Genetic contributions to premenstrual symptoms: revisiting the role of the ESR1 gene

Abstract Premenstrual dysphoric disorder (PMDD) and its subclinical form categorized as premenstrual syndrome (PMS), are severe mood disorders characterized by cyclical depressive symptoms, anxiety, irritability, and other functional impairments, impacting a broad range of women during the late luteal phase. The estrogen receptor 1 ( ESR1) gene encodes the estrogen receptor alpha (ERα) which plays a critical role in mediating estrogen signaling and regulates various physiological and psychological processes. In this study, we investigated the relationship between six single nucleotide polymorphisms (SNPs) in intron 4 of the ESR1 gene and premenstrual symptom severity, emphasizing symptom- genotype associations and SNP interactions. Results demonstrated that specific SNPs were linked to distinct symptom profiles, such as anxiety, difficulty concentrating, and sleep disturbances. Interactions between SNPs revealed both risk-enhancing and protective effects. These findings suggest that premenstrual symptoms may stem from a genotype-linked reduced sensitivity to ovarian hormones, providing a foundation for future research.