A Study Of The Association Between Desmopressin Use And Poor Spermatogenesis In Patients With Pituitary Stalk Interruption Syndrome And Genetic Testing Of Patients

IntroductionPSIS refers to a developmental defect characterized by the triad of an absent or thin pituitary stalk,pituitary hypoplasia,and/or ectopic neurohypophysis,with an incidence of 1 in 200000.Due to heterogeneous pituitary stalk interruption,patients suffer from varying degrees of pituitary hormone deficiency.The main clinical manifestations are growth retardation and absent pubertal development,with or without other midline deformities,including cleft lip,cleft palate,and optic nerve hypoplasia.Patients require life-long hormone replacement therapy,and combinational therapy with human chorionic gonadotropin(HCG)and human menopausal gonadotropin(HMG)can induce spermatogenesis.Lack of arginine vasopressin(AVP)in PSIS is less common.Desmopressin is a long-acting analog of AVP,and is commonly used for patients with central diabetes insipidus(CDI).Studies have found that sperm count and motility in infertile men are negatively correlated with urine AVP levels.Hence,we speculate that desmopressin may have adverse effects on spermatogenesis in PSIS patients while treating central diabetes insipidus.Since all PSIS patients have growth hormone deficiency,it is not clear whether the supplementation of GH could improve spermatogenesis rate and semen quality.In subgroup analyses,we compared the effects of GH replacement therapy on spermatogenic rate and semen quality.ObjectiveTo explore the correlation of desmopressin administration and gonadotropin-induced spermatogenesis in patients with pituitary stalk interruption syndrome(PSIS).Subjects and MethodsA single-center retrospective cohort study was conducted.Retrospective analysis of 85 male patients diagnosed with PSIS who were treated with HCG 5000u combined with HMG 150u i.m.weekly at the Peking Union Medical College Hospital from January 2012 to May 2019.All patients with PSIS had both gonadotropin and growth hormone(GH)deficiency.Patients were divided into desmopressin(n=19)and nondesmopressin(n=66)groups.The desmopressin and nondesmopressin groups were defined by the presence or absence of central diabetes insipidus,which determined whether the patient received desmopressin or not.Results1.The average age of gonadotropin therapy was 24.3 and 26.1 in the desmopressin and nondesmopressin groups,respectively(P=0.253).2.The rate of successful spermatogenesis in the 2 groups was 31.58%and 77.27%,respectively(p=0.003).The period for first sperm appearance was 13.62±5.95 and 13.48±6.69 months,respectively(P=0.962).3.Cox multivariable regression analysis revealed that the risk of spermatogenesis was significantly decreased in desmopressin group(hazard ratio 0.26),with a trend toward decreased risk with higher dose of desmoressin(P<0.01).4.In the nondesmopressin group,the rate of spermatogenesis was similar between the GH group and the non-GH subgroup(73.0%VS.82.1%,P=0.385).5.The GH group had higher sperm count and concentration than the non-GH group.Conclusion1.A minority of patients with PSIS have mild diabetes insipidus and need desmopressin therapy.2.Desmopressin is associated with poor spermatogenesis in PSIS patients.The more serious diabetes insipidus,the more the dose of desmopressin;the lower the spermatogenesis rate as well.3.Desmopressin therapy may be a "marker" of more severe pituitary developmental defects that result in not only central diabetes insipidus but also hypothalamic-pituitary-gonadal axis abnormalities.4.Adults GH supplementation doesn’t affect the spermatogenesis rate.IntroductionPituitary stalk interruption syndrome(PSIS)consisting of the triad:ectopic posterior pituitary,thin or absent pituitary stalk and anterior pituitary hypoplasia is a rare pituitary malformation with variable degrees of pituitary insufficiency,Genetic defects were identified in less than 5%of cases,consisting of mutations,deletions or sequence variations in HESX1,OTX2,LHX4,LHX3,PROKR2,GPR161,CDON,TGIF,GLI2,FGFR1,ARNT2,CHD7 and chromosomal defects such as 18p deletion.Pituitary stalk interruption syndrome(PSIS)is rare and its clinical features and pathogenesis are poorly understood.ObjectiveThis study characterized the clinical and genetic features of PSIS in Chinese patients without perinatal adverse events(PAEs).Patients and DesignClinical data of 10 patients with PSIS without PAEs were collacted.Whole-exome sequencing were performed on them.ResultsDeficiency of GH、TSH and gonadotropin was 100%in both PSIS groups.Other deficiency rates were:ACTH,80%;TSH,90%;AVP,20%.A total of 38 heterozygous mutations and one homozygous mutation were detected in 35 related genes in 10 patients.Among them,the genes with highest mutation frequency are RELN,NCOR2,BRIP1,and CFTR,which could not directly lead to pituitary dysplasia.The mutation frequency of BMP4、BMP2、HHAT which has been reported as the causative gene associated with pituitary dysplasia was 40%.ConclusionsThe frequency of reported gene mutation associated with PSIS in patients without PAEs is low.