Molecular pathways of varicocele and its repair - A paired labelled shotgun proteomics approach

Varicocelectomy is associated to improved semen quality and sperm functional quality, but individual response is highly variable. Thus, a prospective study was performed including 25 men who collected a semen sample before and 12 months after subinguinal microsurgical varicocelectomy. Semen analysis, sperm functional analysis, and seminal plasma proteomic analysis was performed before and 12 months after varicocelectomy, and according to improvement or not of semen quality (positive and negative outcome). Varicocelectomy led to an increase in semen volume and sperm count, morphology, and mitochondrial activity. In the pre- vs. post-samples, 698 proteins were quantified - 91 differentially expressed after varicocelectomy. In the positive vs. negative outcome analysis, 647 proteins were identified - 151 differentially expressed in the negative outcome group and 30 differentially expressed in the positive outcome group. Tripeptidyl peptidase-1 offered a predictive value for outcome, with an area under a ROC curve of 84.5%. It seems TPP1 is an outcome predictor for varicocelectomy in adults. More importantly, this study demonstrates that the seminal plasma proteome is different in men with varicocele when compared to post-treatment samples from the same individuals. Understanding and monitoring the molecular mechanisms of semen may further establish therapeutic options for these men. SIGNIFICANCE: Although several large-scale studies have demonstrated varicocele is unequivocally associated to male infertility, these same studies have also demonstrated that varicocele is not a determinant of male infertility. We have yet to answer the question of why don't all men with varicocele present with infertility. Varicocele treatment improves semen quality, but its results are variable, and one cannot know who will and who will not benefit from surgical treatment. Results from this study strongly advance a concept that our previous studies have shown: that men with varicocele present an inflammatory semen profile. We have further demonstrated that men operated for varicocele present a decrease in this inflammatory profile, and that when they do not, semen quality remains unaltered. Trypeptidil peptidase-1, a seminal protein, was 3-fold higher in men with a positive outcome after the procedure, when compared to men with a negative outcome. Therefore, inflammation seems to be a central point to varicocele-derived male infertility.