Prevalence of gene mutations in a Chinese 46,XY disorders of sex development cohort detected by targeted next-generation sequencing / 亚洲男科学杂志(英文版)

46,XY disorders of sex development (DSD) is characterized by incomplete masculinization genitalia, with gonadal dysplasia and with/without the presence of Müllerian structures. At least 30 genes related to 46,XY DSD have been found. However, the clinical phenotypes of patients with different gene mutations overlap, and accurate diagnosis relies on gene sequencing technology. Therefore, this study aims to determine the prevalence of pathogenic mutations in a Chinese cohort with 46,XY DSD by the targeted next-generation sequencing (NGS) technology. Eighty-seven 46,XY DSD patients were enrolled from the Peking Union Medical College Hospital (Beijing, China). A total of fifty-four rare variants were identified in 60 patients with 46,XY DSD. The incidence of these rare variants was approximately 69.0% (60/87). Twenty-five novel variants and 29 reported variants were identified. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, thirty-three variants were classified as pathogenic or likely pathogenic variants and 21 variants were assessed as variants of uncertain significance. The overall diagnostic rate was about 42.5% based on the pathogenic and likely pathogenic variants. Androgen receptor (AR), steroid 5-alpha-reductase 2 (SRD5A2) and nuclear receptor subfamily 5 Group A member 1 (NR5A1) gene variants were identified in 21, 13 and 13 patients, respectively. The incidence of these three gene variants was about 78.3% (47/60) in patients with rare variants. It is concluded that targeted NGS is an effective method to detect pathogenic mutations in 46,XY DSD patients and AR, SRD5A2, and NR5A1 genes were the most common pathogenic genes in our cohort.

Predictive factors for pituitary response to pulsatile GnRH therapy in patients with congenital hypogonadotropic hypogonadism / 亚洲男科学杂志(英文版)

Pulsatile gonadotropin-releasing hormone (GnRH) may induce spermatogenesis in most patients with congenital hypogonadotropic hypogonadism (CHH) by stimulating gonadotropin production, while the predictors for a pituitary response to pulsatile GnRH therapy were rarely investigated. Therefore, the aim of our study is to investigate predictors of the pituitary response to pulsatile GnRH therapy. This retrospective cohort study included 82 CHH patients who received subcutaneous pulsatile GnRH therapy for at least 1 month. Patients were categorized into poor or normal luteinizing hormone (LH) response subgroups according to their LH level (LH <2 IU l-1 or LH ≥2 IU l-1) 1 month into pulsatile GnRH therapy. Gonadotropin and testosterone levels, testicular size, and sperm count were compared between the two subgroups before and after GnRH therapy. Among all patients, LH increased from 0.4 ± 0.5 IU l-1 to 7.5 ± 4.4 IU l-1 and follicle-stimulating hormone (FSH) increased from 1.1 ± 0.9 IU l-1 to 8.8 ± 5.3 IU l-1. A Cox regression analysis showed that basal testosterone level (β = 0.252, P = 0.029) and triptorelin-stimulated FSH60min(β = 0.518, P = 0.01) were two favorable predictors for pituitary response to GnRH therapy. Nine patients (9/82, 11.0%) with low LH response to GnRH therapy were classified into the poor LH response subgroup. After pulsatile GnRH therapy, total serum testosterone level was 39 ± 28 ng dl-1 versus 248 ± 158 ng dl-1 (P = 0.001), and testicular size was 4.0 ± 3.1 ml versus 7.9 ± 4.5 ml (P = 0.005) in the poor and normal LH response subgroups, respectively. It is concluded that higher levels of triptorelin-stimulated FSH60minand basal total serum testosterone are favorable predictors of pituitary LH response to GnRH therapy.

Pulsatile gonadotropin-releasing hormone therapy is associated with earlier spermatogenesis compared to combined gonadotropin therapy in patients with congenital hypogonadotropic hypogonadism / 亚洲男科学杂志(英文版)

Both pulsatile gonadotropin-releasing hormone (GnRH) infusion and combined gonadotropin therapy (human chorionic gonadotropin and human menopausal gonadotropin [HCG/HMG]) are effective to induce spermatogenesis in male patients with congenital hypogonadotropic hypogonadism (CHH). However, evidence is lacking as to which treatment strategy is better. This retrospective cohort study included 202 patients with CHH: twenty had received pulsatile GnRH and 182 had received HCG/HMG. Patients had received therapy for at least 12 months. The total follow-up time was 15.6 ± 5.0 months (range: 12-27 months) for the GnRH group and 28.7 ± 13.0 months (range: 12-66 months) for the HCG/HMG group. The median time to first sperm appearance was 6 months (95% confidence interval [CI]: 1.6-10.4) in the GnRH group versus 18 months (95% CI: 16.4-20.0) in the HCG/HMG group (P 1 × 10 6 ml-1 was 43.7% ± 20.4% (16 samples) in the GnRH group versus 43.2% ± 18.1% (153 samples) in the HCG/HMG group (P = 0.921). Notably, during follow-up, the GnRH group had lower serum testosterone levels than the HCG/HMG group (8.3 ± 4.6 vs 16.2 ± 8.2 nmol l-1 , P < 0.001). Our study found that pulsatile GnRH therapy was associated with earlier spermatogenesis and larger testicular size compared to combined gonadotropin therapy. Additional prospective randomized studies would be required to confirm these findings.

