Toxic Effects of Trazodone on Male Reproductive System via Disrupting Hypothalamic-Pituitary-Testicular Axis and Inducing Testicular Oxidative Stress

Abstract

Depression and anxiety are recognized as public health problems. Epidemiological studies have shown that depression and anxiety often occur during reproductive ages between 20 and 60 years of age in males. Trazodone is one of the most frequently prescribed drugs in the treatment of depression and anxiety. Drugs used in repeated doses also play a role in the etiology of infertility. In our study, it was aimed to identify the possible toxic effects of trazodone on male rats and elucidate the underlying mechanisms. Vehicle or trazodone (5, 10, and 20 mg/kg/day) was administered to rats for 28 consecutive days (n = 8 per group). At the end of that period, sperm concentration, motility, morphology, and DNA damage were determined and testicular morphology was assessed histopathologically in rats. Additionally, we investigated hormonal status by determining serum testosterone, FSH, and LH levels and oxidative stress by determining glutathione and malondialdehyde levels in testicular tissue to elucidate mechanisms of possible reproductive toxicity. According to our results, sperm concentration, sperm motility, and normal sperm morphology were decreased; sperm DNA damage was increased in trazodone-administered groups. Degenerative findings on the testicular structure were observed after trazodone administration in rats. Additionally, serum FSH, LH, and testosterone levels were elevated in the trazodone-administered groups. Increased MDA levels were the signs of enhanced oxidative stress after trazodone administration in testis tissues. Thus, we concluded that trazodone induced reproductive toxicity in male rats; this reproductive toxicity was accompanied by oxidative stress and hormonal changes, which are considered as important causes of reproductive disorders.

Figure 1

Classification of sperm morphology in rats: (a) normal sperm, (b) banana-shaped head, (c) amorphous head, (d) bent neck, (e) bent neck, (f) headless, (g) tailless, (h) broken tail, and (i) banana-shaped head and bent tail (multiple anomalies).

Figure 2

(a–d) DNA damage in rat sperms in control and experimental group animals exposed to physiological saline (0.9%) or different doses of trazodone. (a) Sperm comet assay photo of control rats. (b) Sperm comet assay photo of 5 mg/kg trazodone-administered rats. (c) Sperm comet assay photo of 10 mg/kg trazodone-administered rats. (d) Sperm comet assay photo of 20 mg/kg trazodone-administered rats. (e) Tail moment graph: ^∗Different from C (p < 0.05); ⁺Different from TRZ5 (p < 0.05); ^!Different from TRZ10.

Figure 3

(a–d) Transverse section of seminiferous tubules. (a) Normal appearance of seminiferous tubules in control rats. (b) Mild central degeneration in seminiferous tubules (arrowhead) in 5 mg/kg trazodone-administered rats. (c) Deformation in the basement membrane of seminiferous tubules (arrowhead) and large vacuoles (arrow) in germinal epithelium in 10 mg/kg trazodone-administered rats. (d) Seminiferous tubules with total degeneration (arrow) in 20 mg/kg trazodone-administered rats.

Figure 4

(A–D) High magnification of seminiferous tubules. (A) Intact structure of germinal epithelium in control rats. (B) Irregularity of basement membrane (^∗) and vacuolation in Sertoli cells (arrowhead) in 5 mg/kg trazodone-administered rats. (C) Detachment of basement membrane (^∗), deformation in Sertoli cells (arrowhead), and vacuolar degeneration (arrow) in germinal epithelium 10 mg/kg trazodone-administered rats. (D) Disintegration of germinal epithelium (^∗), desquamation of cells into the lumen (arrow), and necrosis in Sertoli cells and neighbouring germ cells (n), degenerating cells showing nuclear pyknosis (arrowhead) in 20 mg/kg trazodone-administered rats. (a–d) High magnification of Leydig cells. (a) Normal morphological integrity of Leydig cells in control rats. (b) Slight vacuolation and deformation in Leydig cells (arrowhead) in 5 mg/kg trazodone-administered rats. (c) Intense vacuolation and deformation in Leydig cells (arrowhead) in 10 mg/kg trazodone-administered rats. (d) Complete deformation (arrowhead) and lysis (arrow) of Leydig cells in 20 mg/kg trazodone-administered rats.