically examining how different HC formulations—distinguished by synthetic estrogen (ethinyl estradiol) and synthetic progestin (levonorgestrel) components—influence fear conditioning and extinction processes. The research employs translational animal models to elucidate these effects and explores the role of the gut microbiome in modulating fear-related behaviors, with the ultimate goal of identifying women at risk for psychiatric complications from HC use and developing novel therapeutic strategies to improve treatment outcomes for fear-based mental illnesses such as post-traumatic stress disorder and anxiety disorders.

The project addresses a critical gap in preclinical research by systematically comparing individual HC components rather than treating formulations as monolithic entities, thereby clarifying conflicting findings in existing literature regarding HC effects on fear extinction. By establishing mechanistic understanding through controlled laboratory models, this research will support the development of evidence-based clinical interventions and personalized risk assessment tools for women using hormonal contraception, ultimately enhancing the efficacy of exposure therapy and other fear-extinction-based mental health treatments.

Abstract

Increasing evidence suggests that hormonal contraceptives (HCS) not only impact reproduction, but also affect mental health. However, the biological mechanisms underpinning their psychiatric side effects remain largely unknown. With HC use on the rise and fear-based mental illnesses twice as prevalent in women as they are in men, there is a critical need to improve our understanding of HC effects on fear behavior mechanisms, apply this knowledge to identify women at risk for psychiatric issues with HC use, and develop novel therapeutic strategies to improve their treatment outcomes. Fear extinction processes serve as the basis for exposure therapy, currently a primary treatment for fear-based mental illnesses such as ptsd and anxiety disorders. Unfortunately, our existing understanding of HC effects on this process is conflicted, with some studies indicating fear extinction impairments, while others find the opposite or no effects on fear extinction. These inconsistencies may be due to a failure to distinguish different HC formulations based on their components of synthetic estrogens like ethinyl estradiol (EE) VS. Synthetic progestins like levonorgestrel (LNG). Preclinical models are essential to improving our understanding as they facilitate the comparison of HC effects on behavior beyond what would be possible in the clinical population. However, there is a lack of preclinical research examining HCS, especially broken down into their individual components, in laboratory fear conditioning and extinction models. Another factor that may contribute to the effects of HCS on fear is the GUT microbiome, which is increasingly indicated in the modulation of fear-related behaviors and has implications for mental health. The proposed project will use a translational animal model of fear conditioning to address this critical GAP. Our central hypothesis is that different HC formulations will differentially impact fear extinction, with formulation-specific effects on fear network regions and GUT bacteria composition. We also predict that manipulating the GUT microbiome during HC treatment will alter specific formulation effects on fear conditioning. The rationale for the proposed research is that once HC formulation-specific effects are identified, IT may fill the gaps in our current understanding and contribute to interventions that prevent or minimize negative HC side effects. This project has two specific aims. Aim 1 will identify the differential effects of synthetic hormone formulations, EE, LNG, and EE+LNG on fear extinction behavior and neurocircuitry and the GUT microbiome in naturally cycling female rats. Aim 2 will investigate causal relationships by manipulating the GUT microbiome to determine which microbiota cause HC effects on fear extinction. This study is significant because IT will provide insight into potential target mechanisms underlying HC-induced vulnerability or resilience to fear-related psychiatric disorders, a critical consideration for women's mental health and treatment. The proposed project is innovative because IT will be the first to concurrently study and delineate HC formulation-specific effects on fear learning and extinction, neurocircuitry, and the GUT microbiome. This is a novel approach that overcomes a critical methodological limitation in the current/existing literature.