The Correlation Of Urinary Phthalate Metabolites With Premature Thelarche In Girls And The Progression Of Premature Thelarche

Objective:Urine phthalic acid esters（PAEs）are one of estrogen-mimetic EDCs.Many studies have suggested that urinary phthalic acid esters（PAEs）are closely related to central precocious puberty（CPP）and isolated premature thelarche（IPT）,but there is no study between urinary PAEs and the progression of IPT.First,this study was designed to investigate the association of urinary PAEs metabolites with premature thelarche[idiopathic central precocious puberty（ICPP）、IPT]and pre-puberty girls aged6-8 years.The second part of this study is to explore the influence of PAEs on the progression of IPT to ICPP or early puberty（EP）.Methods:Patients with ICPP（160）and IPT（74）admitted to the Department of Endocrinology of Shenzhen Children’s Hospital from December 2018 to August 2019and 125 pre-pubertal controls with similar nutritional status were enrolled in this case-control study.1.109 CPP and 69 IPT girls were selected through the propensity matching score.Eight phthalate metabolites（creatinine adjusted）were measured in the first spot urine samples in the early morning.2.74 girls with IPT have been asked to be followed up regularly for one year.The girls were followed clinically every 3 months.Assessment of height,weight and pubertal staging was done and their bone age,uterine diameter and ovarian volume,gonadal homones levels were examined.In order to distinguish werther to ICPP/EP,sometimes,gonadotropin-releasing hormone stimulation test were selected.During the follow-up period,girls was divided into transformed group and untransformed group.Respectively,the clinical data（age of onset,diagnosis age,body mass index standard deviation score（BMI-SDS）,breast Tanner stage）,laboratory and imaging data（basal and peak luteinizing hormone,basal and peak follicle stimulating hormone,insulin-like growth factor-1（IGF-1）SDS,estradiol,uterine diameter,mean ovarian volume）of the two groups were compared.In order to identify independent risk factors affecting significantly the progression of IPT to ICPP/EP,we performed a binary logistic regression analysis（forward LR stepwise method）with the progression of IPT to ICPP/EP as the dependent variable.The independent variables were those shown to be significant（p<0.05）in the comparison between two groups（breast Tanner stage,mean ovarian volume,the sun of secondary oxidized Di-（2-ethylhexyl）phthalate（DEHP）metabolites（（50）₄DEHP,（50）₄DEHP=MEHHP+MEOHP+MECPP+MCMHP））,and other factors that may be clinically correlated（basic LH,IGF-1 SDS,uterine diameter）.Result:1.Girls were exposed in More than two PAE metabolites in this study.Low-molecular-weight（LMW）PAEs[Mono-n-butyl phthalate（MBP）,momoisobutyl phthalate（Mi BP）and the sum of LMW phthalate metabolites]were significantly higher in the CPP group than in the pre-pubertal control group and IPT group（P<0.05）.In the study,DEHP was lower around the world.DEHP was significantly lower in ICPP group than in the pre-pubertal control group and IPT group（P<0.05）.2.IPT girls were successfully followed up in 61 cases,39 cases in the untransformed group and 22 cases in the transformed group.The transformed group had significantly higher ovarian volume and breast Tanner stage than that in the untransformed group（P<0.05）.There were no significant difference in basal LH,basal FSH,peak LH,peak fsh,IGF-1,estradiol,uterine diameter between the untransformed group and transformed group（P>0.05）.The transformed group had significantly higher secondary oxidized DEHP metabolites（MECPP,MEHHP,MEOHP,MCMHP）and（50）₄DEHP than that in the untransformed group（all P<0.05）.There were no significant difference in other PAEs between the two groups（P>0.05）.Among the 61 IPT girls,breast Tanner stage（OR=3.75（1.08-13.01））,（50）₄DEHP（OR=3.12（1.33-7.27））were independent risk factors for the progression of IPT.Conclusions:1.All of girls in this research were exposed in PAEs.2.LMW phthalates were associated with CPP.In lower level of DEHP areas,DEHP may be not associated with precocious puberty.3.When breast Tanner stage or（50）₄DEHP is increased by one rank in a year,the possibility of IPT progressed to ICPP or EP may increase to 3.75 and 3.12 times respectively.