Cyclooxygenase enzymes and prostaglandins in reproductive tract physiology and pathology

Prostaglandins & other Lipid Mediators 71 (2003) 97–117

Invited review

Cyclooxygenase enzymes and prostaglandins in reproductive tract physiology and pathology K.J. Sales, H.N. Jabbour∗ MRC Human Reproductive Sciences Unit, Center for Reproductive Biology, The University of Edinburgh Academic Center, 49 Little France Crescent, Old Dalkeith Road, Edinburgh EH16 4SB, UK Received 10 March 2003; received in revised form 15 May 2003; accepted 27 May 2003

Abstract Prostaglandins, thromboxanes (TX) and leukotrienes, collectively referred to as eicosanoids, are cyclooxygenase (COX) metabolites of arachidonic acid (AA). Prostaglandins, have been recognised for many years as key molecules in regulating reproductive tract physiology and pathology. Numerous recent studies in in vitro model systems and knockout mouse models have demonstrated specific functional roles for the respective cyclooxygenase enzymes, prostaglandins and prostanoid receptors. Here we review the findings obtained in several of these studies with emphasis on the roles played by cyclooxygenase enzymes and prostaglandins, specifically prostaglandin E2 (PGE2 ) and F2␣ in reproductive tract physiology and pathology. © 2003 Elsevier Inc. All rights reserved. Keywords: Cyclooxygenase; Prostaglandin; Receptors; Reproductive pathology

1. Introduction Eicosanoid biosynthesis (depicted schematically in Fig. 1) is controlled by the rate-limited release of arachidonic acid (AA), obtained either from plasma membrane phospholipids or derived by desaturation and elongation of dietary fatty acids such as linoleic acid [1,2]. This process is mediated by phospholipase A2 (PLA2), following activation of intracellular signal transduction pathways such as the adenosine 3 ,5 cyclic monophosphate (cAMP) and mitogen-activated protein kinase (MAPK) pathways. Following its release from intracellular stores into the cytoplasm, arachidonic acid is oxidised by either cytochromes P450 to epoxyarachidonic acids, cyclooxygenase (COX) to prostaglandin H2 (PGH2 ) or by lipoxygenases to hydroxyeicosatatraenoic acids (HETEs), leukotrienes and lipoxins ∗

Corresponding author. Tel.: +44-131-2426220; fax: +44-131-2426231. E-mail address: [email protected] (H.N. Jabbour).

1098-8823/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1098-8823(03)00050-9

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Fig. 1. Prostanoid biosynthetic and signalling pathway. The formation of prostaglandins (PG), PGD2 , PGE2 , PGF2␣ , PGH2 , PGI2 and thromboxane (TX)A2 from arachidonic acid (AA) by cyclooxygenases (COX), their respective receptors and second messenger systems triggered.

[2] (Fig. 1). For the purpose of this review, we will focus only on cyclooxygenases and prostaglandins.

2. Cyclooxygenase enzymes The mechanisms involving prostanoid biosynthesis were initially outlined in 1967 by Hamberg and Samuelsson [3]. For several years it was thought that prostanoids were biosynthesised by the two distinct COX enzymes, COX-1 and COX-2, which are the targets for NSAID therapy (the mainstays of therapy for rheumatic disease despite their adverse effects on renal and gastrointestinal function). More recently a third COX enzyme (COX-3), a variant of COX-1, has been cloned [4]. The structures of COX-1 and COX-2 from various species, have been well characterised [5]. COX-1 is transcribed from a 22 kb gene located on chromosome 9, whereas COX-2 is transcribed from an 8.3 kb immediate early gene located on chromosome 1 [6]. COX-1 is generally considered to be involved in performing normal physiological functions [7–9]. By contrast, COX-2 (an immediate early gene which is rapidly induced by growth factors,

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oncogenes, carcinogens and tumour-promoting phorbol esters) is associated with rheumatic disease, inflammation and tumorigenesis [6,9–12]. COX-3 and other recently reported variants such as PCOX-1a originate from the COX-1 gene and are formed by intron retention, where intron-1 is retained in their mRNAs. Human COX-3 is expressed as a 5.2 kb mRNA [4] and shares all the structural and catalytic features of COX-1 and COX-2, however the retained intron significantly alters its enzymatic properties. COX-3 is shown to produce only 20% of the PGE2 produced by COX-1 in response to administration of arachidonic acid. In addition, COX-3 exhibits a vastly different pharmacology towards analgesic and antipyretic therapeutics compared with COX-1 and COX-2. COX-3 appears to be sensitive to drugs that are antipyretic/analgesic which have low anti-inflammatory properties [4], compared with COX-1 and COX-2 which are inhibited by a broad spectrum of anti-inflammatory drugs. This suggests that COX-3 plays a different role in eicosanoid biosynthesis compared with COX-1 and COX-2.

