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Abstract
The relationship between varicocele and fertility has always been a matter of debate because of the absence of predictive clinical indicators or molecular markers able to define the severity of this disease. Even though accumulated evidence demonstrated that the endocannabinoid system (ECS) plays a central role in male reproductive biology, particularly in the testicular compartment, to date no data point to a role for ECS in the etiopathogenesis of varicocele. Therefore, the present research has been designed to investigate the relationship between testicular ECS gene expression and fertility, using a validated animal model of experimental varicocele (VAR), taking advantage of traditional statistical approaches and artificial neural network (ANN). Experimental induction of VAR led to a clear reduction of spermatogenesis in left testes ranging from a mild (Johnsen score 7: 21%) to a severe (Johnsen score 4: 58%) damage of the germinal epithelium. However, the mean number of new-borns recorded after two sequential matings was quite variable and independent of the Johnsen score. While the gene expression of biosynthetic and degrading enzymes of AEA (NAPE-PLD and FAAH, respectively) and of 2-AG (DAGLα and MAGL, respectively), as well as their binding cannabinoid receptors (CB1 and CB2), did not change between testes and among groups, a significant downregulation of vanilloid (TRPV1) expression was recorded in left testes of VAR rats and positively correlated with animal fertility. Interestingly, an ANN trained by inserting the left and right testicular ECS gene expression profiles (inputs) was able to predict varicocele impact on male fertility in terms of mean number of new-borns delivered (outputs), with a very high accuracy (average prediction error of 1%). The present study provides unprecedented information on testicular ECS gene expression patterns during varicocele, by developing a freely available predictive ANN model that may open new perspectives in the diagnosis of varicocele-associated infertility.
Highlights
Varicocele is considered among the most common causes of male infertility and affects approximately 15-20% of the general male population
Varicocele is functionally related to an abnormal dilation and tortuosity of the pampiniform plexus veins, which are BioMed Research International responsible for the testicular venous drainage. This defect is believed to be the main trigger of varicocele, inducing a complex and multifactorial cascade of events that may synergistically lead to infertility and impair spermatogenesis [4,5,6]
The surgical induction of pathology elicited a significant reduction of the mean Johnsen score values recoded in left testes of VAR group (p < 0.0001, VAR left versus CTR; p < 0.0001, VAR left versus LAPARO; p < 0.0001, VAR left versus VAR right)
Summary
Varicocele is considered among the most common causes of male infertility and affects approximately 15-20% of the general male population. Varicocele is functionally related to an abnormal dilation and tortuosity of the pampiniform plexus veins, which are BioMed Research International responsible for the testicular venous drainage. This defect is believed to be the main trigger of varicocele, inducing a complex and multifactorial cascade of events that may synergistically lead to infertility and impair spermatogenesis [4,5,6]. Scrotal hyperthermia, testicular hypoperfusion and hypoxia, oxidative stress, endocrine and paracrine disturbances, backflow of adrenal metabolites, genetic disorders, and autoimmunity can all be detrimental factors for testicular function, participating in varicocelerelated infertility mechanisms [1, 7,8,9,10]
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