Venlafaxine-induced damage to seminiferous epithelium, spermiation and sperm parameters in rats: a correlation with high estrogen levels.

de Santi, Fabiane; Beltrame, Flávia L; Rogridues, Beatriz M; Junior, Marcio J V P; Scaramele, Natália F; Lopes, Flávia L; Cerri, Paulo S; Sasso-Cerri, Estela

BACKGROUND Venlafaxine (selective serotonin and norepinephrine reuptake inhibitor - SNRI) use has increased worldwide. However, the impact of venlafaxine on testes and sperm parameters has not been investigated. OBJECTIVES We evaluated venlafaxine impact on testicular and sperm parameters and verified whether the changes are reversible. METHODS Animals from venlafaxine-35 days (VFG35) and venlafaxine-65 days (VFG65) groups received 30 mg/kg of venlafaxine for 35 days. Control-35 days (CG35) and control-65 days (CG65) received distilled water. In CG65 and VFG65, the treatment was interrupted for 30 days. Sperm concentration, morphology, motility and rate of mitochondrial cytochemical activity (RCA) were analyzed. Number of step 19 spermatids (NLS), frequency of tubules with spermiation failure, Sertoli cells (SC) number and TUNEL-positive germ cells were quantified. Testicular aromatase, connexin 43 (Cx43) immunoexpression, Cx43 protein levels and Cx43 expression were evaluated. Either intratesticular testosterone or estrogen levels were measured. RESULTS Venlafaxine impaired sperm morphology, reduced sperm concentration, RCA and sperm motility. The frequency of tubules with spermiation failure and NLS increased in parallel to increased Cx43 immunoexpression, mRNA and protein levels, and aromatase, testosterone and estrogen levels. An increase in germ cells death and decreased SC number were observed. In VFG65, except for sperm motility, RCA, SC number and germ cells death, all other parameters were partially or totally recovered. CONCLUSION Venlafaxine increases testosterone aromatization and Cx43. This drug, via high estrogen levels, disturbs SC, induces germ cell death, impairs spermiation and sperm parameters. The restoration of spermiation associated with the decreased Cx43 and hormonal levels in VFG65 reinforces that high estrogen levels are related to venlafaxine-induced changes. The presence of damaged SC, germ cells death and low sperm motility in VFG65 indicates that interruption of treatment for 30 days was insufficient for testicular recovery and points to a long-term estrogen impact on the seminiferous epithelium.