role of sex steroid hormones, cytokines and the endocannabinoid system in female fertility

Human Reproduction Update, Vol.17, No.3 pp. 347– 361, 2011 Advanced Access publication on January 12, 2011 doi:10.1093/humupd/dmq058 The role of sex steroid hormones, cytokines and the endocannabinoid system in female fertility T. Karasu 1, T.H. Marczylo 1, M. Maccarrone 2,3†, and J.C. Konje 1,*† 1 Endocannabinoid Research Group (ERG), Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, PO Box 65, Leicester, Leicestershire LE2 7LX, UK 2 Department of Biomedical Sciences, University of Teramo, Teramo, Italy 3European Center for Brain Research (CERC)/Santa Lucia Foundation, Rome, Italy *Correspondence address. Tel: +44-1162525826; Fax: +44-1162525824; E-mail: Submitted on August 2, 2010; resubmitted on September 10, 2010; accepted on September 22, 2010 table of contents ........................................................................................................................... † Introduction † Methods † The endocannabinoid system Metabolism: biosynthesis, transport and degradation of AEA and 2AG Endocannabinoid receptors † The endocannabinoids and sex steroid hormones The role of progesterone The role of oestrogen † The endocannabinoids and cytokines The role of LIF The Th1/Th2 balance The role of leptin † Conclusions background: Marijuana, the most used recreational drug, has been shown to have adverse effects on human reproduction. Endogenous cannabinoids (also called endocannabinoids) bind to the same receptors as those of D9-tetrahydrocannabinol (THC), the psychoactive component of Cannabis sativa. The most extensively studied endocannabinoids are anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol. The endocannabinoids, their congeners and the cannabinoid receptors, together with the metabolic enzymes and putative transporters form the endocannabinoid system (ECS). In this review, we summarize current knowledge about the relationships of ECS, sex steroid hormones and cytokines in female fertility, and underline the importance of this endocannabinoid–hormone –cytokine network. methods: Pubmed and the Web of Science databases were searched for studies published since 1985, looking into the ECS, sex hormones, type-1/2 T-helper (Th1/Th2) cytokines, leukaemia inhibitory factor, leptin and reproduction. results: The ECS plays a pivotal role in human reproduction. The enzymes involved in the synthesis and degradation of endocannabinoids normalize levels of AEA for successful implantation. The AEA degrading enzyme (fatty acid amide hydrolase) activity as well as AEA content in blood may potentially be used for the monitoring of early pregnancies. Progesterone and oestrogen are involved in the maintenance of endocannabinoid levels. The ECS plays an important role in the immune regulation of human fertility. † Equally senior authors. & The Author 2011. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: 348 Karasu et al. conclusions: The available studies suggest that tight control of the endocannabinoid–hormone –cytokine network is required for successful implantation and early pregnancy maintenance. This hormone –cytokine network is a key element at the maternal– foetal interface, and any defect in such a network may result in foetal loss. Key words: endocannabinoids / sex hormones / leukaemia inhibitory factor / leptin / female fertility Introduction The endocannabinoid system Endocannabinoids are a group of fatty-acid derivatives that bind to, and activate, the cannabinoid receptors (Di Marzo, 1998) and have several roles in both the central nervous system (CNS) and the periphery (Fride, 2002). Anandamide (N-arachidonoylethanolamine: AEA) (Devane et al., 1992)—the first endocannabinoid to be identified—was isolated from porcine brain and was closely followed by 2-arachidonoylglycerol (2-AG) (Mechoulam et al., 1995; Sugiura et al., 1995). Most studies conducted to date involve either AEA or 2-AG, which are prototype members of fatty-acid amides and monoacylglycerols, respectively. However, several novel endocannabinoids have been identified, including O-arachidonoylethanolamine (virodhamine) (Porter et al., 2002), N-arachidonoyldopamine (Bisogno et al., 2000) and N-arachidonoyltaurine (Saghatelian et al., 2004). In addition, N-oleoylethanolamine (OEA), N-palmitoylethanolamine (PEA) and N-stearoylethanolamine are ‘endocannabinoid-like’ congeners that are thought to exhibit an ‘entourage’ effect by inhibiting AEA and 2-AG degradation (Ben-Shabat et al., 1998; De Petrocellis et al., 2004). AEA is released along with OEA and PEA when neurons, somatic cells and reproductive cells are stimulated, and are rapidly removed by re-uptake and hydrolysis to modulate signalling processes (Freund et al., 2003). AEA, OEA and PEA are present in human seminal plasma, mid-cycle oviductal fluid, follicular fluid, amniotic fluid and milk (Schuel et al., 2002). Endocannabinoids mimic several actions of the major pharmacologically active component D9-tetrahydrocannabinol (THC) of Cannabis sativa (Piomelli, 2004). The use of Cannabis is associated with implantation failure, spontaneous miscarriage, foetal growth restriction and premature birth in humans (Fergusson et al., 2002). Increasing evidence confirms the significance of endocannabinoids in reproductive events such as folliculogenesis, spermatogenesis (Wang et al., 2006a, b, c; Taylor et al., 2007; Battista et al., 2008b), fertilization, oviductal transport, implantation and embryo development (Wang et al., 2006a, b, c; Battista et al., 2007, 2008a; Taylor et al., 2007) it is known that these events are under the control of steroid hormones and cytokines. Several studies have now shown direct effects of these steroids on elements of the ECS (Maccarrone et al., 2000a, b, 2003a, b). In this review, we examine the role of sex steroids, cytokines and the ECS in the regulation of female fertility. Endocannabinoids, including AEA and 2-AG, bind to G-proteincoupled cannabinoid receptors (CB1 and CB2) (Pertwee and Ross, 2002; Sugiura et al., 2002). The biological effects of AEA and 2-AG are terminated by cellular uptake via a putative endocannabinoid membrane transporter (EMT), followed by enzymatic degradation (see below-mentioned text). The endocannabinoids, their congeners and the cannabinoid receptors, together with the metabolic enzymes and purported transporters, form the ECS. This system is summarized in Fig. 1. Methods A literature research of Pubmed and the Web of Science databases was performed using the terms ‘endocannabinoid system’, ‘anandamide’, ‘sex steroid hormones’, ‘LIF’, ‘Th1/Th2 cytokines’, ‘Leptin’ and ‘reproduction’ for studies published between 1985 and the present. We only included articles published in the English language about studies in (...truncated)