Min Nie

Five novel mutations of SRD5A2 found in eight Chinese patients with 46,XY disorders of sex development

Individuals with male karyotype (46,XY) affected by 5α-reductase type 2 deficiency, a rare autosomal recessive inherited disorder, can have an almost female phenotype or partially virilized external genitalia. Mutations in the steroid-5-α-reductase (SRD5A2) gene, leading to functional impairment of 5α-reductase type 2, are responsible for this disorder. Our present study analyzed SRD5A2 gene mutations in eight unrelated 46,XY Chinese patients with disorders of sex development. Direct sequencing of genomic DNA for SRD5A2 gene revealed the presence of one homozygous (p.Q6X) and seven compound heterozygous mutations (p.G203S/R227Q, p.L20P/R227Q, p.Q6X/p.A228V, p.C222Ffs232X/p.R246Q, p.W140X/F219Sfs278X, p.Q71X/L185Tfs192X and p.Q6X/p.N193S) in our patients. Among them, p.C222Ffs232X, p.A228V, p.Q71X, L185Tfs192X and p.W140X mutations have not been previously reported. These novel mutations may provide us new insights into the molecular mechanism of 5α-reductase type 2 deficiency. Seven out of eight patients had at least one variant in exon 4, and 8 of 12 (66.7%) mutations were located in exon 4. The expanded mutation database of the SRD5A2 gene should benefit patients in the diagnosis and treatment of this disease.

Reversal of idiopathic hypogonadotropic hypogonadism: a cohort study in Chinese patients

Although idiopathic hypogonadotropic hypogonadism (IHH) has traditionally been viewed as a life-long disease caused by a deficiency of gonadotropin-releasing hormone neurons, a portion of patients may gradually regain normal reproductive axis function during hormonal replacement therapy. The predictive factors for potential IHH reversal are largely unknown. The aim of our study was to investigate the incidence and clinical features of IHH male patients who had reversed reproductive axis function. In this retrospective cohort study, male IHH patients were classified into a reversal group (n = 18) and a nonreversal group (n = 336). Concentration of gonadotropins and testosterone, as well as testicle sizes and sperm counts, were determined. Of 354 IHH patients, 18 (5.1%) acquired normal reproductive function during treatment. The median age for reversal was 24 years old (range 21-34 years). Compared with the nonreversal group, the reversible group had higher basal luteinizing hormone (LH) (1.0 ± 0.7 IU l -[1] vs 0.4 ± 0.4 IU l−1 , P< 0.05) and stimulated LH (28.3 ± 22.6 IU l−1 vs 1.9 ± 1.1 IU l−1 , P< 0.01) levels, as well as larger testicle size (5.1 ± 2.6 ml vs 1.5 ± 0.3 ml, P< 0.01), at the initial visit. In summary, larger testicle size and higher stimulated LH concentrations are favorite parameters for reversal. Our finding suggests that reversible patients may retain partially active reproductive axis function at initial diagnosis.

Diabetes insipidus as the first symptom caused by lung cancer metastasis to the pituitary glands: Clinical presentations, diagnosis, and management

BACKGROUND Central diabetes insipidus (CDI), secondary to pituitary metastatic lesions, is uncommon; however, lung and breast cancer are the commonest malignancies to have metastases to the pituitary. Early management of systemic chemotherapy and pituitary irradiation might improve the prognosis of patients. AIMS To investigate the clinical features, diagnosis, and management of CDI caused by lung cancer metastasis to the pituitary glands. MATERIALS AND METHODS We retrospectively reviewed 10 patients who had CDI as their first symptom before their lung cancers were diagnosed. Their clinical presentations, anterior pituitary gland function, sellar magnetic resonance imaging (MRI), management, and prognosis were described. SETTINGS AND DESIGN This retrospective cross-sectional clinical study was conducted in a medical college hospital. RESULTS The patients mean age was 58.6±7.8 years. Diabetes insipidus was the main complaint when they were referred to our hospital. MRI revealed specific dumbbell-shaped masses in the sella turcica in five patients. In seven patients whose hormones were measured, the levels of hormones from adenohypophysis were abnormally low in six patients. The main treatments included surgery, systemic chemotherapy, and sellar irradiation. Although nine patients had poor prognoses, one patient has survived for more than 3 years, suggesting benefit from early diagnosis and treatment. CONCLUSIONS New-onset CDI might be the only symptom presented by the patients with pituitary metastasis (PM) from lung cancer. Dumbbell-shaped sellar masses in MRI are prone to the diagnosis of PM. A thorough examination for primary cancer should be carried out in these aged and elderly patients.

