**1.1 Prostaglandin synthesis and function**

Arachidonic acid (AA) is the precursor of all eicosanoids. Phospholipase A2 splits AA from plasma membrane phospholipids; once free in the cytosol it is cyclized, oxygenated and reduced to the intermediary PGH2 by the COX enzymes; or to hydroperoxyeicosatetraenoic acid (HPETE) by LOX enzymes, when the LT pathway is followed.

Two *COX* genes are known to be highly conserved throughout the species. *COX-1* gene has several splice variants: the most widely known COX-1 enzyme, the less known counterparts COX-3 and other smaller variants of the COX-1 (Chandrasekharan et al., 2002; Chandrasekharan & Simmons, 2004). *COX-2* gene has, up to now, only one known protein. COX-1 is ubiquitously and constitutively expressed. It was long thought of COX-1 as the enzyme that was involved only in physiological conditions, but was proven to be upregulated in various carcinomas and to be involved in tumorigenesis (Hwang et al., 1998; Kitamura et al., 2002; Sales et al., 2002). COX-2 enzyme is physiologically induced by growth factors and cytokines; it functions when the concentrations of AA are very low (Fortier et al., 2008). Furthermore COX-2 was seen to be overexpressed in several pathological circumstances as different types of cancers, where its high expression correlates with a negative prognosis, and other inflammation related diseases, as endometriosis (Matsuzaki et al., 2004; Ota et al., 2001).

PGH2 synthesized by the COXs, is used as a substrate to produce the terminal prostanoids by the PG synthases; each of them is named by their product: PGD2, PGE2, PGF2α, prostacyclin (PGI2) and thromboxane (TX) A2 are produced by PGD synthase (PGDS), PGE

Involvement of Prostaglandins in the Pathophysiology of Endometriosis 117

Arachidonic acid is the precursor for leukotrienes and prostaglandins. Each prostaglandin has a specific seven transmembrane G protein coupled receptor; after binding with its receptor, prostaglandins

**AA**: arachidonic acid; **LTs**: leukotrienes; **LOX**: lipooxygenase; **COX-1/2**: cyclooxygenase-1 or 2; **PGH2:**  prostaglandin H2; **PGIS**: prostacyclin synthase; **PGI2**: prostacyclin; **TXS**: thromboxane synthase; **TXA2**: thromboxane; **PGE2:** prostaglandin E2**; PGD2:** prostaglandin D2**; PGF2:** prostaglandin F2**; PGES**: PGE2 synthase; **PGDS**: PGD2 synthase; **PGFS**: PGF2α synthase; **IP, TPα/β, EP1-4, DP, FPα/β**: specific PG receptors; **cAMP**: cyclic adenosine monophosphate; **IP3**: inositol triphosphate; **Ca2+**: calcium.

In addition, studies using EP and FP knockout mice have demonstrated the specific roles of PGE2 and PGF2α in reproduction. It has been shown that EP2 receptors are essential for ovulation and fertilization (Kennedy et al., 1999; Ushikubi et al., 2000) and FP are indispensible for parturition (Sugimoto et al., 1998). These studies indicate not only the essential role of PGE2 in the fertilization process, but also the importance of PGF2α in natural

As well, it has been described that PGs serve as endogenous ligands for nuclear receptors. In this respect, other prostanoids were identified as good peroxisome proliferator-activated receptors (PPAR) agonists with varying specificity. 15-deoxy-Δ 12,14 prostaglandin J2 (15dPGJ2), a natural PPARγ ligand, has high affinity for PPARγ and has been proposed as a regulator of the inflammatory response (Nosjean & Boutin, 2002; Scher & Pillinger, 2009). Another PPAR ligand is PGI2 that was found to play an important role via PPAR-δ nuclear

The process of implantation is considered to be analogous to pro-inflammatory responses, hence the speculation that PGs play a role in this event (Kennedy, 1979; Maybin et al., 2011; Tranguch et al., 2005). As well, several nonsteroidal anti-inflammatory drugs (NSAIDs) and

produce the up (↓) or downregulation (↑) of second messengers.

Fig. 1. Prostaglandin synthesis and signal transduction

receptor in implantation and decidualization (Pakrasi & Jain, 2008).

parturition.

synthase (PGES), PGF synthase (PGFS), PGI synthase (PGIS) and TX synthase (TXS), respectively. Once synthesized prostanoids are rapidly exported by a PG transporter out of the cell and they function very close to their liberation site, in an autocrine or paracrine fashion. They exert their biological actions through G protein coupled receptors (GPCRs) and, as it happens with the synthases, each prostanoid has a distinctive receptor to which to bind to. DP, EP, FP, IP and TP are the receptors for PGD2, PGE2, PGF2α, PGI2 and TXA2, respectively (Figure 1). The EP receptor has four known subtypes (EP1-EP4), each encoded by a different gene; furthermore, EP3 has eight splice variants; TP and FP have also been described to have two splice variants each (Fortier et al., 2008).

Sequence homology analysis revealed that receptors sharing a common signaling pathway are more closely related than do receptors binding the same ligand. After binding to the corresponding GPCR there is generation of soluble second messengers. Coupled to Gq, DP receptor increases cyclic adenosine monophosphate (cAMP) concentration, whereas IP receptor is coupled to Gs and increases not only cAMP but also mediates responses by phosphatidylinositol increasing free Ca2+ concentration (Narumiya et al., 1999). Both isoforms of TP activate phopspholipase C (PLC), but TPα activates adenylate cyclase while TPβ inhibits it (Narumiya et al., 1999). FP receptors also act through Gq, PLC and Ca2+ release; while EP receptors have distinctive signaling pathways depending on the subtype binding PGE2: EP1 is coupled to Gi and Ca2+ channels, EP2 and EP4 share the pathway coupling to Gs and increasing cAMP intracellular concentration, whereas the EP3 has specific responses depending on the splice variant, but is usually assumed as an inhibitory receptor coupled to Gi (Fortier et al., 2008) (Figure 1).
