134 ENDOMETRIOSIS The role of prostaglandin E 2 in endometriosis Keith Sacco 1 , Mark Portelli 1 , Joël Pollacco 1 , Pierre Schembri-Wismayer 1 & Jean Calleja-Agius 1,2 1 Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, Tal-Qroqq, Msida MSD, Malta, and 2 Department of Obstetrics and Gynaecology, Mater Dei Hospital, Msida MSD, Malta Gynecological Endocrinology, 2012; 28(2): 134–138 Copyright © 2012 Informa Healthcare USA, Inc. ISSN 0951-3590 print/ISSN 1473-0766 online DOI: 10.3109/09513590.2011.588753 Correspondence: Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, Tal-Qroqq, Msida MSD2080, Malta. Phone & Fax: +356 21 319527. E-mail: jean.calleja-agius@um.edu.mt Endometriosis is a leading cause of infertility in women of reproductive age. It involves the occurrence of endometrial tissue outside the uterine endometrium, mainly in the peritoneal cavity. Prostaglandin E 2 is up regulated in the peritoneal cavity in endometriosis and is produced by macrophages and ectopic endometrial cells. This prostaglandin is involved in the pathophysiology of the disease and elicits cell signals via four receptor types. Prostaglandin E 2 increases estrogen synthesis by up regulating steroidogenic acute regulatory protein (StAR) and aromatase. It inhibits apoptosis and up regulates fibroblast growth factor-9 (FGF-9) promoting cell proliferation. Prostaglandin E 2 affects leukocyte populations and promotes angiogenesis through its effect on estrogen and up regulation of vascular endothelial growth factor (VEGF). Dienogest is a synthetic progestin targeting expression of genes involved in prostaglandin synthesis. Keywords: Endometriosis, infertility, estrogens, prostaglandins Abbreviations: cAMP, Cyclic adenosine monophosphate; CD36, Cluster of Differentiation 36; COUP-TF, Chicken ovalbumin upstream-transcription factor; COX, Cyclooxygenase enzyme; CREB, cAMP response element-binding; ELK-1, Ets LiKe gene1; EP1/2/3/4, Prostaglandin receptor subtypes 1, 2, 3 and 4; FGF-2, Fibroblast Growth Factor-2; FGF-9, Fibroblast Growth Factor-9; FGFR1, Fibroblast Growth factor receptor-1; GnRH, Gonadotropin-releasing hormone; IL-1, Interleukin-1; IL-1ß, Interleukin-1ß; IL-6, Interleukin-6; MIF, Macrophage migration inhibitory factor; MMP-9, Matrix metalloproteinase-9; mPGES-1, Microsomal prostaglandin E synthase-1; PGE, synthase Prostaglandin E synthase; PGE 2 , Prostaglandin E 2 ; PGH 2 , Prostaglandin H 2 ; PKA, Protein kinase A; PKCδ, Protein kinase C-δ; SF1, Steroidogenic factor-1; StAR, Steroidogenic acute regulatory protein; TNF-α, Tumour necrosis factor-alpha; VEGF, Vascular endothelial growth factor Introduction Prostaglandins are a group of bioactive lipid products derived from arachidonic acid metabolism. Teir efects are ubiquitous both in physiological and pathophysiological mechanisms. Free arachidonic acid is the prostaglandin precursor. Te synthesis of the various prostaglandin subtypes is governed by a committed step, catalysed by cyclooxgenase (COX) enzyme. At present, three isoforms are known to catalyse this step (COX-1, COX-2 and COX-3 [1]). Various studies have shown that the COX-2 isoform is over expressed in ectopic endometrial cells and that there is an elevated level of a specifc prostaglandin, prostaglandin E 2 (PGE 2 ) in uterine tissues of women with menorrhagia, dysmen- orrhoea and endometriosis [2–4]. Such evidence has lead to questioning the role of this prostaglandin in the pathogenesis of endometriosis. Tis review aims to highlight the various underlying mechanisms elucidated so far, by which prosta- glandin E 2 exerts its efect on ectopic endometrial cells. Tis provides a clearer understanding of the pathophysiology of the disease to elucidate the potential for novel drugs that target such mechanisms. Endometriosis: an overview Endometriosis is a female pelvic disorder whereby endometrial tissue is found outside the uterine cavity, mainly within the pelvic cavity. With a prevalence of 6–10% in the general female population, this condition is a major cause of infertility [5,6]. Endometriotic foci may settle and proliferate in the fallopian tubes, the ovaries or enter the peritoneal cavity and deposit in sites such as the recto-uterine pouch [7]. Laparoscopy is the key tool for diagnosing this condition and treating visible endometrial foci. As yet, medical therapy aims to minimise pain as a result of endometriosis [8]. Te various drugs available are either oral contraceptives, aromatase inhibitors, gonadotropin-releasing hormone (GnRH) receptor agonists and androgenic agents. Tese aim to reduce ovarian estrogen production or inhibit ovarian activity [9]. Surgery through operative laparoscopy is used to excise visible foci. However such treatments are far from ideal as the recurrence rate following surgery or termination of therapy is 50–60% [10]. Precise aetiology and pathogenesis is primarily required to enable formation of drugs that target the pathophysiological mechanisms of endometriosis. At present, there are various theories on the pathogenesis of endometriosis. Te retrograde menstruation hypothesis suggests that endometriosis develops as a result of endometrial cells being swept towards the infundibulum of the fallopian tube and into the pelvic cavity [11,12]. Other theories are those of metaplasia [13] and the development of endometrial tissue from induced mesenchyme [14,15]. Estrogens seem to play a critical role in the development of the disease [16–19]. Gynecol Endocrinol Downloaded from informahealthcare.com by Universitaets- und Landesbibliothek Duesseldorf on 12/15/13 For personal use only.