3. Prostaglandins and their receptors Prostanoids are members of a group of compounds composed of oxygenated C18 , C20 and C22 derived from ␻3 (n = 3) and ␻6 (n = 6) fatty acids [13] and can be categorised into prostaglandins, containing a cyclopentane ring or thromboxanes (TX) containing a cyclohexane ring. Prostanoids are produced by COX enzymes which both cyclizes arachidonic acid and adds the 15-hydroperoxy group to form prostaglandin G2 (PGG2 ). The hydroperoxy group of PGG2 is reduced to the hydroxy group of PGH2 [2] (Fig. 1). This intermediate serves as the substrate for terminal prostanoid synthase enzymes. These are named according to the prostaglandin they produce such that prostaglandin D2 is synthesised by prostaglandin-d-synthase (PGDS), prostaglandin E2 (PGE2 ) by prostaglandin-E-synthase (PGES); prostaglandin F2␣ by prostaglandin-F-synthase (PGFS), prostacyclin by prostaglandin-I-synthase (PGIS) and thromboxane by thromboxane synthase (TXS) [1,2,14–16] (Fig. 1). The physiological response to arachidonic acid oxygenation is determined by the level of expression of terminal synthase enzymes in the cells and tissues as each prostaglandin has its own range of biological activities and may be cell-type specific [17]. Following biosynthesis, prostanoids are transported out of the cell by means of a carriermediated process [18] where they exert their biological function through G protein receptormediated interaction. There are eight types and subtypes of prostanoid receptors that are encoded by different genes. Separate receptors, showing selective ligand binding specificity, have been described for PGD2 , PGE2 , PGF2␣ , TxA2 and PGI2 [2,15]. The genes encoding the human DP, EP1, EP2, EP3, EP4, FP, IP and TP receptors have been mapped to chromosomes bands 14q22.1, 13p13.1, 14q22, 1p31.2, 5p13.1, 1p31.1, 19q13.3 and 19p13.3, respectively [19–22]. Prior to 1989, little was known about the structure of prostanoid receptors. In 1989, the TXA2 receptor (TP receptor, Fig. 1) was purified from blood platelets [23] and its cDNA cloned in 1991 [24]. These studies revealed that the TXA2 receptor was a G protein-coupled seven transmembrane domain rhodopsin-type receptor. Subsequently, homology screening using mouse cDNA libraries identified the structures of all the remaining prostanoid receptors, which have now been well characterised [15,25]. The predominant prostanoids present

