Abstract
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 × 10(6); 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.