Hormonal contraceptives and depression: A proteomic analysis using neuronal models

Purpose: Hormonal contraceptives are linked to a higher prevalence of depressive symptoms. Given their popularity in Western countries, understanding the biochemical effects on neuronal cells is crucial to minimizing mental health risks.Experimental design: Neural progenitor cells were treated with ethinyl estradiol (EE) and levonorgestrel (LNG), two synthetic sex hormones commonly used in oral contraception, and S-23, a selective androgen receptor modulator developed as a potential synthetic sex hormone for male hormonal contraception. Label-based quantitative proteomics with the TMTpro 16plex tandem mass tags was used to assess protein expression changes between treated and untreated cells.Results: Treatment of human neural progenitor cells with EE, LNG, EE + LNG, and S 23 led to distinct and overlapping proteomic changes, with enrichment in pathways related to inflammation, oxidative stress, transcriptional regulation, and cell death. Disease association analyses linked these changes to neurodegenerative and psychiatric conditions, including mechanisms relevant to depression.Conclusions and Clinical Relevance: These findings suggest that hormonal compounds used in contraception and performance enhancement may influence molecular pathways implicated in mental health, particularly depression. While not directly translatable to clinical outcomes, the results support the need for further investigation into the neuropsychiatric effects of hormonal treatments.