Molecular Mechanisms of Menstrual Cycle-Related Suicide Risk: A Selective Review of Promising Candidate Systems

Females of reproductive age experience more suicidal ideation, suicide attempts, and psychiatric hospitalizations than their male counterparts-with high risk during periods of hormonal transitions (e.g., puberty, the menstrual cycle, and pregnancy), suggesting a role for cyclical ovarian hormone fluctuations in suicide risk. This role is supported by cross-sectional and longitudinal studies showing that the menstrual cycle can trigger or exacerbate suicidal symptoms in susceptible individuals, particularly during the luteal and perimenstrual phases. However, brain-based mechanisms linking hormonal dynamics to suicidality remain underexplored. In hormone-sensitive individuals, normal fluctuations in estradiol (E2), progesterone (P4), and the neuroactive steroid allopregnanolone (ALLO) may disrupt the molecular mechanisms of mood regulation, cognitive processing, and behavioral control. This selective review synthesizes evidence across 6 promising molecular systems-serotonergic, GABAergic (gamma-aminobutyric acidergic), dopaminergic, neurotrophic, lipid, and DHEA(S) (dehydroepiandrosterone/dehydroepiandrosterone sulfate)-that are modulated by E2, P4, or ALLO and implicated in suicide pathophysiology. Drawing on neuroimaging, genetic, pharmacologic, and hormone manipulation studies, we describe potential mechanisms of cyclical suicide risk and their interactions with genetic and epigenetic vulnerability. Framed within the Dimensional Affective Sensitivity to Hormones across the Menstrual Cycle model, we outline the following research priorities: high-frequency within-person designs, hormone-informed neuroimaging, and personalized modeling approaches to identify modifiable, temporally precise mechanisms. Integrating menstrual cycle dynamics into suicide neuroscience may advance precision prevention for a large and underserved population.