Expression of RXFP2 receptor on human spermatozoa and the anti‐apoptotic and antioxidant effects of insulin‐like factor 3

Abstract

Insulin-like peptide 3 (INSL3) belongs to the large family of peptide hormones called 'insulin relaxin' (Shabanpoor et al., 2011). INSL3 is secreted by testicular Leydig cells as a marker for the complete differentiation of adult Leydig cells in men and all mammalians that mediates the descent of the testicle during the embryonic period and, as a paracrine factor, mediates gonadotropin activity in adults (Anand-Ivell et al., 2006; Muda et al., 2005). This hormone binds to the RXPF2 receptor and plays an important role in regulating spermatogenesis in adolescents. INSL3 is a peptide hormone that is known as a significant marker for the function and amount of Leydig cells and steroid capacity, and despite testicular steroids, it is free of the HPG axis effects (Anand-Ivell, Heng, Hafen, Setchell, & Ivell, 2009). Analysis of different sections of the semen fluid shows a high concentration of INSL3 in the interstitial cells. It passes through the blood-testis barrier to enter the seminiferous, testis and epididymis, and if its concentration is sufficient, RXFP2 as its specific receptor can be discovered on the post-mitotic cells and also in the epididymis. This hormone is a G protein of class C that binds to the RXFP2 receptor and generates Gs-dependent signals to produce cAMP. The cAMP activates protein kinase A (PKA), which in turn can inhibit Bid (BH3 interacting domain death agonist), a proapoptotic protein. Therefore, this hormone has an

Insulin‐like peptide 3 in domestic animals with normal and abnormal reproductive functions, in comparison to rodents and humans

“… Schematic illustrations of RXFP2 localization and the roles of INSL3 in testicular tissue. 9 , 27 , 55 , 56 , 63 , 64 , 65 , 66 , 67 BV, blood vessel; INSL3, insulin‐like peptide 3; LHR, luteinizing hormone receptor; Ly, Leydig cell; RS, round spermatid; S, spermatozoon; Sc, spermatocyte; Sg, spermatogonia; Sr, Sertoli cell; T, testosterone …”

“… 66 The addition of INSL3 to human sperm reportedly reduced oxidative stress and enhanced their motility. 67 The abovementioned studies advocate considerable functions of INSL3 in testicular spermatogenesis and steroidogenesis in animals, but not for humans. Direct effects of INSL3 on sperm functions remain to be determined in every species in spite of the receptor's expression on sperm in some animals.…”

“…66 The addition of INSL3 to human sperm reportedly reduced oxidative stress and enhanced their motility. 67 The abovementioned studies advocate considerable functions of INSL3 in testicular spermatogenesis and steroidogenesis in animals, but not for humans.…”

Physiology and evolution of the INSL3/RXFP2 hormone/receptor system in higher vertebrates

“…There is some evidence to suggest that RXFP2 may also be expressed in or on free spermatozoa (Feugang et al, 2011(Feugang et al, , 2015Pitia et al, 2017;Shokri et al, 2020), or on cells of the epididymal epithelium (Anand-Ivell et al, 2006b;Filonzi et al, 2007), from where it might be transferred to transiting or stored sperm by transcytosis of epithelial vesicles. Effects of INSL3 on ejaculated sperm function have also been shown for the human, but only at very high, supraphysiological INSL3 concentrations (Shokri et al, 2020), so that a natural role in vivo must be doubted. Our own studies using human sperm indicated no effect at physiological concentrations (unpublished).…”