Mutational analysis of androgen receptor gene in four Chinese patients with male pseudohermaphroditism

OBJECTIVE To show mutational analysis for androgen insensitivity syndrome (AIS)-associated male pseudohermaphroditism (MPH). DESIGN Case report. SETTING Key laboratory of endocrinology at a university hospital. PATIENT(S) Four unrelated Chinese patients with MPH referred to our clinic were investigated in this study. INTERVENTION(S) Genomic DNA was extracted from peripheral blood leukocytes, and coding sequence abnormalities of androgen receptor (AR) gene were assessed by polymerase chain reaction and direct sequencing analysis. MAIN OUTCOME MEASURE(S) Molecular characterization of the AR gene. RESULT(S) Four mutations (p.P913R, p.D732 N, p.N848 K, fs879X, and p.R608 K) in the AR gene were identified in our study. The p.P913R mutation in the AR gene has not been described previously. CONCLUSION(S) Our study identified a novel mutation in the AR gene that may provide us new insights into the molecular mechanisms of AIS. The expanded database of these mutations should benefit patients in the diagnosis and treatment of this syndrome.

Pulsatile gonadotropin-releasing hormone therapy is associated with earlier spermatogenesis compared to combined gonadotropin therapy in patients with congenital hypogonadotropic hypogonadism

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 < 0.001). The median time to achieve sperm concentrations ≥5 × 10 6 ml−1 was 14 months (95% CI: 5.8-22.2) in the GnRH group versus 27 months (95% CI: 18.9-35.1) in the HCG/HMG group (P < 0.001), and the median time to concentrations ≥10 × 10 6 ml−1 was 18 months (95% CI: 10.0-26.0) in the GnRH group versus 39 months (95% CI unknown) in the HCG/HMG group. Compared to the GnRH group, the HCG/HMG group required longer treatment periods to achieve testicular sizes of ≥4 ml, ≥8 ml, ≥12 ml, and ≥16 ml. Sperm motility (a + b + c percentage) evaluated in semen samples with concentrations >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.

Computational Analysis of Missense Variants of G Protein-Coupled Receptors Involved in the Neuroendocrine Regulation of Reproduction.

Introduction: Many missense variants in G protein-coupled receptors (GPCRs) involved in the neuroendocrine regulation of reproduction have been identified by phenotype-driven or large-scale exome sequencing. Computational functional prediction analysis is commonly performed to evaluate their impact on receptor function. Methods: To assess the performance and outcome of functional prediction analyses for these GPCRs, we performed a statistical analysis of the prediction performance of SIFT and PolyPhen-2 for variants with documented biological function as well as variants retrieved from Ensembl. We obtained missense variants with documented biological function testing from patients with reproductive disorders from a comprehensive literature search. Missense variants from individuals with known reproductive disorders were retrieved from the Human Gene Mutation Database. Missense variants from the general population were retrieved from the Ensembl genome database. Results: The accuracies of SIFT and PolyPhen-2 were 83 and 85%, respectively. The performance of both prediction tools was greater in predicting loss-of-function variants (SIFT: 92%; PolyPhen-2: 95%) than in predicting variants that did not affect function (SIFT: 54%; PolyPhen-2: 57%). Concordance between SIFT and PolyPhen-2 did not improve accuracy. Surprisingly, approximately half of the variants retrieved from Ensembl were predicted as loss-of-function variants by SIFT (47%) and PolyPhen-2 (54%). Conclusion: Our findings provide new guidance for interpreting the results and limitations of computational functional prediction analyses for GPCRs and will help to determine which variants require biological function testing. In addition, our findings raise important questions regarding the link between genotype and phenotype in the general population.