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in the reproductive tract are the E and F series of prostaglandins, which exert their biological functions via EP and FP receptors, respectively. 3.1. EP receptors PGE2 elicits its autocrine/paracrine effects on target cells following interaction with four subtypes of PGE2 transmembrane G protein-coupled receptors (GPCRs) [26], which have been pharmacologically divided into EP1, EP2, EP3 and EP4. These receptors utilize alternate and in some cases opposing intracellular pathways [27] (Fig. 1). Expression of the EP1 receptor is found in the kidney, lung [28] and muscularis mucosa of the stomach [29]. PGE2 interaction with the EP1 receptor mobilises intracellular calcium and inositol trisphosphates (IP3 ) via Gq (Fig. 1). EP2 expression is most abundant in the uterus and placenta, however mRNA is detected in a variety of other tissues [21]. The EP2 receptor gene contains a number of response elements including NF-IL6 and NF␬B response elements as well as a progesterone response element and is thus regulated by both pro-inflammatory mediators as well as hormonal stimuli [21,30]. Activation of the EP2 and EP4 receptors results in an increase in cAMP accumulation via G␣s [15,31]. Of all the EP receptors, the EP3 and EP4 isoforms are the most widely distributed throughout the body, with expression determined in almost all mouse tissues examined [32,33]. The human EP3 receptor gene contains E-boxes, AP-2 sites, an interferon-responsive element, a c-binding motif, and a GC box [34]. Several splice variants exist for EP3 receptor and are coupled to different signalling pathways resulting in either a positive or negative cAMP response to PGE2 administration or increase in intracellular calcium mobilisation and accumulation of IP3 depending on the splice variant and cell type [15,31] (Fig. 1). The human EP4 receptor gene contains several response elements for pro-inflammatory stimuli by agents such as NF-IL6, NF␬B, H-apf-1 as well as containing an AP-1 and AP-2 site and a Y box [35]. It has generally been assumed that signal transduction cascades are initiated following ligand–receptor binding at the plasma membrane level. Recently however a nuclear location for EP receptors has been ascertained, suggesting that PGE2 may directly regulate transcription of target genes following release of calcium from nuclear calcium pools or by activation of calcium channels [36,37]. In addition, it is feasible to propose that PGE2 may influence transcription of target genes by interacting with nuclear peroxisome proliferator-activated receptors (PPARs). Although no role for PGE2 and PPARs in regulation of gene transcription has been described, prostanoids such as PGI2 and PGJ2 have been reported as ligands for PPARs, which alter transcription of target genes [38] and may be involved in implantation [39]. This diversity of receptors with opposing functions may confer a homeostatic control of an autocoid, which is released in high concentrations close to its site of synthesis [27]. 3.2. FP receptors PGF2␣ exerts its action via FP receptors. Although splice variants for the FP receptor exist, there are no known subtypes for the FP receptor. PGF2␣ is a potent inducer of luteolysis in animals with estrous cycles and most studies have focused on FP receptor expression and regulation in the ovary. PGF2␣ is also a major metabolite of COX enzyme biosynthesis in

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human endometrium, and as well as being present in menstrual fluid, is released by human endometrial explants in culture [40]. FP receptor expression and the role of PGF2␣ within the human endometrium have not been fully examined. However, recent data demonstrate elevated FP receptor expression during the proliferative phase of the menstrual cycle, suggesting a potential role for PGF2␣ in proliferation of the endometrium [41]. Activation of FP receptors by PGF2␣ results in receptor tyrosine phosphorylation and subsequent increase in intracellular calcium flux, PLC activation and DNA synthesis and cellular proliferation [42].

4. COX enzymes and prostaglandins in reproductive physiology Prostaglandins have been recognised for many years as potent mediators of female reproductive tract physiology, including ovulation, implantation, cervical ripening, cervical dilatation, menstruation, luteolysis, myometrial contractility, placental vascular tone and parturition [43–45]. In the human and primate ovary, PGE2 and PGF2␣ act synergistically and antagonistically to modulate ovarian function. PGE2 acts on the hypothalamus to induce the secretion of gonadotropins such as luteinizing hormone-releasing hormone [46], which ensures expansion of the follicle and ovulation. The main luteolytic hormone is PGF2␣ , which triggers regression of the corpus luteum [47]. Prostanoid ligand–receptor binding results in triggering of the PLC/IP3 /Ca2+ -protein kinase C (PKC) pathway and activation of the Raf/MEK1/MAPK signalling cascade [48] and induction of message for c-fos and c-jun [49]. This ultimately allows progesterone synthesis and the estrous cycle to resume under non pregnant conditions. The overall effect of prostanoid biosynthesis and release on ovarian function is a finely balanced interplay between the respective prostanoids, and/or prostanoid receptors and intracellular signalling molecules present during a specific part of the reproductive cycle [50]. In the endometrium, PGE2 and PGF2␣ are the principal prostanoids produced, however PGD2 , TXA2 and PGI2 are also present in lesser amounts [51–53]. In the human endometrium, COX-2 expression and PGE2 /PGF2␣ synthesis have been associated with proliferation [41,54]. COX enzyme expression and PGE2 synthesis are maximal during the proliferative phase of the menstrual cycle and localised in epithelial and perivascular cells [53,55–57]. This is coincident with an elevated EP4/FP receptor expression and signalling [41,54]. This suggests an autocrine/paracrine regulation of function in the endometrium via an epithelial–epithelial or epithelial–perivascular cell interaction by prostanoids produced by the endometrium. A role for prostanoids in vascular function of the endometrium has also been established. PGE2 and PGI2 cause vasodilatation whilst PGF2␣ and TXA2 cause vasoconstriction. Prostanoids produced locally in endometrial epithelial, vascular and stromal cells interact also with receptors on smooth muscle cells to control myometrial contractility in an autocrine/paracrine manner. In in vitro model systems, PGE2 and PGI2 have an inhibitory effect on myometrial contractility. By contrast PGF2␣ induces contractility in vitro as well as in vivo [51–53]. Prostanoids also play an important role in cervical function, setting in motion a cascade of events leading to evacuation of the uterine contents, including foetuses and menses, and

