Oral antioxidants for varicocele-related infertility, either as a therapeutic alternative or as an adjuvant treatment to varicocele repair have been recently examined.

In a rat model of varicocele, the use of a NOS inhibitor (aminoguanidine) resulted in an increase in semen parameters and reduction in sperm DNA fragmentation [209, 210]. Vitamin E has been also shown to significantly reduce seminal ROS levels in experimental rat varicocele model [211]. In humans, daily oral administration of pentoxifylline, zinc, and folic acid for 3 months improved sperm morphology for at least 4 weeks after the end of treatment [212]. However, this evidence comes from small non-controlled series with poor methodology. In another study, Cavalleni et al. [213] studied the effects of a 6-month course of the oral antioxidants L-carnitine (1 g/day) and acetyl-L-carnitine (2 g/day) given with the anti-inflammatory cinnoxicam (30 mg suppository given every 4 days) in oligozoospermic infertile men with or without varicocele. The researchers found that both men with low-grade varicocele and idiopathic oligoasthenoteratozoospermia responded better to the combination than those who were prescribed placebo or just the antioxidants. In a subsequent study by the same group, a 1 year course of cinnoxicam, improved the semen quality of men with low-grade varicocele [214]. Taken together, these results support the rationale of impaired fertility caused by elevated oxidative stress in men with varicocele, and the beneficial effect of improving the antioxidant defense system by exogenous antioxidant administration.

Chinese medicine exhibiting antioxidant activity has also been explored as therapeutic alternatives to surgery in animal and human studies. Qiangjing, a herbal medicine that was administered to rats with experimental varicocele, was found to increase glutathione peroxidase and reduce malondialdehyde in the epididymal fluid [215]. Semi-synthetic forms of bioflavonoid—a plant pigment that imparts color to flowers and displays anti-inflammatory and antioxidant properties—have also been used in men with varicocele. In one study, Zampieri et al. [216] administered 1000 mg/day of O-beta-hydroxyethylrutoside in a cyclical 3-month on/off therapy for 1 year to 36 infertile men with subclinical left-sided varicocele. The authors observed a slowed progression of varicocele in treated patients compared with 95 patients with subclinical varicocele who did not receive the bioflavonoid. The patients in the untreated group failed to demonstrate any protective effects against testicular growth arrest. Kiliç et al. [217] used micronized flavonoid supplements to relieve pain in normozoospermic men with varicocele and found that sperm motility was markedly improved.