Growth Hormone Improves Spermatogenesis In Patients With Pituitary Stalk Interruption Syndrome And The Role Of Seminal Plasma Metabolomics In Predicting Spermatogenesi

Part Ⅰ Growth hormone is beneficial for induction of spermatogenesis in adult patients with pituitary stalk interruption syndromeContextGametogenesis disorder is a common problem for adult patients with pituitary stalk interruption syndrome(PSIS),leading to physical,psychological,and social stress.The primary treatment is gonadotropin therapy or pulsatile gonadotropin-releasing hormone therapy,which induces spermatogenesis in the majority of patients(75-90%).However,the extended duration of treatment cycles(1-3 years)leads to reduced adherence to therapy,which may impact the effectiveness of spermatogenesis.Previous research has demonstrated a reciprocal facilitation between the hypothalamic-pituitary-somatotropic(HPS)and the hypothalamic-pituitary-testicular(HPT)axis.Despite this knowledge,there is a paucity of research investigating whether recombinant human growth hormone(rhGH)combination therapy can enhance gonadotropin-induced spermatogenesis.ObjectiveThis study aimed to assess the efficacy of combining rhGH with gonadotropin treatment in facilitating early spermatogenesis among PSIS patients and to evaluate the impact of rhGH on metabolic parameters.MethodsWe did a retrospective study using recordings from patients with a confirmed diagnosis of PSIS admitted to a single center from mainland China between Dec 2019 and Dec 2021.Male patients were included if they were aged 18 years or older and had a desire for fertility.Participants were sorted into two groups:patients with a combination of rhGH and gonadotropins treatment(GH/Gn group)or patients with gonadotropin therapy alone(Gn group).The primary outcome was spermatogenesis(≥1 sperm/ejaculate)and secondary outcome included semen parameters,testicular volume,serum testosterone,and serum lipid parameters.ResultsSixty patients with PSIS were included,with a mean follow-up period of 21.5 months.According to the different treatment regimens,we included 31 patients in the GH/Gn group and 29 patients in the Gn group.The time for initial sperm appearance in the GH/Gn group was shorter than that in the Gn group(14 versus 23 months,P<0.001).The spermatogenesis rate was 96.77%(30/31)and 62.07%(18/29)in the GH/Gn and Gn group,respectively(P<0.001).A higher level of serum testosterone was achieved in the GH/Gn group than in the Gn group(4.79 versus 3.38 ng/mL,P=0.026).After adjustment for potential confounders,rhGH supplementation was an independent beneficial factor on earlier spermatogenesis(HR=2.29,95%CI:1.14-4.60,P=0.019).Additionally,the GH/Gn group exhibited a greater decrease in total cholesterol levels compared to the Gn group,with reductions of 0.38 mmol/L and 0.06 mmol/L,respectively(P=0.049).Triglyceride levels decreased significantly by 0.27 mmol/L in the GH/Gn group,whereas they remained largely unchanged in the Gn group(P=0.029).ConclusionOur findings suggest that the combination of rhGH with gonadotropin treatment induces earlier sperm production in patients with pituitary stalk disruption syndrome.Moreover,our results indicate that rhGH treatment reduces total cholesterol and triglyceride levels in this patient population.Part Ⅱ Prediction of gonadotropin therapy efficacy in pituitary stalk interruption syndrome by seminal plasma metabolomic analysisContextIt is well-established that gonadotropin supplementation is the mainstay of treatment to induce spermatogenesis in patients with pituitary stalk interruption syndrome(PSIS).However,the spermatogenesis induction protocol is often very long,with no objective biomarker currently available to predict treatment efficacy.Recently,metabolomics has been widely used to identify biomarkers for early disease detection and therapeutic efficacy prediction.No previous study has employed metabolomics to predict the longterm efficacy of gonadotropin therapy in PSIS patients.ObjectiveThis study aimed to explore potential predictive biomarkers for successful gonadotropin therapy in patients with PSIS based on seminal plasma metabolomic analysis.MethodsWe did a prospective,single-center cohort study in mainland China,including consecutive patients with a confirmed diagnosis of PSIS between Sep 2020 to Aug 2022.Male patients were included if they were aged 18-40 years and had a desire for fertility.All participants underwent gonadotropin therapy for 12 months and were separated into success and failure groups based on treatment response(onset of spermatogenesis).The seminal plasma samples were collected during the first phase of the follow-up and underwent metabolomics profiling using ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS).Orthogonal partial least square-discriminant analysis(OPLS-DA)and univariate statistical analyses were carried out to evaluate the discrepancy in metabolic parameters between the two groups.Finally,the associations between the differentially expressed metabolites and seminal parameters were explored.ResultsA total of 33 patients were enrolled in this study.According to the gonadotropin treatment response,21 and 12 patients were classified into success and failure groups,respectively.Metabolomics analysis uncovered 40 differentially expressed metabolites,mainly including lipids,amino acids,and benzenoids.Further analysis using Spearman’s correlation identified sulfatide(SHexCer(d34:1))as being closely related to sperm concentration(r=0.79,P<0.001),while lysophosphatidylcholine(LysoPC(22:6))was closely related to total sperm count(r=0.82,P<0.001).Receiver operating characteristic analysis of the identified metabolites showed excellent discrimination between the success and failure groups based on LysoPC(22:6)(AUC=0.92)and SHexCer(d34:1)(AUC=0.85).ConclusionOur data provide preliminary evidence that LysoPC(22:6)and SHexCer(d34:1)are promising biomarkers to predict the efficacy of gonadotropin therapy in PSIS male patients and are closely related to sperm outcomes.