Correlation Study On Serum 25 Hydroxyvitamin D With Pregnancy Outcomes In ART With Different Phenotypes Of Polycystic Ovary Syndrome

Polycystic ovary syndrome(PCOS)is a common endocrine disease in women of reproductive age.In addition to biochemical changes such as abnormal menstruation and hyperandrogenism,it also affects about 40% of PCOS patients to suffer from infertility,which brings serious harm to the physical and mental health of patients.Vitamin D receptor(VDR)is expressed in almost all human cells.It is widely distributed in the ovary,endometrium and placenta in the female reproductive system,which is of great significance to female reproductive health.Liver 25-hydroxyvitamin D(25(OH)D)is used to assess the true status of serum vitamin D in humans because of its longest half-life and final structure.Most studies have shown that proper serum 25(OH)D can predict the success rate of assisted reproductive technology and have a beneficial effect on all stages of in vitro fertilization-embryo transfer(IVF-ET).However,some scholars still say that25(OH)D is not correlated or negatively correlated with pregnancy outcomes.Therefore,this study intends to investigate the correlation between different phenotypes of PCOS and vitamin D levels through retrospective analysis.At the same time,meta-analysis was used to further explore the effect of exogenous vitamin D supplementation on sex hormone changes and pregnancy outcomes in women with PCOS.Part I: Association of serum 25(OH)D with IVF outcomes in different clinical phenotypes of polycystic ovary syndrome.Objective: To investigate the correlation between serum 25(OH)D and sex hormone changes,embryo culture and IVF outcomes in different phenotypes of PCOS.Methods: Retrospectively collected The medical records of 689 infertility patients who underwent IVF-ET therapy for the first time from January 2020 to June2021 at the Fertility Center of the First Hospital of Lanzhou University,including 305 cases in the PCOS group and 384 cases in the tubal infertility-only group.Firstly,we compared the basic information and differences in serum 25(OH)D levels between the two groups;secondly,we analyzed the differences in general information,embryo culture and pregnancy outcome under different clinical phenotypes of PCOS and different 25(OH)D levels by cohort study;finally,we used one-way analysis of variance,multiple logistic regression analysis and curve fitting to assess the effects of serum 25(OH)D concentration on key quality control indicators and pregnancy outcome in patients with PCOS.Results:1.689 infertility patients were included in this study,including 305 patients with PCOS and tubal infertility-only 384 cases.25(OH)D was significantly lower in the PCOS group than in the tubal infertility-only group(11.4±4.6ng/ml vs 12.7±5.5ng/ml,P<0.003),and basic data and metabolic indicators such as age,menstrual period and cycle,AFC,BMI,AMH,TC,TG,LDL-C,HDL-C were also significantly different from the tubal infertility-only group(P<0.05).2.In this study,the incidence of four phenotypes of PCOS was the highest in type C(ovulatory type)30%(92/305),the lowest in type A(complete type)20 %(62/305),followed by type B(non-PCO type)and type D(non-hyperandrogenic type).There were significant differences in menstrual cycle,BMI,AFC and AMH,25(OH)D,FSH,LH and TT,the total number of 2PN,the number of transferable embryos and the rate of MⅡ oocytes among the four phenotypes(P <0.05).3.According to the definition of vitamin D deficiency in the Institute of Medicine(IOM)guidelines,113 cases of vitamin D deficiency in 305 PCOS patients in this study,accounting for 37.05%;Vitamin D insufficiency in 150 cases,accounting for49.18%;There were 42 patients with vitamin D sufficiency,accounting for 13.77%,and no patients with vitamin D excess were found.Through the cohort study,it was found that the degree of vitamin D deficiency was significantly correlated with LH,total number of follicles on HCG day,total number of 2PN,D3 available embryos,D3high-quality embryos,transferable embryos,number of follicles >14mm on HCG day,total MⅡ and endometrial thickness on embryo transfer day(P <0.05).4.Univariate analysis of the number of MⅡ,2PN and pregnancy outcomes in the key quality control indicators of the embryo