Effects of subchronic and prolonged exposure to sibutramine and/or rosuvastatin on reproductive parameters and fertility of adult male Wistar rats

Abstract

Obesity is a public health problem that is growing worldwide in recent years. This disease, characterized by presenting cardiovascular risk factors such as dyslipidemia, is intrinsically associated with several morbidities such as diabetes, metabolic syndromes and cancer. To minimize characteristic manifestations of obesity, several drugs have been used, including sibutramine and statins. Sibutramine is an anorectic agent used in the reduction of body weight, and when administered for prolonged periods, assists in maintaining the weight. This compound acts on the central nervous system by inhibiting the reuptake of serotonin and norepinephrine in the synaptic clefts, inducing satiation and reducing food intake. Statins, in turn, are hypolipidemic agents that inhibit the action of HMG-CoA reductase, the key enzyme in the cholesterol biosynthetic pathway. Currently, several obese patients have been treated with sibutramine combined with statins, however, the effects on the reproductive parameters of these patients were not investigated. Studies in our laboratory have demonstrated that adult rats exposed to sibutramine and prepubertal rats exposed to rusovastatin, a next generation statin, showed changes in reproductive parameters. Given this context, this study aims to investigate the immediate effects of subchronic and prolonged treatment with rosuvastatin combined with sibutramine on sperm quality and fertility in rats. For this, adult Wistar male rats (90 days) will be placed in the control (saline solution and dimethyl sulfoxide), sibutramine (10 mg/kg), rosuvastatin (5 mg/kg) and sibutramine associated with rosuvastatin groups, treated orally for 30 days for the analysis of possible effects of subchronic treatment on reproductive parameters, or for 70 days, a period that includes a complete spermatogenic cycle and sperm transit through the epididymis. After the end of treatment, the following parameters will be evaluated: sexual behavior and fertility after natural mating (n = 12/ group); hormone levels (serum and intratesticular testosterone, FSH and LH), sperm analysis (number and transit time of sperm in the testis and epididymis, sperm motility and morphology), weight of vital and reproductive organs, fertility after in utero artificial insemination and quantification of androgen receptors in the testis and epididymis (n = 12/ group); ex vivo pharmacological reactivity and norepinephrine dosage in the epididymis (n = 5/ group);immunolocalization of androgen receptors, epididymal and testicular histomorphometry and histopathology (n =7/ group). Six untreated animals will be used for the evaluation of in vitro pharmacological reactivity of the epididymal duct upon exposure to rosuvastatin and/or sibutramine. Other animals (n = 6) will be used for in vitro analysis of testosterone synthesis by Leydig cells. The theme of the project is of great importance, considering the use of these drugs in the treatment of obesity. Thus, it is intended that, besides the formation of qualified human resources in Biology and Toxicology of Reproduction, new knowledge is acquired on the effects of subchronic treatment with sibutramine and/or rosuvastatin, and prolonged exposure, on the male genital system and fertility in rats, disseminating the results through publications in international journals with indexed impact, as well as communications in scientific events in the area.