Identification Of Nonclassical 21-hydroxylase Deficiency And Polycystic Ovary Syndrome

Background and objective:The clinical manifestation of nonclassical 21-hydroxylase deficiency(NC21-OHD)and polycystic ovary syndrome(PCOS)complicated with hyperandrogen are similar.The laboratory and imaging examinations of the two diseases are overlapped and both lack specific diagnostic criteria.Therefore,NC21-OHD is easily misdiagnosed as PCOS in clinical practice that ineffective treatment is carried out for a long time.The study intends to explore the differential diagnosis methods between NC21-OHD and PCOS by camparing the clinical data of 31 confirmed NC21-OHD and 29 identified PCOS patients complicated with hyperandrogen,so as to provide theoretical basis for early accurate diagnosis and treatment of the two diseases.Patients:We randomly selected for 31 women with NC21-OHD and 29 patients with PCOS complicated with hyperandrogen diagnosed in the Endocrine Department of the First Affiliated Hospital of Zhengzhou University from January 2015 to December 2019.Methods:1.The detection results of serum electrolytes,blood lipids,follicle stimulating hormone(FSH),Luteinizing hormone(LH),prolactin(PRL),cortisol(COR),sex hormone binding globulin(SHBG),renin activity(PRA),aldosterone(ALD),Oral glucose tolerance test(OGTT)and insulin release test were collected.The body mass index(BMI),LH/FSH ratio,free testosterone index(FAI),homeostasis model insulin resistance index(HOMA-IR),glucose area under curve(GAUC)and insulin area under curve(IAUC)were calculated.The detection results of adrenocorticotrophin hormone(ACTH),17-hydroxy progesterone(17-OHP),progesterone(P),totaltestosterone(TT),dehydroepiandrosterone sulfate(DHEAS)and androstenedione(AD)before and after the 1-day medium-dose dexamethasone inhibition test(DAST)were collected,and the percentage of decline of each index was calculated as the inhibition rates.FSH,LH,P,TT,PRL,DHEAS,AD and 17-OHP were measured on the 2nd to 4th day of the menstrual cycle or on any day for amenorrhea patients.The results were also collected for the uterine adnexal ultrasound,liver ultrasound and adrenal enhancement CT of all patients as well as the mutation of CYP21A2 gene in 25 patients with NC21-OHD.2.The clinical manifestations,imaging features,hormone levels and metabolic indexes of 31 patients with NC21-OHD were cpmpared with those of 29 women with PCOS.The ROC curve was used to analyze the differential diagnostic value of each index for the two diseases.3.SPSS22.0 and MedCalc v1 9.0.7 statistical software were used to analyze the data.The difference was statistically significant with P<0.05.Results:1.Women with NC21-OHD showed a higher prevalence of adrenal hyperplasia and lower height and likelihood of polycystic ovary(PCO)than those with PCOS(P<0.05).There was no significant difference in age,BMI,systolic blood presure,diastolic blood pressure,serum potassium,serum sodium and the incidence of menstrual disorder,infertility and hirsutism between the two groups(P>0.05).There were 12 patients(38.71%)with slight clitoral hypertrophy in NC21-OHD group,but this feature was not obvious in PCOS group.2.The levels of ACTH,17-OHP,AD,P,TT and PRL were mush higher in NC21-OHD group compared with the PCOS group(P<0.05).Women with PCOS had higher levels of LH and LH/FSH ratio than those with NC21-OHD(P<0.05).ROC curves analysis was carried out for the above indicators.The area under the curve(AUC)was 0.673,0.959,0.848,0.917,0.786,0.686,0.843 and 0.867,respectivelly.It was found that there was no significant difference in AUC among 17-OHP,P and LH/FSH(P>0.05),but which were signigicantly greater than AUC of other indexes(P<0.05).According to Youden index,the optimal cut-off points of 17-OHP,P and LH/FSH were 3.34 ng/ml(sensitivity 89.7%,specificity93.1%),0.64 ng/ml(sensitivity 90.0%,specificity75.9%)and 1.25(sensitivity85.7%,specificity85.7%),respectively.Correlation analysis of 17-OHP and P in NC21-OHD group showed that there was a significant positive correlation(P<0.05),while LH/FSH had no significant correlation with 17-OHP or P(P>0.05).3.During the 1-day mid-dose dexamethasone suppression test(DAST),women with NC21-OHD had higher inhibition rates of 17-OHP,AD,TT and P than those with PCOS(P<0.01).The ROC curve analysis of the above indicators showed that AUC was 0.996,0.972,0.960 and 0.873,respectively.The AUC of inhibition rates of 17-OHP,AD,TT and P were compared,and it was found that there was no significant difference(P>0.05).According to Youden index,the best cut-off values of suppression rates were 73.5%(sensitivity 95.2%,specificity 100.0%),55.5%(sensitivity 100%,specificity 88.9%),61.4%(sensitivity 84.2%,specificit 100.0%),54.2%(sensitivity 85.0%,specificity 80.0%),respectively.4.The incidence of overweight or obesity,abnormal elevation of blood sugar,hyperlipidemia,fatty liver and metabolic syndrome in the two groups had no significant difference(P>0.05).In OGTT and insulin release test,there was no significant difference in blood glucose and insulin levels between the two groups at each time point(P>0.05),and there was no statistical difference in HOMA-IR,GAUC and IAUC between the two groups(P>0.05)5.In NC21-OHD group,HOMA-IR was positively correlated with BMI(P<0.05),and neatively correlated with high density lipoprotein(HDL)(P<0.05).There was no significant correlation between TT with HOMA-IR,BMI in NC21-OHD groups(P>0.05).HOMA-IR in PCOS group has a siginificant positive correlation with BMI,triglyceride(TG)and low density lipoprotein(LDL)(P<0.05).HOMA-IR and HDL in PCOS group showed siginificantly negative correlation(P<0.05).In PCOS group,TT was negatively correlated with HDL(P<0.05)and TT was positively correlated with TG(P<0.05).There was no significant correlation between TT with HOMA-IR,BMI in PCOS groups(P>0.05).6.CYP21A2 gene was detected in 25 patients with NC21-OHD.20.0%(5/25)of patients were homozygous mutations and 80.0%(20/25)of patients were compound heterozygous mutation.Among the 50 alleles,17 mutations were tested,of which c.518T>A(p.I173N(12/50,24.0%)and c.844G>T(p.V282L)(11/50,22.0%)were the most common mutation types.Conclutions:1.For polycystic ovary patients complicated with hyperandrogenism,whose serum P level repeatedly checked in follicular phase is higher than the upper limit of follicular phase and LH/FSH is not significantly increased,the posssibility of congenital adrenal hyperplasia(CAH)should be considered.If serum 17-OHP level is higher in follicular phase,NC21-OHD is highly suggested.2.If 17-OHP,P and LH/FSH alone are difficult to identify NC21-OHD and PCOS complicated with hyperandrogen,and the gene detection is performed unconditionally,the 1-day mid-dose DAST can be applied to identify the two diseases.