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

Abstract

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.

Impaired macrophages and failure of steroidogenesis and spermatogenesis in rat testes with cytokines deficiency induced by diacerein

“…For the estimation of the TNF-α immunofluorescent area in the ST, the tubular area of around 15 tubules at stages IX-XI was measured since the immunoexpression of TNF-α is stage-specific and more accentuated and specific in IX-XI tubules (De et al 1993). Thus, in a standardized tubular area of each animal from CG and DIAG, the TNF-α immunofluorescent area was measured, and the immunofluorescent area/mm 2 of seminiferous tubule was calculated (de Santi et al 2021).…”

Role of serotonin, estrogen, and TNF‐α in the paroxetine‐impaired steroidogenesis and testicular macrophages polarization

“…Using the image analysis system (Image Pro‐Express 6.0; Olympus), the nuclear area of 100 LC was measured at x272 in three non‐serial testicular sections per animal 52 …”

“…The protocol was performed according to de Santi et al 52 For antigen recovery, the slides were immersed in 0.001 M sodium citrate buffer (pH 6.0) and heated in a microwave oven until 90 • C, as previously described. Subsequently, the sections were incubated with 1% BSA for 30 min to block non-specific binding and incubated overnight in a humidified chamber at 4…”

“…Total protein extraction was performed according to de Santi et al, 52 and protein concentration was determined by Bradford assay. Protein samples (35 μg) were separated in 12% SDS-PAGE and transferred…”

“…In studies where high estrogen levels have also been related to spermatogenic failure in serotonin and norepinephrine reuptake inhibitor treated-rats. 52,66 A few in vivo studies have addressed the endocrine disrupting effect of paroxetine. This drug blocks 5-HT reuptake by central neurons successively, increasing 5-HT concentration in the synaptic cleft and bloodstream.…”