A Retrospective Study of Semen Quality in Infertile Men with Varicoceles: Urological Expertise in Designing and Conducting a Testicular Safety Evaluation Study

Abstract

ObjectivesDesigning and conducting a phase 1 study to evaluate the potential for testicular toxicity of a new drug requires urological expertise. Because varicoceles are present in 15–20% of the normal male population and associated with progressive testicular damage and a consequent reduction in fertility, we evaluated semen quality in infertile men with varicoceles, in comparison with control subjects. Information from this study may provide insight into the design and conduct of semen analyses in clinical trials of new drugs.MethodsIn a retrospective study, the records of 12 infertile patients with clinical varicoceles (mean age, 32.6 years) and 8 fertile men without clinical varicoceles (mean age, 32.0 years) between October 2005 and March 2015 were evaluated. Serum follicle‐stimulating hormone (FSH), luteinizing hormone (LH) and testosterone levels and semen parameters (semen volume, sperm concentration, total sperm number and total motility) were assessed in all the subjects. Two semen samples were collected at 4‐week intervals for initial evaluation and semen analyses were performed according to the WHO laboratory manual. Sperm concentration was measured by the same urologist using Makler counting chamber.ResultsAt initial evaluation, inter‐ and intra‐individual variations in semen quality were observed in both the infertile men with grade 1 (palpable during Valsalva maneuver, but not otherwise) varicoceles and the fertile men, and both groups had similar profiles of hormone levels and semen parameters. On the other hand, the infertile men with grade 2 (palpable at rest, but not visible) or grade 3 (visible and palpable at rest) varicoceles had significantly higher FSH and LH levels and lower testosterone levels and semen quality compared with the fertile men. There was a significant increase in FSH levels and a decrease in semen quality in the infertile men with grade 1 varicoceles over a 4‐year period.ConclusionsOur data indicate the presence of large biological variations in semen quality in the normal male population. These findings are considered to have consequences for the interpretation of semen analyses in clinical trials to evaluate testicular safety. Because a significant decline in semen quality over time was observed in the infertile men with grade 1 varicoceles and these small varicoceles could not be detected by hormone levels and semen parameters, men with varicoceles should be excluded from testicular safety evaluation studies by palpation and Valsalva maneuver.