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cervical ripening. At least three prostanoids are known to be involved in cervical ripening, namely PGE2 , PGF2␣ and PGI2 . These prostanoids are produced locally in uterine and cervical tissues and act in an autocrine/paracrine manner during cervical ripening to facilitate cervical softening, affacement and dilatation during the onset of labour [58–60]. 4.1. Studies in knockout mouse models The roles played by COX enzymes in reproductive biology, have been demonstrated using COX-deficient mice. Studies in COX-1-deficient mice have shown that the gestation period is prolonged and parturition is reduced coincident with a reduction in the number of viable offspring. Interestingly, conception and foetal development are unaltered suggesting that prostanoids produced by COX-1 are not critical for ovulation, fertilisation or implantation, but are essential for bringing on normal labour at term. This is confirmed by observations between wild-type mice giving natural birth and COX-1 deficient females having their pups delivered by caesarean section, where there are no noticeable differences in the number or size of the pups delivered [61,62]. By contrast, ablation of the COX-2 gene in mice results in multiple reproductive failures, including ovulation, fertilisation, implantation and decidualization confirming that prostaglandins produced by COX-2 play a crucial role in these processes [63–66]. Prior to ovulation, pituitary gonadotropins trigger the expression of COX-2 and synthesis of PGE2 to promote follicle expansion and ovulation. In COX-2 deficient mice, absence of PGE2 in preovulatory follicles disrupts follicle expansion and results in anovulation. Under these conditions administration of exogenous PGE2 has been shown to rescue ovulation [67]. Thus, although both COX isoforms essentially catalyze the same reaction, in the reproductive tract there are clear differences in the prostanoid profile and functions of the two COX enzymes. The specific roles played by prostanoids, especially PGE2 and PGF2␣ in modulating reproductive physiology, have been demonstrated using mice deficient for each of the prostanoid receptors [15]. The most startling observations have been derived from the EP2 and FP receptor knockouts. Recent studies have shown that the EP2 and FP receptors are indispensable in female reproduction [25,68–70]. Loss of EP2 receptor function in murine model systems by gene ablation, results in impaired ovulation and dramatic reduction in litter size [68–70], whereas ablation of the FP receptor in mice results in loss of parturition [25]. This is similar to the observation in COX-2 deficient and COX-1 deficient mice, respectively, suggesting that receptor expression and COX enzyme expression may be co-regulated.

5. COX enzymes and prostaglandins in reproductive pathology The initial observations in the early 1980s that prostaglandin production was elevated in human breast cancers was paramount to the idea that cyclooxygenase enzymes played a potential role in the development of tumorigenesis [71]. This hypothesis was based on the findings that prostaglandin production in human breast carcinomas correlated with neoplastic cell density and active tumour invasion. Further epidemiological studies revealed that long-term continual administration of the NSAID aspirin reduced the risk of colorectal disease by 40–50%. This demonstrated a

