Clinical Characteristics and Spermatogenesis in Patients with Congenital Hypogonadotropic Hypogonadism Caused by FGFR1 Mutations

Objective. The aim of this study was to investigate the clinical characteristics of patients diagnosed with congenital hypogonadotropic hypogonadism (CHH) caused by FGFR1 (fibroblast growth factor receptor 1) gene mutations and to evaluate the effect of gonadotropin or pulsatile gonadotropin-releasing hormone (GnRH) therapy on spermatogenesis. Methods. A retrospective study was conducted on CHH patients admitted to Peking Union Medical College Hospital from January 2012 to March 2020. Clinical features and laboratory results were recorded. Testicular volume and sperm count responding to gonadotropin and pulsatile GnRH therapy were compared between the FGFR1 mutation group and the mutation-negative group. Results. (1) FGFR1 mutation group included 14 patients who received sperm-induction therapy, and the mutation-negative group enrolled 25 CHH patients. (2) The incidence of cryptorchidism was 50.0% (7/14) and 12.0% (3/25) in the FGFR1 group and the mutation-negative group, respectively ( p = 0.019 ). The baseline testicular volume of the FGFR1 mutation group was smaller than that of the mutation-negative group, 1.6 (0.5–2.0) mL vs. 2 (1.75–4) mL ( p = 0.033 ). The baseline luteinizing hormone (LH), Follicle-stimulating hormone (FSH), and testosterone levels were similar between the two groups. (3) Using the Kaplan–Meier and log-rank tests for the analysis of spermatogenesis, it was found that there was no significant difference in the first sperm appearance between the FGFR1 mutation group and the mutation-negative group (χ2 = 1.974, p = 0.160 ). The median time of spermatogenesis in the FGFR1 mutation group was longer than that in the mutation-negative group, 16 months vs. 10 months, respectively. The cumulative spermatogenesis success rate at 12 months in the FGFR1 mutation group (35.71%) was lower than that in the mutation-negative group (68.75%) ( p = 0.047 ). The sperm concentration in the mutation-negative group was more easily achieved for different thresholds compared with that in the FGFR1 mutation group, but no significant difference was observed ( p > 0.05 ) between the two groups. The last follow-up examination showed that the testicular volume was 7.00 (4.75–12.00) mL and 10.56 ± 4.82 mL ( p = 0.098 ), the ejaculate volume of sperm was 2.20 (1.40–2.26) mL and 3.06 ± 1.42 mL ( p = 0.175 ), and the sperm concentration was 7.19 (1.00–9.91) million/mL and 18.80 (4.58–53.62) million/mL ( p = 0.038 ) in the FGFR1 mutation and mutation-negative groups, respectively, while the sperm motility (A%, A + B%, and A + B + C%) was similar for the two groups ( p = 0.839 , 0.909, and 0.759, respectively). The testosterone level during treatment was 366.02 ± 167.03 ng/dL and 362.27 ± 212.86 ng/dL in the FGFR1 mutation and mutation-negative groups, respectively ( p = 0.956 ). Conclusion. Patients with FGFR1 mutations have a higher prevalence of cryptorchidism and smaller testicular volume. Although patients with FGFR1 mutations have a similar rate of success for spermatogenesis compared to that of the mutation-negative patients, a longer treatment period was required and a lower sperm concentration was achieved.

GnRH in the treatment of Hypogonadotropic hypogonadism

: Gonadotropin Releasing Hormone (GnRH) is at the centre of the scientific debate for the treatment of hypogonadotropic hypogonadism. Sexual maturation and reproductive function depend on the pulsatile secretion of GnRH are mainly congenital and may or may not be associated with other genetic anomalies or syndromes. Clinical manifestations include a wide range of metabolic, endocrine and psychologic dysfunctions. The following manuscript focuses on the effects of GnRH therapy on fertility and cognitive abilities, aiming to investigate the current level of evidence for this treatment regimen. Current literature has been reviewed and synthesized with the aim of highlighting the key messages on these two aspects.

Complete Kisspeptin Receptor Inactivation Does Not Impede Exogenous GnRH-Induced LH Surge in Humans

Context Mutations in the kisspeptin receptor (KISS1R) gene have been reported in a few patients with normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). Objectives To describe a female patient with nCHH and a novel homozygous KISS1R mutation and to assess the role of kisspeptin pathway to induce an ovulation by GnRH pulse therapy. Design, Setting, and Intervention Observational study of a patient including genetic and kisspeptin receptor functions and treatment efficiency using a GnRH pump. Main Outcome Measure Response to pulsatile GnRH therapy Results A partial isolated gonadotropic deficiency was diagnosed in a 28-year-old woman with primary amenorrhea and no breast development. A novel homozygous c.953T>C variant was identified in KISS1R. This mutation led to substitution of leucine 318 for proline (p.Leu318Pro) in the seventh transmembrane domain of KISS1R. Signaling via the mutated receptor was profoundly impaired in HEK293-transfected cells. The mutated receptor was not detected on the membrane of HEK293-transfected cells. After several pulsatile GnRH therapy cycles, an LH surge with ovulation and pregnancy was obtained. Conclusion GnRH pulsatile therapy can induce an LH surge in a woman with a mutated KISS1R, which was previously thought to be completely inactivated in vivo.