extraction laboratories showed that serum25(OH)D level was correlated with the number of MⅡ,2PN,clinical pregnancy rate and live birth rate(P =0.0008,P =0.0001,P <0.0001,P <0.0001).After adjusting for confounding factors such as BMI,age and duration of infertility,multivariate logistic regression analysis still supported the above conclusion: the correlation between25(OH)D and the total number of MⅡ,the total number of 2PN,the clinical pregnancy rate,and the live birth rate was: P =0.0007,P <0.0001,P <0.0001,P<0.0001.Curve fitting intuitively showed that there was a curvy relationship between25(OH)D and the outcome of assisted reproductive technology in PCOS patients: with the increase of 25(OH)D,the total number of MⅡ,the total number of 2PN,the clinical pregnancy rate and the live birth rate generally showed an upward trend(P<0.05).Conclusion:1.serum vitamin D deficiency or insufficiency was prevalent in infertility patients undergoing IVF-ET assisted conception in this study,more so in patients with PCOS;there were significant differences in general condition,sex hormonal changes and embryo culture in patients with different phenotypes of PCOS(P<0.05).2.There was a significant correlation between the degree of vitamin D deficiency and serum 25(OH)D,sex hormone levels,embryo culture status,and clinical pregnancy;25(OH)D was positively correlated with total MII,total 2PN,clinical pregnancy rate,and live birth rate,and there was an overall increasing trend in the above pregnancy outcomes with increasing 25(OH)D(P<0.05).3.Both the different clinical phenotypes and the degree of vitamin D deficiency had a large impact on PCOS patients,especially the differences in sex hormones and embryonic development interfered with pregnancy outcomes to different degrees.Therefore,the present study may explain the controversy of some scholars who concluded that there is no or negative correlation between vitamin D and PCOS assisted conception outcome.Part Ⅱ: Effect of exogenous vitamin D supplementation on pregnancy outcome and sex hormone levels in polycystic ovary syndrome-Meta-analysis based on the GRADE systemObjective: To systematically evaluate the effects of exogenous vitamin D supplementation on menstrual cycles,clinical pregnancy rates and related sex hormone changes in patients with PCOS,and to evaluate the evidence level of the observed indicators using the GRADE system.Methods: Computer searches of Medline,Embase,CENTRAL,Clinicaltrials.gov,Web of science,CBM,CNKI,VIP database,and Wanfang database to collect randomized controlled trials(RCTs)about PCOS patients given vitamin D in the experimental group and placebo in the control group,and the search time frame was established until November 2022(see the attached figure for details of the specific search formula).The study used Rev Man 5.4 software for Meta-analysis and GRADEprofile for evidence quality grading.Results: A total of 15 RCT studies,including 796 patients,found in the 9 search databases.1.Compared with placebo,exogenous vitamin D supplementation significantly increased increased pregnancy rate(RR=2.01,95%CI: 1.31～3.11,P=0.002),increased total antioxidant capacity(TAC)(SMD=0.45,95%CI: 0.45～2.21,P=0.03);decreased testosterone(SMD=-0.64,95% CI:-0.96～-0.32,P=0.01),hypersensitive C-reactive protein(hs-CRP)(SMD=-1.08,95%CI:-1.73～-0.44,P=0.001),malondialdehyde(MDA)(MD=-0.45,95% CI:-0.65～-0.26,P=0.001).2.No statistical difference was found in the exogenous administration of vitamin D supplementation in improving menstruation and inducing dominant follicle maturation(P >0.05).3.GRADE evidence grading confirmed that the evidence grading for menstruation,follicle maturation,testosterone levels,MDA and TAC,which were observed in this study were low;moderate quality evidence was found for pregnancy rate and hs-CRP.Conclusions: Vitamin D supplementation significantly increased clinical pregnancy rates and antioxidant levels and significantly decreased testosterone levels and inflammatory indicators in patients with PCOS;As moderate quality evidence for increasing pregnancy rates,decreasing hs-CRP,and MDA,and low quality evidence for improving menstruation and inducing dominant follicles,decreasing testosterone,and increasing TAC,as assessed by the GRADE evidence system.