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negative correlation between NSAID use and development of colorectal cancer [72]. Treatment of patients suffering from familial adenomatous polyposis (FAP), an autosomal dominant disorder characterised by the formation of hundreds of colorectal adenomas and eventual colorectal cancer, with NSAIDs showed a marked reduction in the amount of colorectal polyps developed [72,73]. The mechanism by which NSAIDs reduced the formation of polyps was unknown at the time, however, it was postulated that NSAIDs mediated the anti-tumourigenic effect by inhibiting eicosanoid biosynthesis. It was later discovered that COX-2 was up-regulated from 2- to 50-fold in 85–90% of colorectal adenomas and adenocarcinomas and an association between COX-2 and colon cancer was established [7,8,11,72]. COX-2 was thus considered a likely target for the treatment and management of colorectal disease and ensuing studies in animal models of colorectal carcinogenesis further supported this hypothesis by demonstrating a decrease in the size and number of colorectal polyps upon administration of selective COX-2 inhibitors [74]. Subsequently, several investigators discovered up-regulated expression of COX-2 in human gastric ulcers [75] and numerous epithelial cancers including pulmonary, colonic, breast, head and neck, oesophagus, pancreas, lung, prostate and bladder [8,11,76–85]. The up-regulation of COX-2 in epithelial tumours suggests a common pathway for a role for COX-2 in epithelial cell neoplasia. General dogma acknowledges the role of COX-1 as regulatory and one of a ‘housekeeping’ nature. However, a role for COX-1 in tumorigenesis has also recently been established following the observation that endothelial cells transfected with COX-1 become tumourigenic [86]. In vivo studies have demonstrated that genetic disruption of COX-1 in mice results in a decrease in the number of intestinal polyps coincident with decreased PGE2 levels [87]. Similarly selective inhibition of COX-1 in Apc716 gene knockout mice (a murine model of FAP) results in a significant reduction in the number of intestinal polyps produced in response to chemical carcinogens [88], suggesting that both COX enzymes can contribute to tumorigenesis. 5.1. Reproductive tract carcinomas Tumours of the endometrium and ovary are the most common gynaecological malignancies in the western world, imposing quite a burden on female reproductive health and medical resources. The aetiology of carcinoma of the uterus and ovary is unknown and generally associated with post-menopausal women [89–91]. By contrast, cervical cancer is a less common malignancy in the western world and is a disease particularly common in less developed countries, including South and Central America, Southeast Asia and Sub-Saharan Africa, where 80% of the world’s cervical cancers occur [92]. Current evidence indicates that the main cause of cervical cancer is by infection of the uterine cervix with human papillomavirus (HPV) [93,94]. However, other sexually transmitted infections and venereally transmitted disease are also known to occur in patients with cervical carcinomas [95–98] and thought to play a role in the initiation or progression of the disease. Recent studies have indicated a correlation between up-regulated expression of COX enzymes and reproductive tract carcinoma. Elevated expression of COX-1 has been observed in ovarian adenocarcinomas and cervical carcinomas [99,100]. Expression of COX-1 is unaltered in endometrial carcinomas [101]. Similarly, COX-2 expression is up-regulated

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in endometrial [101–103] and cervical carcinomas [104–106]. There is conflicting evidence regarding the expression of COX-2 in ovarian carcinomas. Two studies have reported little COX-2 expression in ovarian adenocarcinomas [99,107]. By contrast, other studies have demonstrated elevated expression of COX-2 [103,108,109] and inducible nitric oxide synthase in ovarian adenocarcinomas, borderline and benign ovarian tumours (cystadenoma) [108,109], mature cystic teratomas with squamous cell carcinoma [110] and tumour-associated macrophages [108]. Furthermore, expression of peroxisome proliferator-activated receptor delta [101] and expression of PGES, EP receptors (EP2 and EP4) and synthesis and signalling of PGE2 are elevated in carcinomas of the endometrium [102] and cervix [104–106]. This suggests an autocrine/paracrine/intracrine regulation of neoplastic cell function by PGE2 in response to coupling with either transmembrane EP receptors or nuclear PPARs. A role for PGE2 in tumorigenesis has been established recently by the observation that administration of selective EP1 antagonists to carcinogen-treated mice, or EP1 gene ablation in mice, reduces the formation of aberrant crypt foci associated with chemical carcinogens [111,112]. Similarly, PGE2 interaction with the EP4 receptor enhances proliferation and motility of colon carcinoma cells, following activation of the phosphatidyl inositol-3-kinase pathway [113] and ablation of the EP2 receptor in Apc716 mice (a mouse model for human FAP) causes decreases in the size and number of intestinal polyps [114]. PGE2 may act similarly upon coupling to the up-regulated EP receptors in reproductive tract carcinomas and raises the possibility that PGE2 interaction with target receptors may potentiate tumorigenesis by activating various signal transduction cascades and consequently transcription of target genes involved in enhancing or maintaining the neoplastic state. 5.2. Menorrhagia Menorrhagia is a clinical definition for menstrual disorders with a pathology of excessive menstrual blood loss (defined as greater than 80 ml of blood lost per menstrual cycle) [115–117]. Menorrhagia affects 10–30% of women of reproductive age and up to 50% of perimenopausal women. Although the aetiology of aberrant menstruation, including menorrhagia is poorly understood, several studies have associated heavy menstrual loss with abnormalities in prostanoid production and secretion from the uterus [118–120]. Of all the prostaglandins measured in uteri of patients diagnosed with having menorrhagia, the vasodilatatory prostaglandins, 6-keto-PGF1␣ , and PGE2 appear to be the most abundant [121]. Recent studies have confirmed a role for prostaglandins in menorrhagia. PGE2 synthesis and binding sites are greater in women diagnosed with menorrhagia compared with normal women and correlates directly with menstrual blood loss [53,119,122,123]. A role for PGI2 in excessive menstrual bleeding has also been established. In women with abnormal menstrual blood loss, an elevated synthesis of PGI2 has been observed [120,124]. Thus, the degree or duration of menstrual bleeding in women diagnosed with menorrhagia may be augmented following elevation of the vasodilatatory prostanoids. Recent studies have shown that the menorrhagic endometrium produces higher amounts of vasodilatatory nitric oxide than normal endometrium. This may further enhance menstrual bleeding and vascular dysfunction [125], as well as promote a positive feedback loop

