**2. The control of spermatogenesis and sperm quality**

Intricate neuronal circuitries, mainly governed by hypothalamic kisspeptin and gonadotropin releasing hormone (GnRH) reciprocal communications, centrally orchestrate reproduction [1] and lead to pituitary gonadotropin discharge and sex steroid biosynthesis in order to sustain spermatogenesis and sperm release. In addition to hormonal milieu, a complex network of intratesticular cell-to-cell communications regulates germ cell progression, coordinating mitosis, meiosis, differentiation, and maturation [2, 3]. Thus, SPZ morphological feature is critical to ensure proper physiological activity.

Spermatogenesis is highly sensitive to environmental stressors as energy availability, stress, life style, temperature, pollutants, heavy metals, or endocrine disruptor chemicals that act at several levels along the hypothalamus-pituitary-gonad axis [14–16]. In this respect, the activity of molecular chaperone/cochaperone, ubiquitination, but also DNA repair systems and antioxidants defenses ensures the physiological progression of spermatogenesis, avoids that damaged germ cells differentiate into SPZ, and deeply contributes to produce high-quality mature SPZ [17–19].

Conversely, impaired autocrine/paracrine/endocrine communication along the hypothalamus-pituitary-gonadal axis may impact spermatogenesis and have deleterious effects on male fertility due to: (1) spermatogenesis arrest and lack of SPZ, as in the case of hypogonadotropic hypogonadism; (2) defective production of gonadotropins/sex steroids with outcomes on spermatogenesis onset/progression and SPZ maturation; and (3) low sperm count and/ or the production of defective spermatozoa with morphological abnormalities or impaired motility [20]. However, in 30–40% of male infertility cases, the etiology remains unknown and infertility is therefore idiopathic, being a multifactorial disorder in which molecular defects in spermatogenesis and sperm function occur [21].
