Artificial Neural Network to Predict Varicocele Impact on Male Fertility through Testicular Endocannabinoid Gene Expression Profiles

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.

Artificial Intelligence in Andrology: From Semen Analysis to Image Diagnostics

“…AI further plays an essential role as a clinical diagnostic tool aiming to predict sperm parameters and reproductive outcomes. ANNs have been trained to accurately estimate the impact of varicocele on rat fertility as well as post-thaw motility before freezing in bulls [ 77 ]. Recently, a computerized staging system of spermatogenesis in mice enabled the evaluation of the quality of the spermatogenic process and the detection of developmental defects facilitating a less laborious assessment [ 78 ].…”

The Role of Artificial Intelligence in Male Infertility: Evaluation and Treatment: A Narrative Review

“…Although treatments include surgical modalities, there has recently been development in the use of AI for the prevention and treatment of varicoceles. Bernabó et al identified a significant downregulation of vanilloid expression in varicocele-affected testes, correlating with fertility, and developed an artificial neural network model predicting varicocele's impact on fertility with high accuracy, offering potential diagnostic insights [60]. Moreover, machine learning models utilizing pre-operative hormonal, clinical, and semen laboratory data have been used to forecast clinically significant post-varicocelectomy sperm characteristics [18].…”

AEC and AFMSC Transplantation Preserves Fertility of Experimentally Induced Rat Varicocele by Expressing Differential Regenerative Mechanisms

“…Varicocele (VAR) is considered as one of the main causes of male infertility which accounts for about 40% of primary and 80% of secondary male factor infertility, respectively [1][2][3][4]. It is characterized by the abnormally enlarged veins of the spermatic cord pampiniform plexus inside the scrotum by inducing different degrees of altered sperm count, motility, and viability as well as abnormal sperm morphology and DNA fragmentation [1].…”

“…Of note, significant differences in the expression of enzymes and downstream molecules of ECS have been observed between fertile and infertile men [26]. Using an experimental animal model, ECS was recently proposed as a prognostic pathway to correlate VAR to infertility [3]. Scientific evidence collected to date on both animals and humans have shown that the Transient Receptor Potential cation channel subfamily V member 1 (TRPV1) is affected by VAR-induced hyperthermia [26][27][28].…”