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Fig. 2. Autocrine/paracrine regulation of COX-2 expression in epithelial and/or endothelial cells. A positive feedback loop is formed by PGs to promote COX enzyme expression, initiation of intracellular signalling and transcription of target genes involved in angiogenesis, inhibition of apoptosis, mitogenesis and proliferation and tissue invasion and metastasis.

to up-regulate the COX/PGE biosynthetic pathway and induce further synthesis of PGE2 as well as vascular endothelial growth factors (VEGF), inducible nitric oxide synthase and synthesis of nitric oxide [126,127] (Fig. 2). Thus, in the menorrhagic endometrium, vascular tone and bleeding may be controlled in an autocrine/paracrine manner by COX enzymes and their products. The elevated expression of prostanoids present in the menorrhagic endometrium has lead to the administration of NSAIDs as a means of therapy [128] as COX inhibitors such as ibuprofen have been shown to reduce menstrual blood loss [124]. More recently, a dual mode of action has been demonstrated for fenamates such as sodium meclofenamate and mefenamic acid. As well as reducing PG synthesis, they also inhibit binding of PGE to its receptor [129].

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5.3. Dysmenorrhoea and painful periods Primary dysmenorrhoea is a frequent occurrence in ovulating women and often preceded by premenstrual tension and intense painful menstrual cramps occurring in the absence of a pelvic abnormality [130,131]. Secondary dysmenorrhoea is clearly differentiated from primary dysmenorrhoea, because it is a symptom of uterine abnormalities or adnexal diseases such as endometriosis, pelvic inflammatory disease, or submucous leiomyomas [130,131]. The pathogenesis is more clarified now but nevertheless not yet completely investigated. Primary dysmenorrhoea is a cyclic repetition and everlasting painful expectation associated with spastic uterine hypercontractility. During contractions endometrial blood flow decreases and there is now good correlation between minimal blood flow and maximal pain, suggesting that ischaemia due to hypercontractility is the primary cause [130,131]. There is evidence that under the dominating role of sexual hormones paracrine sequelae are occurring, which result in a local increase of prostaglandins [132]. Many investigators have confirmed the findings that PGE2 and PGF2␣ levels are higher in menstrual fluid of women with dysmenorrhoea than women with painless periods [130,133]. Furthermore in vitro studies have demonstrated that endometrial explants from dysmenorrhoeic women produce more PGF2␣ in response to arachidonic acid compared with endometrium from pain-free women [134]. This confirms a role for COX enzymes and prostaglandins in this pathology. COX enzyme inhibitors such as mefenamic acid, ibuprofen and naproxen have proved effective in the management of this disorder and only need to be administered during menstruation, or prior to the onset of menses [130]. More recently selective COX-2 inhibitors have proven to be even more efficacious in treatment of dysmenorrhoea and the pain associated with it [135], making it a potential choice for treatment of women with primary dysmenorrhoea. 5.4. Endometriosis Endometriosis is a chronic disease of unknown aetiology manifested by pelvic pain, infertility, abnormal uterine bleeding and dyspareunia. Endometriosis is defined as the presence of endometrial glands and stroma within the pelvic peritoneum and other extra-uterine sites. In patients with endometriosis, surgical findings range from microscopic disease to frozen pelvis with extensive pelvic adhesions, complete cul-de-sac obliteration and large ovarian endometriomas [136]. It is considered to be a polygenetically inherited disease affecting 2–10% of women of reproductive age [137,138]. Sampson’s theory of transplantation of endometrial tissue on the pelvic peritoneum via retrograde menstruation is one of the most widely recognised explanations for the development of pelvic endometriosis [139]. Retrograde menstruation is observed in nearly all cycling women, and endometriosis is postulated to develop as a result of a coexistence of a defect in clearance of the menstrual efflux from the pelvic peritoneal surfaces possibly involving immune function [140]. Endometriosis is an oestrogen-dependent disorder and immunohistochemical studies have localised estrogen receptor alpha and beta in both epithelial and stromal cells of endometriotic tissues and peritoneum [141] coincident with elevated expression of aromatase [142]. Other factors including aberrant expression of cytokines, matrix metalloproteinases

