Alteration in male reproductive system in experimental cholestasis: roles for opioids and nitric oxide overproduction

Cirrhosis is associated with impairment of the male reproductive system, hypogonadism and feminization. It is important to rule out whether the impairment in the reproductive system exists earlier in the course of cholestatic liver disease to target effective therapies at the best time point. In this study we investigated the role of endogenous opioid and nitric oxide system in alterations of the reproductive system in male rats. We performed sham or bile duct ligation surgery on male Sprague-Dawley rats and treated the animals for seven days with saline, naltrexone, an opioid receptor blocker (20 mg/kg) and N (G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor (10 mg/kg). We then evaluated the plasma level of testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH), sperm count and motility as well as biomarkers of cholestasis and nitric oxide productions. The results showed that following cholestasis, total testosterone level decrease and LH level increase in plasma of cholestatic rats and treatment with L-NAME and naltrexone could improve the plasma level of testosterone. Naltrexone could decrease the elevated level of LH in cholestatic animals. In addition, the weight of seminal vesicles and prostate significantly decreased in cholestasis as compared to the control group and treatment with L-NAME and naltrexone could improve the weights of the two organs in cholestasis. Our results demonstrate for the first time that the male reproductive system is impaired early in cholestasis and that endogenous opioid and nitric oxide system contribute to these impairments in the early course of the disease.