Abstract
PURPOSE: This study aimed to investigate the causal relationship between sleep and Premature ovarian insufficiency (POI) using genetic methods and to evaluate the efficacy and safety of the Chinese herbal medicine Ningxin-Tongyu-Zishen Formula (NTZF) combined with hormone replacement therapy (HRT) on reproductive hormone levels and sleep quality in patients with POI through a clinical controlled trial. PATIENTS AND METHODS: A multi-stage research design was implemented. Initially, a cross-sectional analysis was conducted on 200 POI patients. Two -sample Mendelian randomization analysis (MR) was then performed using publicly available data from the UK Biobank and FinnGen to infer causal relationships. Finally, a clinical observational study involving 119 patients compared three regimens over a 6-month treatment period: NTZF combined with HRT, NTZF alone, and HRT alone. The primary outcomes were reproductive hormone levels and the Pittsburgh Sleep Quality Index (PSQI). RESULTS: Cross-sectional analysis showed that decreased sleep quality was an independent risk factor for altered reproductive hormone levels in POI patients. MR analysis further provided genetic evidence that insomnia may be a causal risk factor for POI. The clinical study indicated that NTZF combined with HRT was significantly more effective than either monotherapy in improving reproductive hormone levels, enhancing sleep quality, and overall clinical efficacy, with a favorable safety profile. CONCLUSION: This study confirmed a strong association between sleep quality and POI from both epidemiological and genetic perspectives. NTZF combined with HRT, as an integrated traditional Chinese and Western medicine therapy, can synergistically improve reproductive endocrine and sleep disturbances in POI patients, providing a new and effective strategy for clinical management.