S-Nitrosoglutathione Reductase (GSNOR) Deficiency Results in Secondary Hypogonadism

Background: Excess reactive oxygen species and reactive nitrogen species are implicated in male infertility and impaired spermatogenesis. Aim: To investigate the effect of excess reactive nitrogen species and nitrosative stress on testicular function and the hypothalamic-pituitary-gonadal axis using the S-nitrosoglutathione reductase-null (Gsnor^−/−) mouse model. Methods: Testis size, pup number, and epididymal sperm concentration and motility of Gsnor^−/− mice were compared with those of age-matched wild-type (WT) mice. Reproductive hormones testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone were compared in Gsnor^−/− and WT mice. Immunofluorescence for Gsnor^−/− and WT testis was performed for 3β-hydroxysteroid dehydrogenase and luteinizing hormone receptor (LHR) and compared. Human chorionic gonadotropin and gonadotropin-releasing hormone stimulation tests were performed to assess and compare testicular and pituitary functions of Gsnor^−/− and WT mice. Outcomes: Evaluation of fertility and reproductive hormones in Gsnor^−/− vs WT mice. Response of Gsnor^−/− and WT mice to human chorionic gonadotropin and gonadotropin-releasing hormone to evaluate LH and T production. Results: Gsnor^−/− mice had smaller litters (4.2 vs 8.0 pups per litter; P <.01), smaller testes (0.08 vs 0.09 g; P <.01), and decreased epididymal sperm concentration (69 vs 98 × 10⁶; P <.05) and motility (39% vs 65%; P <.05) compared with WT mice. Serum T (44.8 vs 292.2 ng/dL; P <.05) and LH (0.03 vs 0.74 ng/mL; P =.04) were lower in Gsnor^−/− than in WT mice despite similar follicle-stimulating hormone levels (63.98 vs 77.93 ng/mL; P =.20). Immunofluorescence of Gsnor^−/− and WT testes showed similar staining of 3β-hydroxysteroid dehydrogenase and LHR. Human chorionic gonadotropin stimulation of Gsnor^−/− mice increased serum T (>1,680 vs >1,680 ng/dL) and gonadotropin-releasing hormone stimulation increased serum LH (6.3 vs 8.9 ng/mL; P =.20) similar to WT mice. Clinical Translation: These findings provide novel insight to a possible mechanism of secondary hypogonadism from increased reactive nitrogen species and excess nitrosative stress. Strengths and Limitations: Limitations of this study are its small samples and variability in hormone levels. Conclusion: Deficiency of S-nitrosoglutathione reductase results in secondary hypogonadism, suggesting that excess nitrosative stress can affect LH production from the pituitary gland. Masterson TA, Arora H, Kulandavelu S, et al. S-Nitrosoglutathione Reductase (GSNOR) Deficiency Results in Secondary Hypogonadism. J Sex Med 2018;15:654–661.