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

Abstract

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