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(MMPs) and reduction in progesterone levels are contributing factors important in the pathophysiology of the disease [143]. Aromatase activity is absent in normal endometrium. By contrast, aromatase expression is elevated in patients with endometriosis and gives rise to local biosynthesis of oestrogen. Both aromatase expression and activity are stimulated by PGE2 . This results in local production of oestrogen, which promotes PGE2 synthesis, establishing a positive feedback loop to induce transcription of COX-2 and synthesis of PGE2 (Fig. 2). This favours accumulation of oestrogen and synthesis of prostaglandins which potentiate inflammation [142,144,145]. This positive feedback cycle is partially mediated by cAMP following ligand binding to the cAMP-linked EP receptors and induction of COX-2 [143] (Fig. 2). Although a role for COX enzyme and EP receptor function in this disorder has yet to be fully clarified, immunohistochemical studies have shown that COX-2 expression is up-regulated in endometriotic endometrium [146]. Moreover, elevated prostaglandin levels have been reported in the peritoneal fluid of infertile women with endometriosis, suggesting that ectopic endometrium directly synthesises and releases prostanoids into the peritoneal fluid which could have an adverse impact on tubal function and spermatozoa, oocyte and embryo transport, thereby reducing the likelihood of conception [147]. Prostanoids in peritoneal fluid may also act in a paracrine manner on surrounding tissues to sustain the state of endometriosis or facilitate further reproductive tract dysfunction. A large number of agents have been used as potential therapy for suppression of endometriosis, these include methyl testosterone, danazol, gonadotrophin-releasing hormone agonists/antagonists, tamoxifen and combined estrogen–progesterone oral contraceptives [147]. Many of these agents suppress endometriosis by estrogen deprivation. However, endometriosis returns in 75% of these women [148], probably by the production and release of estrogens in adipose tissue, skin and endometriotic implant [142]. Since aromatase and the COX/PGE biosynthetic pathway are up-regulated in endometriosis, NSAIDs or prostaglandin receptor antagonists in combination with aromatase inhibitors, such as anastrozole, may prove more beneficial in managing the disease. Clinical studies have yet to prove the efficacy of such treatment regimens, however preliminary evidence suggests that aromatase inhibitors may be useful in treatment of endometriosis [142].

6. Potential cellular mechanisms for COX enzymes and prostaglandins in regulation of reproductive tract biology Although the exact role for COX enzymes and their respective products in reproductive tract pathology is still currently unclear, studies using in vitro model systems have shown that enhanced synthesis of PGE2 resulting from up-regulated COX enzyme expression plays a role in promoting angiogenesis [149], inhibiting apoptosis [150] and increasing the proliferation and metastatic potential of epithelial cells [151]. In this section, we will outline the potential cellular mechanisms whereby COX enzymes and prostaglandins mediate their role in reproductive biology and pathophysiology. It is important to note that the available literature on cellular mechanisms of COX enzymes and prostanoid action are focused on inflammatory disease and tumorigenesis. However, such mechanisms can potentially function in other pathologies that are associated with up-regulation in the COX/prostanoid signalling pathway.