Congenital combined pituitary hormone deficiency patients have better responses to gonadotrophin-induced spermatogenesis than idiopathic hypogonadotropic hypogonadism patients

STUDY QUESTION Do patients with congenital combined pituitary hormone deficiency (CCPHD) have different responses to gonadotrophin-induced spermatogenesis compared with those with idiopathic hypogonadotropic hypogonadism (IHH)? SUMMARY ANSWER CCPHD patients have a better response to gonadotrophin therapy than IHH patients. WHAT IS KNOWN ALREADY Gonadotrophins are effective in inducing spermatogenesis in patients with hypogonadotropic hypogonadism. DESIGN, SIZE AND DURATION This retrospective cohort study included 75 patients, 53 of whom had IHH and 22 CCPHD. They were diagnosed, treated and followed up between January 2008 and December 2013. PARTICIPANTS/MATERIALS, SETTING AND METHODS Combined gonadotrophin therapy, consisting of human chorionic gonadotrophin and human menopausal gonadotrophin, was administered for 24 months. The success rate of spermatogenesis (≥1 sperm in ejaculate), serum total testosterone level, testicle size and sperm concentration during the treatment, as well as the first time sperm were detected in the ejaculate, were compared between the two diagnostic groups. All patients were treated in Peking Union Medical College Hospital. MAIN RESULTS AND THE ROLE OF CHANCE Spermatogenesis was successfully induced in 85% of IHH patients and 100% of CCPHD patients after 24-month combined gonadotrophin treatment (P = 0.03). In comparison with IHH, CCPHD patients had larger mean testicle sizes during the gonadotrophin treatment at 6, 12, 18 and 24 months (all P < 0.05). The initial time for sperm appearance in IHH group (n = 45) and CCPHD group (n = 22) was 13.2 ± 5.9 versus 10.4 ± 3.8 months (P = 0.045). Generally, CCPHD patients had higher sperm counts [median (quartiles)] than IHH patients during the treatment, but the difference was only statistically significant at 12 months of treatment, 3.3 (1.8, 12.0) versus 1.0 (0.0, 4.6) million/ml, P = 0.001. There was a higher level of serum total testosterone [mean (SD)] in the CCPHD group than the IHH group (676 ± 245 versus 555 ± 209 ng/dl, P = 0.035). LIMITATIONS, REASONS FOR CAUTION First, the inherent nature of a retrospective designed study was a main shortcoming. Secondly, pathological gene mutations in IHH and CCPHD patients should be further investigated. Clarification of the underlying mechanisms between cryptorchidism and mutated genes may provide more information for the divergent therapeutic responses between two groups. Only a minority of patients were actively seeking to have children so information about fertility is limited. WIDER IMPLICATIONS OF THE FINDINGS CCPHD patients had a lower incidence of cryptorchidism and a better response to gonadotrophin therapy than IHH patients, reflecting multiple defects on the different levels of reproduction axis in IHH. Furthermore, growth hormone is not indispensable for spermatogenesis in CCPHD patients. STUDY FUNDING/COMPETING INTERESTS The study was supported by Natural Science Foundation of China (No: 81100416). None of the authors has any conflicts of interest to declare.

Adult-onset idiopathic hypogonadotropic hypogonadism: possible aetiology, clinical manifestations and management

Correspondence to: Dr Xue-Yan Wu, Department of Endocrinology, Peking Union Medical College Hospital, Beijing 100730, China. Fax: +86-10-6529-5073 E-mail: wsheyan@vip.sina.com Received: 8 February 2010 Revised: 8 March 2010 Accepted: 25 March 2010 Published online: 7 June 2010 Letters to the Editor Asian Journal of Andrology (2010) 12: 611–614

Predictive factors for pituitary response to pulsatile GnRH therapy in patients with congenital hypogonadotropic hypogonadism

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.