Lipopolysaccharide, TNFα, IL-6, dexamethasone, and insulin increase the expression of GPR54 in the MCF7 breasr cancer cell line / 中华男科学杂志

<p><b>OBJECTIVE</b>To investigate the effects of different concentrations of lipopolysaccharide (LPS), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), dexamethasone (Dex), and insulin on the mRNA and protein expressions of GPR54 in the MCF7 cell line in vitro.</p><p><b>METHODS</b>MCF7 breasr cancer cells were cultured and treated with different concentrations of LPS (10 and 20 µg/ml), TNFα (20 and 100 ng/ml), IL-6 (10 and 20 ng/ml), Dex (10(-6) and 10(-7) mol/L), and insulin (0.01 and 0.1 IU/L). Those treated with culture fluid only served as controls. The mRNA and protein expressions of GPR54 were measured by real-time PCR and Western blot, respectively, after 6, 24, 48, and 72 hours of treatment.</p><p><b>RESULTS</b>Compared with the blank con- trol, LPS (10 and 20 µg/ml), TNFα (20 and 100 ng/ml), IL-6 (10 and 20 ng/ml), Dex (10(-6) and 10(-7) mol/L), and insulin (0.01 and 0.1 IU/L) significantly increased the expressions of GPR54 mRNA (P < 0.05) and protein (P < 0.05).</p><p><b>CONCLUSION</b>LPS, TNFα, IL-6, Dex, and insulin evidently increase the expression of GPR54 in the MCF7 cell line, indicating their influence on the function of gonads by regulating the GPR54 level.</p>

Relationship between serum uric acid level and metabolic syndrome in Uygur children and adolescents with overweight or obesity / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study the relationship between serum uric acid (SUA) level and metabolic syndrome (MS) in Uygur children and adolescents with overweight or obesity.</p><p><b>METHODS</b>A total of 173 Uygur children or adolescents who were either overweight or obese and 200 controls with normal body weight were included in the study. Body weight, height, waist circumference, fasting blood glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and SUA were measured.</p><p><b>RESULTS</b>The overweight and obesity groups had significantly higher SUA levels (235 ± 42 and 285 ± 42 μmol/L respectively) than the control group (199 ± 32 μmol/L; P<0.01). The subjects with SUA levels of 300-349 μmol/L and ≥ 350 μmol/L had significantly higher incidence of MS, overweight/obesity, hypertension and dyslipidemia than those with SUA levels of <250 μmol/L and 250-299 μmol/L (P<0.01). There were significant differences in SUA levels between groups with different MS components. SUA level was significantly increased in groups with more MS components (P<0.01). Every 1 kg/m2 increment in body mass index (BMI) was associated with 5.74 μmol/L increase in SUA level, according to a multivariate regression analysis.</p><p><b>CONCLUSIONS</b>Uygur children and adolescents who are either overweight or obese have higher SUA levels than those with normal body weight. The incidence of MS and its components rises with increasing SUA level. BMI has a positive relationship with SUA.</p>

Clinical values of single or repeated triptorelin stimulating test in the differential diagnosis between idiopathic hypogonadotropic hypogonadism and constitutional delayed puberty / 中国医学科学院学报

<p><b>OBJECTIVE</b>To investigate the values of single or repeated luteinizing hormone (LH) releasing hormone analogue (triptorelin) stimulating test in the differential diagnosis between idiopathic hypogonadotropic hypogonadism (IHH) and constitutional delayed puberty (CDP).</p><p><b>METHODS</b>Male patients (n = 133) without puberty onset after the age of 14 were recruited for triptorelin stimulating test and were followed up for 24 - 48 months until the diagnosis were confirmed: 86 were IHH and the other 47 were CDP. Repeated triptorelin stimulating tests were conducted in 9 IHH patients and 13 CDP patients one year after the first stimulating tests with an attempt to evaluate the dynamic change of hypothalamus-pituitary-testis axis function. The relationship between the final diagnosis and the peak LH value (LH(max)), and the changes of repeated LH(max) were investigated.</p><p><b>RESULTS</b>In the single triptorelin stimulating test, LH(max) was (1.9 +/- 1.2) U/L in IHH group, which was significantly lower than that in CDP group [(13.7 +/- 8.3) U/L] (P < 0.01); 75 IHH patients (87.2%) had a LH(max) lower than 4 U/L, while only 2 CDP patients (4.3%) had a LH(max) lower than 4 U/L. When LH(max) < 4U/L was used as a criteria for the diagnosis of IHH, the single triptorelin stimulating test had a sensitivity of 87.2%, a specificity of 95.7%, and a positive predictive value of 97.4%. The repeated triptorelin stimulating tests performed one year later showed that the LH(max) in the 9 IHH patients increased from (4.7 +/- 2.5) U/L to (5.1 +/- 3.3) U/L (P = 0.78), while that in the 13 CDP patients increased from (10.7 +/- 3.3) U/L to (24.5 +/- 5.7) U/L (P < 0.05).</p><p><b>CONCLUSIONS</b>A single triptorelin stimulating test is highly effective in differentiating IHH from CDP. For some patients without definitive diagnosis, a repeated triptorelin stimulating test performed one year later may provide more valuable information on the dynamic change of the hypothalamus-pituitary-testis axis function.</p>

