Association between adverse life events, DNA methylation and risk of premature ovarian insufficiency

This study aimed to assess psychological and lifestyle risk factors for premature ovarian insufficiency (POI) and their association with DNA methylation. A case–control study was conducted in Shanghai (2017–2022), including 304 controls and 160 newly diagnosed cases with POI (diagnosed within the past 6 months). Cumulative adverse life events were assessed using the life event scale (LES), and genome-wide DNA methylation was evaluated in whole blood-derived DNA obtained from a sub-sample. The median total event score for POI patients and control individuals was 48.5 and 20.0, respectively (p < 0.001). Participants experiencing more stressful life events (LES >32) were 2.33‐fold more likely to have POI compared to controls (odds ratio 2.33, 95% confidence interval 1.53–3.56). Genome-wide DNA methylation analysis identified 5582 differentially methylated sites (DMSs) between POI patients and controls. Further analysis showed that higher negative life events scores were significantly associated with accelerated DNA methylation aging in the POI group (β = 0.06, p < 0.001). This case–control study revealed that cumulative stressful or adverse life events were associated with an increased risk of POI, and that accelerated epigenetic aging was correlated with chronic stress in POI patients. These findings suggest potential links that warrant further mechanistic investigation. Premature ovarian insufficiency (POI) occurs when ovarian function declines before age 40 and can lead to infertility and long-term health risks. While genetic and medical causes are known, the role of psychological stress remains unclear. In this study, we compared women with newly diagnosed POI to healthy women of similar age. Women with POI reported significantly more stressful life events, particularly related to family and work, and high stress levels were associated with a higher risk of POl. Blood-based DNA methylation analysis showed that women with POI had specific epigenetic changes and signs of accelerated biological aging. These findings suggest that chronic psychological stress may contribute to biological alterations linked to POI, highlighting the importance of psychological support in women’s reproductive health care.