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

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 × 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.

Alterations of tumor microenvironment by nitric oxide impedes castration-resistant prostate cancer growth

“…We have previously shown that mice lacking the S-nitrosoglutathione reductase (GSNOR) gene showed increased nitrosative stress and exhibited secondary hypogonadism (19). Therefore, in this study we examined if increased NO levels are able to suppress testosterone (T) and luteinizing hormone (LH) in control C57BL/6J mice.…”

“…A key molecule in the regulation of TME interactions is the ubiquitous nitric oxide (NO) (10)(11)(12). We have previously established the importance of NO in the cardiovascular and immune systems and in male secondary hypogonadism (13)(14)(15)(16)(17)(18)(19)(20).…”

Effect of nitroso-redox imbalance on male reproduction

“…Nitrosative stress is an inhibitor of Leydig cell steroidogenesis function through NO. Experiments examining the impact of NO on steroid biosynthesis in Leydig cells demonstrate that NO administration has an inhibitory effect on steroidogenesis leading to suppressed testosterone levels in mice ( 10 , 33 , 34 ). Research suggests that NO impacts testosterone synthesis directly by inhibiting cholesterol modification, an important precursor to steroid products ( 33 ).…”

“…Research suggests that NO impacts testosterone synthesis directly by inhibiting cholesterol modification, an important precursor to steroid products ( 33 ). However, the hypothalamus-pituitary-gonadal axis remains inducible because administration of GnRH and human chorionic gonadotrophin (hCG) into nitrosatively stressed mice stimulated LH and testosterone, respectively ( 10 ). Thus, nitrosative stress in excess can inhibit testosterone production likely due to hypothalamic-pituitary dysfunction.…”

“…Similar to oxidative stress, nitrosative stress also arises from dysfunction in the antioxidant defense system. Specifically, elevated levels of ROS/RNS can damage sperm DNA, lipids, carbohydrates and proteins ( 1 , 9 , 10 ). Nitroso-redox imbalance can affect male reproduction through its effects on sperm and the hypothalamic-pituitary-gonadal (HPG) axis ( 1 , 9 , 10 ).…”