The endocannabinoid system and spermatogenesis

Abstract

Spermatogenesis is a complex process in which male germ cells undergo a mitotic phase followed by meiosis and by a morphogenetic process to form mature spermatozoa. Spermatogenesis is under the control of gonadotropins, steroid hormones and it is modulated by a complex network of autocrine and paracrine factors. These modulators ensure the correct progression of germ cell differentiation to form mature spermatozoa. Recently, it has been pointed out the relevance of endocannabinoids as critical modulators of male reproduction. Endocannabinoids are natural lipids able to bind to cannabinoid receptors and whose levels are regulated by specific biosynthetic and degradative enzymes. Together with their receptors and metabolic enzymes, they form the "endocannabinoid system" (ECS). In male reproductive tracts, they affect Sertoli cell activities, Leydig cell proliferation, germ cell differentiation, sperm motility, capacitation, and acrosome reaction. The ECS interferes with the pituitary-gonadal axis, and an intricate crosstalk between ECS and steroid hormones has been highlighted. This mini-review will focus on the involvement of the ECS in the control of spermatogenesis and on the interaction between ECS and steroid hormones.

Keywords: cannabinoid; endocannabinoid system; male germ cells; sex hormones; spermatogenesis.

Figure 1

Effect of CB₂ activation on the early steps of spermatogenic differentiation. Mitotic male germ cells express CB₂ receptor and high level of 2-AG. Activation of CB₂ receptor by 2-AG, through an autocrine pathway, promotes meiotic entry and progression of spermatogonia, as revealed by the meiotic organization of nuclear SCP3 (green) during the prophase I phases (leptotene, zygotene, pachytene).

Figure 2

Regulation of AEA-degrading enzyme FAAH expression by estrogen in Sertoli cells. E₂ regulates FAAH transcription by direct binding of estrogen receptor (ER) and epigenetic mechanisms including histone modification and DNA methylation. On the left: in the absence of estrogens, faah proximal promoter is methylated at DNA CpG sites and at lysine 9 of H3 histone and it is not competent for transcription. The final outcome is an increase AEA-induced apoptosis of Sertoli cells. On the right: estrogens activates the AEA-degrading enzyme FAAH transcription, through ER binding at ERE sites and reduction of DNA and H3K9me3 methylation. The direct/indirect interaction with histone demethylase LSD1, constitutively recruited at this site, is necessary for estrogen-induced transcription. The final outcome is a decrease of AEA-induced apoptosis of Sertoli cells (ERE, estrogen response element).