Sleep Disruption and Shift Work Associate with Increased Risk of Reproductive Endocrine Disorders: Evidence from UK Biobank and Mendelian Randomization.

BACKGROUND

Disrupted sleep and shift work are linked to multiple adverse health outcomes, but their association with reproductive endocrine disorders (REDs) and underlying mechanisms remain unclear. Understanding this relationship is crucial for public health, given the growing prevalence of sleep disturbances and shift work in modern societies.

PURPOSE: To investigate the impact of sleep traits and shift work on RED risk in women, explore inflammatory mediation, and assess potential causality using Mendelian randomisation (MR).

METHODS

We analysed 244,561 women in the UK Biobank. Sleep duration, quality, and shift work were self-reported. Cox models estimated hazard ratios (HRs) adjusting for demographic, lifestyle, and comorbidities. Interaction models tested joint effects of sleep and shift work. Mediation analyses examined inflammatory biomarkers. Two-sample MR analyses were conducted using large-scale genome-wide association study (GWAS) summary statistics to evaluate causal effects of sleep length or sleep quality traits on REDs.

RESULTS

A U-shaped association was observed between sleep duration and RED risk, lowest at 7 h/day. Short (≤5 h/day; HR = 1.15, 95% CI: 1.02-1.31) and long (≥9 h/day; HR = 1.16, 95% CI: 1.04-1.29) sleep duration, poor sleep quality, and night shift work (HR = 1.40, 95% CI: 1.11-1.75) independently increased RED risk. The combination of night shift work and ≤5 h/day sleep duration showed the highest risk (HR = 1.72, p = 0.0219). Neutrophils, CRP, and leukocytes mediated 5-13% of these associations. MR analyses supported significant causal effects of short sleep duration, insomnia, and daytime napping on REDs.

CONCLUSION

Abnormal sleep duration, insomnia, and night shift work are independent risk factors for REDs in women, with inflammation partially mediating these associations. The highest risk was observed in women with short sleep combined with night shift work. MR analyses provide genetic evidence for the causal role of short sleep, insomnia, and daytime napping in REDs. These findings highlight the importance of screening for sleep disturbances and shift work in RED risk assessment, suggesting that interventions targeting sleep duration and shift work schedules may help reduce RED incidence and improve reproductive health. This study is the first to integrate both prospective and genetic evidence to identify causal pathways.