Distinct Steroid Mechanisms in Menstrual Cycle Exacerbation of Psychopathology

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SUMMARY Changes in reproductive hormones across the menstrual cycle may be a key biological source of symptom variability in psychopathology. Strong individual differences in neural sensitivity to normal hormone changes can result lability of a wide range of emotional, interpersonal, and behavioral symptoms; however, the biobehavioral mechanisms underlying these effects are not yet well understood. Borderline personality disorder (BPD) is a severe and costly psychiatric condition comprising labile symptoms across many domains of functioning. Our pilot data suggest three distinct biologically based mechanisms may produce cycle-based symptom exacerbation, contributing to symptom lability: 1) reactive and interpersonal symptoms due to irritability from changes in progesterone (P4) levels, 2) depressive symptoms due to impaired cognitive functioning and increased rumination during estrogen (E2) withdrawal, and 3) risk-taking symptoms due increased reward responsiveness during E2 peaks (ovulation). The objectives of this research are to test a model of three RDoC-consistent biologically-based mechanisms underlying how the menstrual cycle exacerbates psychopathology. A sample of 170 women ages 18 to 45 with ≥3 BPD symptoms will be recruited from specialized clinical services and social media. Participants will be comprehensively assessed for BPD and exclusion criteria (e.g., use of hormone-based medication or hormonal conditions). Participants will complete well-established assessment measures of BPD and other psychopathological symptoms and diagnoses during a baseline laboratory visit within the within the first few days of the start of their menstrual cycle. Then, they will provide complete questionnaires about BPD symptoms and proposed mechanisms every evening for two complete cycles. During one cycle, they will complete tasks targeted to key cycle phases, based on menses onset and ovulation test results, and daily urine samples for hormone assay each morning. Specific Aims. Aim 1 is to evaluate whether shifts in hormones across cycle predict within-person changes in symptoms consistent with proposed triadic hormone sensitivity theory, with rising levels of P4 predicting increases in rejection sensitivity, interpersonal conflict, and impulsive reactivity to stress, decreasing levels of E2 predicting increases in depression, hopelessness, and suicidal ideation, and peaks in E2 (ovulation) predicting increases in proactive aggression and substance misuse. Aim 2 is to evaluate whether proposed psychological mechanisms mediation associations between hormonal changes and symptom effects, with increased irritability expected to mediate P4 effects, decreased cognitive functioning expected to mediate E2 withdrawal effects, especially for individuals with greater rumination-proneness, and increased reward responsiveness expected to mediate ovulatory effects. An exploratory Aim 3 will examine the extent to which presence of these three forms of hormone sensitivity are associated. Findings will inform development of individualized, transdiagnostic interventions to mitigate the impact of cycle-based symptom exacerbation.