Testosterone replacement therapy improves insulin sensitivity and decreases high sensitivity C-reactive protein levels in hypogonadotropic hypogonadal young male patients / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Many clinical studies suggest the inverse relationship between testosterone levels and insulin sensitivity in men, however the causative relationship of these two events is still not determined. The purpose of this study was to investigate the effects of testosterone replacement therapy (TRT) on insulin sensitivity, body composition, serum lipid profiles and high sensitivity C-reactive protein (hsCRP) in hypogonadotropic hypogonadal (HH) puberty undeveloped male patients.</p><p><b>METHODS</b>In this prospectively designed study, we compared homeostasis model assessment of insulin resistance (HOMA-IR), insulin areas under the curves (AUC) of 3-hour oral glucose tolerance test (OGTT) and other metabolic parameters between 26 HH patients and 26 healthy men. The patients' HOMA-IR, insulin AUC, body composition, lipid profiles, hsCRP and other parameters were compared before and after nine-month TRT.</p><p><b>RESULTS</b>The average levels of total testosterone (TT) in HH and healthy group were (0.9 +/- 0.6) nmol/L and (18.8 +/- 3.4) nmol/L, respectively. HOMA-IR in HH group was significantly higher than the healthy group (5.14 +/- 5.16 vs 2.00 +/- 1.38, P < 0.005). Insulin AUC in 3-hour OGTT in HH group was significantly higher than the healthy group (698.6 +/- 414.7 vs 414.2 +/- 267.5, P < 0.01). Fasting glucose level in HH group was significantly higher than control group ((5.1 +/- 0.6) mmol/L vs (4.7 +/- 0.3) mmol/l, P < 0.005). Height, weight and grasp strength of the patients were significantly increased after 9-month TRT. Significant reductions in HOMA-IR (from 5.14 +/- 5.16 to 2.97 +/- 2.16, P < 0.01), insulin AUC (from 698.6 +/- 414.7 to 511.7 +/- 253.9, P < 0.01) and hsCRP (from (1.49 +/- 1.18) mg/L to (0.70 +/- 0.56) mg/L, P < 0.05) were found after TRT. Serum total cholesterol, LDL-C, HDL-C and triglyceride were all decreased, albeit with no significant difference compared to the level prior to TRT.</p><p><b>CONCLUSIONS</b>HOMA-IR, insulin AUC and fasting glucose level in HH young male patients were significantly higher than those of the control group, which suggests that low level of testosterone in male adolescents might be a risk factor for insulin resistance. TRT can significantly improve patients' insulin sensitivity and suppress serum hsCRP, which in return suggests that TRT may prevent the HH patients from developing diabetes mellitus and cardiovascular diseases (CVD) in future.</p>

Hypogonadism may cause insulin resistance in young males / 中华男科学杂志

<p><b>OBJECTIVE</b>To investigate the relationship between hypogonadism and insulin resistance in young male.</p><p><b>METHODS</b>Twenty-one hypogonadism young males aged 15 to 30 years were included in the clinical trial group, and 11 healthy young males of similar age and BMI in the control. Height, weight, serum FSH, LH, total testosterone (TT), nuclear type and bone age were measured for all the subjects. Serum glucose and insulin levels were taken through 3 h OGTT at 0, 30, 60, 120 and 180 min. And comparisons were made of the levels of fast glucose and insulin, areas under the curve of glucose and insulin and HOMA insulin resistance indexes (HOMA-IR) between the two groups.</p><p><b>RESULTS</b>(1) In the hypogonadism group the average value of TT was (0.9 +/- 0.6) nmol/L and 5 cases of Klinefelter syndrome had pubertal development with Tanner stage above P3, while the other 16 had no. (2) No significant differences were found in BMI, age, areas under the glucose and insulin secretory curve in OGTT between the two groups. (3) Three patients were diagnosed as IGT by OGTT in hypogonadism group, whose serum glucose levels at 120 min were 8.6, 7.9 and 8.2 mmol/L respectively. The maximal insulin excretion time was 30 min after glucose loading. No IGT or DM was found in the control group. (4) Significant difference was found in HOMA-IR and fast insulin level between the two groups.</p><p><b>CONCLUSION</b>(1) IGT incidence was higher in the hypogonadism group than in the control. (2) HOMA-IR and fast insulin levels were significantly higher in the hypogonadism group than in the control, which suggests that lower serum testosterone may cause insulin resistance in young male patients.</p>