The endocannabinoid system (ECS) is an evolutionarily conserved master system deeply involved in the central and local control of reproductive functions in both sexes. The tone of these lipid mediators—deeply modulated by the activity of biosynthetic and hydrolyzing machineries—regulates reproductive functions from gonadotropin discharge and steroid biosynthesis to the formation of high quality gametes and successful pregnancy. This review provides an overview on ECS and reproduction and focuses on the insights in the regulation of endocannabinoid production by steroids, in the regulation of male reproductive activity, and in placentation and parturition. Taken all together, evidences emerge that the activity of the ECS is crucial for procreation and may represent a target for the therapeutic exploitation of infertility. 1. Introduction Reproductive functions are under a fine regulation exerted at multiple levels along the hypothalamic-pituitary-gonadal axis. The formation of high quality gametes, followed by a successful pregnancy event, is the result of deep cell to cell communications. In this respect, the list of potential modulators of reproductive activity is still growing. In the last two decades the upcoming role of lipid mediators that share some of the effects with delta-9-tetrahydrocannabinol (Δ9-THC), the active principle of marijuana plant, Cannabis sativa, emerged. These bioregulators, collectively named endocannabinoids (eCBs), are amides, esters, and ethers of long-chain polyunsaturated fatty acid and have been detected in most reproductive tissues and fluids [1–3].Besides ligands, a wide range of receptors, biosynthetic and hydrolyzing enzymes, and putative membrane transporters (EMT) all together form the endocannabinoid system (ECS) (Figure 1), a master system that is deeply involved in the central and local control of male and female reproduction. Since their discovery, research made giant strides in the comprehension of physiological, cellular, and molecular events in reproduction driven by eCBs. Many inputs in the field came from studies conducted in invertebrates and nonmammalian vertebrates, indicating that ECS is an evolutionarily conserved master system deeply involved in the control of reproductive functions. Thus, the aim of this review is just to provide new insights into the complex field of eCBs and reproduction. Figure 1: Schematic representation of the ECS. N-arachidonoyl-ethanolamine (AEA) is mainly produced by the activity of an N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD), whereas its degradation
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