Jekyll and Hyde: Two Faces of Cannabinoid Signaling in Male and Female Fertility

0163-769X/06/$20.00/0 Printed in U.S.A. Endocrine Reviews 27(5):427– 448 Copyright © 2006 by The Endocrine Society doi: 10.1210/er.2006-0006 Jekyll and Hyde: Two Faces of Cannabinoid Signaling in Male and Female Fertility Haibin Wang, Sudhansu K. Dey, and Mauro Maccarrone Departments of Pediatrics, Cell and Developmental Biology, and Pharmacology (H.W., S.K.D.), Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Biomedical Sciences (M.M.), University of Teramo, Teramo 64100, Italy; and Mondino-Tor Vergata Neuropharmacology Center (M.M.), University of Rome Tor Vergata, 00133 Rome, Italy Mammalian reproduction is a complicated process designed to diversify and strengthen the genetic complement of the offspring and to safeguard regulatory systems at various steps for propagating procreation. An emerging concept in mammalian reproduction is the role of endocannabinoids, a group of endogenously produced lipid mediators, that bind to and activate cannabinoid receptors. Although adverse effects of cannabinoids on fertility have been implicated for years, the mechanisms by which they exert these effects were not clearly understood. With the identification of cannabinoid receptors, endocannabinoid ligands, their key synthetic and hydrolytic pathways, and the generation of mouse models missing cannabinoid receptors, a wealth of information on the significance of cannabinoid/endocannabinoid signaling in spermatogenesis, fertilization, preimplantation embryo development, implantation, and postimplantation embryonic growth has been generated. This review focuses on various aspects of the endocannabinoid system in male and female fertility. It is hoped that a deeper insight would lead to potential clinical applications of the endocannabinoid signaling as a target for correcting infertility and improving reproductive health in humans. (Endocrine Reviews 27: 427– 448, 2006) I. Lipid Signaling in Reproduction II. The Endocannabinoid System A. Introduction B. Metabolic routes C. Molecular targets and signaling pathways III. Endocannabinoids and Male Fertility A. Introduction B. The endocannabinoid system in Sertoli cells C. The endocannabinoid system in sperm IV. Endocannabinoids and Female Fertility: Embryo Implantation A. Introduction B. Endocannabinoids and preimplantation embryo development C. Endocannabinoids and oviductal embryo transport D. Biphasic endocannabinoid sensor in blastocyst implantation V. Endocannabinoids and Female Fertility: Immunoregulation A. Th1/Th2 cytokines and fertility B. The endocannabinoid system in lymphocytes of pregnant women C. FAAH as a molecular integrator of fertility signals VI. Endocannabinoids and Clinical Implications VII. Conclusions and Future Direction I. Lipid Signaling in Reproduction S EXUAL PROCREATION IS initiated by interactions between a sperm and an egg leading to fertilization (1– 4). The fertilized egg (embryo) undergoes several mitotic cell divisions, ultimately producing the blastocyst with two distinct cell types: the inner cell mass (ICM) and the trophectoderm (5–9). The nurturing of an offspring within the body and production of a live birth is an enduring task, requiring safeguard regulatory systems at various critical steps. Despite success in producing embryos and initiating embryonic development outside the womb by in vitro fertilization and embryo transfer, there is still a significant knowledge gap in understanding the mechanisms by which a successful pregnancy is achieved. A deeper insight into these processes will help to generate new ideas and concepts for improving fertility and pregnancy-associated health issues in humans. It is difficult to define the hierarchical landscape of the molecular pathways during human pregnancy, because of experimental difficulties and ethical restrictions on research with human embryos. It is hoped that experiments on mice and other animal models that bear certain reproductive similarities with humans combined with those feasible experiments in humans would generate meaningful information to address this critical issue. Over the past several years, molecular and genetic studies have provided evidence that lipid mediators serve as important signaling molecules in coordinating a series of events during early pregnancy. First Published Online May 8, 2006 Abbreviations: AA, Arachidonic acid; AdR, adrenergic receptor; AEA, N-arachidonoylethanolamine (also known as anandamide); 2-AG, 2-arachidonoylglycerol; AMT, AEA membrane transporter; CB1, braintype cannabinoid receptor; CB2, spleen-type cannabinoid receptor; COX, cyclooxygenase; cPLA2␣, cytosolic PLA2␣; DAG, diacylglycerol; DAGL, DAG lipase; E2, 17␤-estradiol; FAAH, fatty acid amide hydrolase; ICM, inner cell mass; INF-␥, interferon-␥; LIF, leukemia inhibitory factor; LPA, lysophosphatidic acid; MAGL, monoacylglycerol lipase; NAPE, N-acylphosphatidylethanolamine; NAT, N-acyltransferase; NK, natural killer; NO, nitric oxide; P4, progesterone; PG, prostaglandin; PL, phospholipase; Th1, type 1 T-helper; Th2, type 2 T-helper; THC, ⌬9tetrahydrocannabinol; TRPV1, transient receptor potential vanilloid 1 (vanilloid receptor); ZP, zona pellucida. Endocrine Reviews is published by The Endocrine Society (http:// www.endo-society.org), the foremost professional society serving the endocrine community. 427 428 Endocrine Reviews, August 2006, 27(5):427– 448 Under pathophysiological conditions when a cell is activated in response to a stimulus, membrane phospholipids generate numerous lipid-signaling molecules, such as eicosanoids and lysophospholipids. Prostaglandins (PGs), one of the major group of eicosanoid lipid mediators, are generated from arachidonic acid (AA), which is released from membrane phospholipids by phospholipase (PL)A2. AA thus released is transformed by cyclooxygenases (COXs) to PGH, which is then converted to various PGs by specific PG synthases (10). Distinct expression profiles of cytosolic PLA2␣ (cPLA2␣), COX-1, and COX-2 in the ovary and uterus at different stages of pregnancy implicate their differential functions (11–14). In mice, COX-1-derived PGF2␣, as a luteolytic hormone acting on the corpus luteum, is critical for the onset of parturition (15–18), whereas PGI2 and PGE2 generated by COX-2 are essential for ovulation, fertilization, implantation, and decidualization (11, 13, 19 –22). The role of PG during pregnancy is further illustrated by poor fertility, resulting from deferred implantation, in mice lacking cPLA2␣ (12). Collectively, these studies in mice establish the importance of lipid signaling through the cPLA2␣-COX axis during early pregnancy (23, 24). Observations of COX-2 expression in the periovulatory ovary and uterus during implantation as well as delayed follicular rupture and increased incidence of miscarriages upon pharmacological inhibition of COX further suggest that cPLA2␣-COX-derived PG signaling is also oper (...truncated)