Risk Factors And Inflammatory Mechanism Of Polycystic Ovary Syndrome In Patients With Bipolar Disorder

Objective:This dissertation aims to investigate the risk factors of polycystic ovary syndrome(PCOS)among patients with bipolar disorder and analyze the impact of bipolar disorder itself on the development of PCOS,reveal the inflammatory mechanisms underlying the development of PCOS in patients with bipolar disorder through proteomic studies,and validate these mechanisms in clinical samples.Methods:1.A cross-sectional study involved 72 first-diagnosed drug-na?ve patients with bipolar disorder,72 long-term medication-treated women patients with bipolar disorder,and 98 women healthy controls.General demographic and clinical data were collected for all participants,and metabolic indicators such as lipid levels,fasting blood glucose,and fasting insulin were measured,along with reproductive hormone markers including total testosterone(TT),androgens,dehydroepiandrosterone sulfate(DHEAS),sex hormone-binding globulin(SHBG),and anti-Müllerian hormone(AMH).Menstrual information was recorded,and pelvic ultrasounds were performed.The objective was to assess the risk of PCOS and related reproductive disorders in first-diagnosed drug-na?ve women patients with bipolar disorder and analyze the impact of bipolar disorder itself on the development of PCOS.Additionally,the study aimed to explore the correlation between valproate,demographic factors,clinical and metabolic indicators,and the development of PCOS in patients with bipolar disorder.2.A longitudinal study involved 50 first-diagnosed drug-na?ve women patients with bipolar disorder who were followed up at baseline and after six months.Based on their medication usage during the follow-up period,they were divided into three groups:drug-na?ve patients,valproate-treated patients,and non-valproate-treated patients.The changes in reproductive markers before and after the follow-up period were compared among the three groups,and the association between early course of illness,valproate,and the development of PCOS along with changes in reproductive markers was analyzed.3.A inflammatory mechanism study collected peripheral blood mononuclear cell samples from 15 first-diagnosed drug-na?ve women patients with bipolar disorder(including 5 comorbid with PCOS and 10comorbid without PCOS)and 5 women healthy controls for proteomics analysis.Proteomics techniques were employed to explore and validate the immune-inflammatory-related proteins and pathways involved in the pathogenesis of PCOS in patients with bipolar disorder.Subsequently,ten peripheral serum inflammatory factors,including IL-2、IL-6、IL-8、IL-1βand IL-12p70,were detected in 66 matched first-diagnosed drug-na?ve patients and healthy controls to validate the results of the proteomics study.Results:1.The cross-sectional study:The comparison results of first-diagnosed drug-na?ve patients with bipolar disorder and healthy contraols showed that the incidence of menstrual rareness/amenorrhea(χ~2=9.14,p=0.004),length of menstrual cycle(Z=-4.28,p<0.001),anti-mullerian hormone level(AMH)(Z=-1.97,p=0.049),luteotropic hormone(LH)level(Z=-2.50,p=0.012),incidence of polycystic ovarian morphology(χ~2=8.76,p=0.005),antral follicle count(AFC)(Z=-4.07,p<0.001),2-5mm follicle count(t=-4.13,p<0.001),and ovarian volume(Z=-2.17,p=0.029)in first-diagnosed drug-na?ve patients were all higher than those in the healthy controls,with statistically significant differences.The follicle-stimulating hormone(FSH)level(Z=-2.06,p=0.039)and LH:FSH(Z=-2.86,p=0.004)in first-diagnosed drug-na?ve patients were significantly lower than those in the healthy controls,with statistically significant differences.The incidence of PCOS in first-diagnosed drug-na?ve patients was significantly higher than that in healthy controls,with statistically significant differences(χ~2=7.35,p=0.011),with an OR of 2.86(β=1.05,95%CI:1.21-6.76,p=0.017).After controlling for demographic and statistical confounding factors through multiple conditional logistic regression analysis,the difference still had statistical significance,and the adjusted OR was 3.98(β=1.38,95%CI:1.04-15.33,p=0.044).The comparison results between first-diagnosed drug-na?ve patients with bipolar disorder and long-term medication-treated patients with bipolar disorder showed that BMI,triglyceride(TG)level,AMH level,2-5mm follicle count,and the incidence of PCOS in valproate-treated patients were significantly higher than first-diagnosed drug-na?ve patients(p<0.05).The dehydroepiandrosterone sulfate(DHEAS)level in first-diagnosed drug-na?ve patients was significantly higher than that in valproate-treated patients(p<0.05).Further analysis using multiple logistic regression showed that long-term use of valproate(β=1.35,p=0.031),younger age(β=-0.97,p=0.040),and higher insulin resistance index(β=0.54,p=0.017)were risk factors of PCOS in patients with bipolar disorder.2.The comparison results of the longitudinal study showed that there were no statistically significant differences between the three groups for the inter-group comparison at baseline and after six months.However,the valproate-treated patients showed a significant increase in the incidence of menstrual rarity/amenorrhea,free androgen index(FAI),and AMH level compared to baseline after 6 months(p<0.05),and the the non-valproate-treated patients also showed an increase in the incidence of menstrual rarity/amenorrhea compared to baseline after 6months(p<0.05).3.The inflammatory mechanism study:The proteomic study results showed that T lymphocyte immune disfunction was found to be a common differential protein functional item between drug-na?ve patients and healthy controls,as well as between drug-na?ve patients with and without PCOS.The results of inflammatory factor detection in clinical samples showed that the levels of IL-8 and IL-13 in first-diagnosed drug-na?ve patients were significantly higher than those in the healthy controls(P<0.05).Moreover,the level of IL-8 in first-diagnosed drug-na?ve patients comorbid with PCOS was also obviously higher than that in whose comorbid without PCOS(P=0.07).Conclusion:1.Patients with bipolar disorder are more susceptible to PCOS.In addition,long-term use of valproate,younger age,and higher insulin resistance index further increase the risk of developing PCOS.2.Abnormal activation of T lymphocytes-mediated chronic inflammatory response may be an important mechanism in the development of PCOS in patients with bipolar disorder,and the level of IL-8 in peripheral blood may play a significant regulatory role in this process.