Worldwide the incidence of andrological diseases is rising every year and, together with it, also the interest in them is increasing due to their strict association with disorders of the reproductive system, including impairment of male fertility, alterations of male hormones production, and/or sexual function. Prevention and early diagnosis of andrological dysfunctions have long been neglected, with the consequent increase in the incidence and prevalence of diseases otherwise easy to prevent and treat if diagnosed early. In this review, we report the latest evidence of the effect of andrological alterations on fertility potential in both young and adult patients, with a focus on the link between gonadotropins’ mechanism of action and mitochondria. Indeed, mitochondria are highly dynamic cellular organelles that undergo rapid morphological adaptations, conditioning a multitude of aspects, including their size, shape, number, transport, cellular distribution, and, consequently, their function. Since the first step of steroidogenesis takes place in these organelles, we consider that mitochondria dynamics might have a possible role in a plethora of signaling cascades, including testosterone production. In addition, we also hypothesize a central role of mitochondria fission boost on the decreased response to the commonly administrated hormonal therapy used to treat urological disease in pediatric and adolescent patients as well as infertile adults.

Testicular germ cell tumors (TGCTs) are the most common malignancies affecting young men between the ages of 14 and 44, accounting for about 95% of all testicular cancers. Despite being relatively rare compared to other cancers (~3.0 cases per 100,000 population, with high worldwide variability), TGCTs’ incidence is increasing, particularly in industrialized countries. The initial phase of TGCT diagnosis is performed by detecting in the blood the presence of three proteins, i.e., alpha-fetoprotein (AFP), lactate dehydrogenase (LDH), and human chorionic gonadotropin (hCG). Despite these proteins being defined as markers of TGCTs, they present limitations in specificity. Indeed, AFP is not elevated in pure seminomas; LDH serum levels can be elevated in other conditions, such as liver disease or tissue damage, and hCG can be elevated in both seminomas and non-seminomas, reducing its ability to differentiate between tumor types. However, the existence of hCG variants, characterized by distinct glycosylation profiles that are differentially expressed in TGCT types and subtypes, may increase the diagnostic and prognostic potential of this hormone. Furthermore, emerging molecular biomarkers, including miRNAs and tumor cells-related epigenetic status, may offer new promising alternatives to improve diagnostic accuracy. Nonetheless, standardized diagnostic protocols still need to be implemented. Finally, understanding the biological roles of hCG isoforms and their “canonical” (e.g., LHCGR) and “non-canonical” (e.g., TGF-βR) receptor interactions may help in understanding tumor biology and therapeutic targeting.

Testicular descent is a crucial event in male sexual development, and alterations in this process during gestation can lead to reduced fertility in adulthood. Cryptorchidism, i.e., failure of one or both testicles to descend into the scrotum, is one of the most common birth defects and represents a principal cause of infertility in adulthood. Therefore, identifying effective approaches for preserving fertility in childhood is of primary importance. In this context, the key role played by the gubernaculum testis during the placement of the testes in the scrotal bursa emerges. Given its close affinity to testicular tissue and its richness in mesenchymal cells, our prime aim is to characterize this para-testicular tissue to explore its potential ability to differentiate into testicular cells for fertility preservation. The first step of our task is represented by the present study that aimed to obtain in vitro stem-like cells starting from gubernaculum testis biopsies of four pediatric patients affected by cryptorchidism, aiming to differentiate them into testicular functioning cells. Our results show that the obtainment of aggregates with stem features is not dependent on the age of the patients and, therefore, not even on the damage suffered by the testis during its stay in the abdomen. This study opens the possibility of extending this approach to older patients, offering a new potential approach to support their fertility potential.