Premature menopause and risk of kidney stone disease: evidence from the UK biobank and National Health and Nutrition Examination Survey.

Abstract

Objective: Kidney stone disease (KSD) is a global health burden. Premature menopause (PM) may increase the likelihood of KSD, but the influence of hormone therapy (HT) and genetic predisposition is unclear. We examined the association between PM and KSD in two large cohorts and evaluated potential modification by HT and polygenic risk scores (PRS).

Methods: We conducted cross-sectional analyses in 7,112 women from the National Health and Nutrition Examination Survey and 189,900 women from UK Biobank (UKB), with PM defined as menopause before age 40 years. Logistic regression estimated odds ratios (ORs) for prevalent KSD, and Cox models estimated hazard ratios (HRs) for incident KSD over a mean follow-up of ∼15 years in UKB. Sensitivity analyses and PRS stratification were performed to assess robustness and potential effect modification. Statistical analyses were conducted using R software.

Results: In National Health and Nutrition Examination Survey (N = 7,112), KSD prevalence was higher in women with PM compared with women without PM (13.4% vs. 8.4%), with logistic regression showing 50% higher odds (OR: 1.54, 95% CI: 1.11-2.13). In the UKB baseline analysis (N = 189,900), PM was associated with higher odds of KSD (OR: 1.55, 95% CI: 1.32-1.83). In the prospective cohort (N = 188,282), women with PM had a 29%-55% higher hazard of incident KSD (HR: 1.29-1.55). Cumulative hazard curves showed early divergence (P < 0.001). PRS analyses demonstrated increasing hazards of KSD with higher genetic predisposition (HR: 1.22-1.80). HT use partially attenuated, but did not eliminate, the elevated association.

Conclusion: PM was consistently associated with KSD across two large cohorts. This association remained robust across multiple analytical approaches. Genetic predisposition was associated with higher hazards of KSD, whereas HT did not meaningfully modify these associations. These findings suggest a clinically relevant link that warrants further investigation in prospective and mechanistic studies.