Venlafaxine-induced adrenergic signaling stimulates Leydig cells steroidogenesis via Nur77 overexpression: A possible role of EGF.

Venlafaxine, a norepinephrine and serotonin reuptake inhibitor, impairs rat sperm parameters, spermatogenesis and causes high intratesticular estrogen and testosterone levels, indicating that Leydig cells (LCs) may be a venlafaxine target. We evaluated the effect of venlafaxine treatment on rat LCs, focusing on adrenergic signaling, EGF immunoexpression and steroidogenesis. Germ cells mitotic/meiotic activity and UCHL1 levels were also evaluated in the seminiferous epithelium. Eighteen adult male rats received 30 mg/kg of venlafaxine (n = 9) or distilled water (n = 9). The seminiferous tubules, epithelium and LCs nuclear areas were measured, and the immunoexpression of Ki-67, UCHL1, StAR, EGF, c-Kit and 17ß-HSD was evaluated. UCHL1, StAR and EGF protein levels and Adra1a, Nur77 and Ndrg2 expression were analyzed. Malondialdehyde (MDA) and nitrite testicular levels, and serum estrogen and testosterone levels were measured. Venlafaxine induced LCs hypertrophy and Ndrg2 upregulation in parallel to increased number of Ki-67, c-Kit- and 17ß-HSD-positive interstitial cells, indicating that this antidepressant stimulates LCs lineage proliferation and differentiation. Upregulation of Adra1a and Nur77 could explain the high levels of StAR and testosterone levels, as well as aromatization. Enhanced EGF immunoexpression in LCs suggests that this growth fact is involved in adrenergically-induced steroidogenesis, likely via upregulation of Nur77. Slight tubular atrophy and weak Ki-67 immunoexpression in germ cells, in association with high UCHL1 levels, indicate that spermatogenesis is likely impaired by this enzyme under supraphysiological estrogen levels. These data corroborate the unchanged MDA and nitrite levels. Therefore, venlafaxine stimulates LCs steroidogenesis via adrenergic signaling, and EGF may be involved in this process.

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

BACKGROUND: 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. OBJECTIVES: We evaluated venlafaxine impact on testicular and sperm parameters and verified whether the changes are reversible. METHODS: Animals from venlafaxine-35 days and venlafaxine-65 days groups received 30 mg/kg of venlafaxine for 35 days. Control-35 days and control-65 days received distilled water. In control-65 days and venlafaxine-65 days, the treatment was interrupted for 30 days. 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. RESULTS: 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-65 days, except for sperm motility, mitochondrial activity, Sertoli cells number, and germ cell death, all other parameters were partially or totally recovered. CONCLUSION: 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-65 days 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-65 days 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.