Damaged Sperm Parameters and Spermiation Failure in Venlafaxine-Treated Rats: a Correlation with High Testicular Aromatase Immunoexpression and Reduced Epididymal V-ATPASE

The antidepressant venlafaxine (Serotonin Norepinephrine Reuptake Inhibitor-SNRI) has impaired sexual function in male patients. We investigated the impact of this SNRI on sperm parameters, relating them to testicular and epididymal histophysiological markers. The recovery of sperm and testicular changes was also evaluated following the interruption of treatment. Adult male rats were grouped: Venlafaxine-35 days (VFG-35; n=6) and Venlafaxine-65 days (VFG-65; n=6) received venlafaxine (30mg/kg BW) by gavage for 35 days; Control-35 days (CG-35; n=6) and Control-65 days (CG-65; n=6) received saline. After treatment, the animals from CG-35 and VFG-35 were killed while the animals from CG-65 and VFG-65 were maintained without treatment for 30 days to evaluate reversibility of changes. In these groups, sperm parameters were evaluated in association to seminiferous epithelium integrity, steroidogenesis, testicular aromatase and epididymal V-ATPase immunoexpression. Rats received 30mg/kg (therapeutic dosage) of venlafaxine for 35 days (minimal period for the antidepressant effect). The concentration, morphology and mitochondrial cytochemical activity (MCA) of sperm from cauda epididymis were analyzed. In epididymal and testicular sections, the following parameters were evaluated: epididymal duct diameter, frequency of tubules with spermiation failure, number of Sertoli cells (NSC), viability of germ cells by TUNEL, Leydig cells nuclear diameter (LCn), StAR immunoexpression (steroidogenesis), testicular aromatase (Cyp19) and epididymal V-ATPase immunofluorescent intensity. Serum and testicular testosterone levels were also measured. Data were submitted to two-way ANOVA with Tukey post-hoc test. In VFG-35, the epididymal duct diameter, sperm concentration and MCA decreased, and a high frequency of sperm tail abnormalities was found. Changes in seminiferous epithelium and high frequency of post-spermiation tubules with retained spermatids were found. The NSC decreased whereas the number of TUNEL-positive germ cells and Cyp19 immunoexpression increased in this group. In VFG-35, LCn was larger than CG; a high immunoexpression of StAR and elevated serum and testicular testosterone levels were observed. Venlafaxine also impaired the epididymal V-ATPase immunoexpression. Except for the tail changes and MCA, sperm concentration and testicular parameters were improved following the interruption of treatment. Venlafaxine stimulates LC steroidogenesis and increases aromatase levels, impairing spermiation and sperm concentration and quality. Therefore, the evaluation of fertility together with a careful analysis of spermatogenesis and hormonal status of patients treated with SNRI is useful. The changes in sperm parameters may also be associated with disturbs in the acid/basic milieu of epididymal lumen due to reduction in V-ATPase. The improvement of sperm parameters following the interruption of treatment is, at least in part, due to recovery of aromatase/estrogen levels and the restoration of spermiation process.