ABSTRACT
Objective: Congenital hypogonadotropic hypogonadism (CHH) is a rare congenital gonadal dysplasia caused by defects in the synthesis, secretion or signal transduction of hypothalamic gonadotropin releasing hormone. The main manifestations of CHH are delayed or lack puberty, low levels of sex hormones and gonadotropins, and may be accompanied with other clinical phenotypes. Some patients with CHH are also accompanied with anosmia or hyposmia, which is called Kalman syndrome (KS). ANOS1, located on X chromosome, is the first gene associated with CHH in an X-linked recessive manner. This study aims to provide a basis for the genetic diagnosis of CHH by analyzing the gene variant spectrum of ANOS1 in CHH and the relationship between clinical phenotype and genotype. Methods: In this study, whole exome sequencing (WES) was used to screen rare sequencing variants (RSVs) of ANOS1 in a Chinese cohort of 165 male CHH patients. Four commonly used in silico tools were used to predict the function of the identified RSVs in coding region, including Polyphen2, Mutation Taster, SIFT, and Combined Annotation Dependent Depletion (CADD). Splice Site Prediction by Neural Network (NNSPLICE) was employed to predict possibilities of intronic RSVs to disrupt splicing. American College of Medical Genetics and Genomics (ACMG) guidelines was used to assess the pathogenicity of the detected RSVs. The ANOS1 genetic variant spectrum of CHH patients in Chinese population was established. The relationship between clinical phenotype and genotype was analyzed by collecting detailed clinical data. Results:Through WES analysis for 165 CHH patients, ANOS1 RSVs were detected in 17 of them, with the frequency of 10.3％. A total of 13 RSVs were detected in the 17 probands, including 5 nonsense variants (p. T76X, p. R191X, p. W257X, p. R262X, and p. W589X), 2 splicing site variants (c. 318+3A>C, c. 1063-1G>C), and 6 missense variants (p. N402S, p. N155D, p. P504L, p. C157R, p. Q635P, and p. V560I). In these 17 CHH probands with ANOS1 RSVs, many were accompanied with other clinical phenotypes. The most common associated phenotype was cryptorchidism (10/17), followed by unilateral renal agenesis (3/17), dental agenesis (3/17), and synkinesia (3/17). Eight RSVs, including p. T76X, p. R191X, p. W257X, p. R262X, p. W589X, c. 318+3A>C, c. 1063-1G>C, and p. C157R, were predicted to be pathogenic or likely pathogenic ANOS1 RSVs by ACMG. Eight CHH patients with pathogenic or likely pathogenic ANOS1 variants had additional features. In contrast, only one out of nine CHH patients with non-pathogenic (likely benign or uncertain of significance) ANOS1 variants according to ACMG exhibited additional features. And function of the non-pathogenic ANOS1 variants accompanied with other CHH-associated RSVs. Conclusion: The ANOS1 genetic spectrum of CHH patients in Chinese population is established. Some of the correlations between clinical phenotype and genotype are also established. Our study indicates that CHH patients with pathogenic or likely pathogenic ANOS1 RSVs tend to exhibit additional phenotypes. Although non-pathogenic ANOS1 variants only may not be sufficient to cause CHH, they may function together with other CHH-associated RSVs to cause the disease.
ABSTRACT
Partial congenital hypogonadotropic hypogonadism (PCHH) is caused by an insufficiency in, but not a complete lack of, gonadotropin secretion. This leads to reduced testosterone production, mild testicular enlargement, and partial pubertal development. No studies have shown the productivity of spermatogenesis in patients with PCHH. We compared the outcomes of gonadotropin-induced spermatogenesis between patients with PCHH and those with complete congenital hypogonadotropic hypogonadism (CCHH). This retrospective study included 587 patients with CHH who were treated in Peking Union Medical College Hospital (Beijing, China) from January 2008 to September 2016. A total of 465 cases were excluded from data analysis for testosterone or gonadotropin-releasing hormone treatment, cryptorchidism, poor compliance, or incomplete medical data. We defined male patients with PCHH as those with a testicular volume of ≥4 ml and patients with a testicular volume of <4 ml as CCHH. A total of 122 compliant, noncryptorchid patients with PCHH or CCHH received combined human chorionic gonadotropin and human menopausal gonadotropin and were monitored for 24 months. Testicular size, serum luteinizing hormone levels, follicle-stimulating hormone levels, serum total testosterone levels, and sperm count were recorded at each visit. After gonadotropin therapy, patients with PCHH had a higher spermatogenesis rate (92.3%) than did patients with CCHH (74.7%). During 24-month combined gonadotropin treatment, the PCHH group took significantly less time to begin producing sperm compared with the CCHH group (median time: 11.7 vs 17.8 months, P < 0.05). In conclusion, after combined gonadotropin treatment, patients with PCHH have a higher spermatogenesis success rate and sperm concentrations and require shorter treatment periods for sperm production.
ABSTRACT
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.