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6.1. Angiogenesis In the reproductive tract, vascular remodelling and angiogenesis is crucial for maintaining follicle expansion and ovulation, and establishing normal uterine function following menstruation and labour. Enhanced angiogenesis, in response to a nutrient-demanding tumour, is also one of the hallmarks of a pathological state. Several studies have now confirmed a role for COX enzymes and their bioactive products in angiogenesis. These studies using in vitro model systems have demonstrated that COX enzymes, EP receptors and PGE2 may control vascular remodelling by promoting angiogenesis. In an in vitro model system, overexpression of COX-1 in HeLa cells promoted the expression of COX-2, PGES and the cAMP-linked EP receptors and signalling. These findings were associated also with up-regulation of several pro-angiogenic factors regulated by COX-1 [100]. Similar in vitro model systems overexpressing COX-2 and synthesis of PGE2 in colon epithelial cells have demonstrated enhanced expression of angiogenic factors that act on endothelial cells resulting in enhanced cell migration and microvascular tube formation [149]. COX-2 and PGE2 produced by endothelial cells may also directly regulate the process of angiogenesis by acting on endothelial cells [152]. The arrangement of rat aortic endothelial cells into tubular structures is reduced following treatment with selective COX-2 inhibitors, which is partially reversed by co-treatment with PGE2 [152]. Moreover recent studies have shown that angiogenesis may be controlled by PGE2 acting via specific EP receptors and their signalling pathways [114]. In murine models of familial adenomatous polyposis, ablation of the EP2 receptor is associated with a decrease in the size of intestinal polyps coincident with a decrease in COX-2 and angiogenic factor expression [114]. Conversely, in this model system COX-2, EP2 and angiogenic factor expression correlate strongly with an increase in microvessel density in intestinal polyps [153]. Thus, elevated COX enzyme expression and subsequent biosynthesis of prostaglandins exert an autocrine/paracrine regulation of cellular function resulting in the release of angiogenic factors to promote vascular growth through an epithelial–endothelial and/or endothelial–endothelial cell interaction via specific transmembrane receptors and intracellular signal transduction pathways (Fig. 2). This is especially important under pathological conditions to sustain tumour growth. Under disease conditions, the elevated ligand–receptor interaction brought about by the elevation in prostanoid biosynthesis and prostanoid receptor expression, as a consequence of elevated COX enzyme expression in reproductive tract carcinomas [100,102,104], can support tumour vascular function by promoting the transcription of target genes involved in angiogenesis. This may in turn result in further regulation of the COX/PGE biosynthetic pathway via a positive feedback loop as depicted schematically in Fig. 2. 6.2. Inhibition of apoptosis Another cellular function for COX and prostanoids in reproductive biology and pathology may be control of cell death or apoptosis. Controlled cell death is an important event in the female reproductive tract to ensure uniform sloughing of the endometrium during menstruation. It is also an important event under pathological conditions such as cancer, to sustain tumour growth by rendering tumour cells unresponsive to normal cell cycle control. Under these conditions COX enzymes and prostaglandins may confer resistance to apoptosis

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by suppression of transcription of target genes (such as p53) that may be involved in cellular growth/transformation [154]. In vitro model systems, in which the COX-2 cDNA is overexpressed in epithelial cells, have demonstrated a decrease the apoptotic rate consequent with increased synthesis of prostaglandins. The apoptotic rate can be restored to normal by administration of the NSAID sulindac [150]. Similar results have been observed in vivo following administration of COX-2 inhibitors to rats with chemically induced colon cancers [155]. These results show not only an important correlation between COX enzymes, prostaglandins and programmed cell death, but also a mechanism whereby NSAIDs exert their function as cancer therapies. Further studies to elucidate the mechanism whereby COX enzymes control apoptosis have shown that overexpression of COX-2 leads to prolongation of the G1 phase of the cell cycle through effects on cyclin D, resulting in inhibition of apoptosis [150,156]. In reproductive tract carcinomas, similar mechanisms may regulate tumorigenesis as overexpression of COX-2 in cervical tumours correlates also with a reduction in apoptosis at the site of tumour invasion [105]. 6.3. Mitogenesis and proliferation Cells require mitogenic growth signals in order to proliferate under normal physiological conditions. Under pathological conditions, cells acquire growth signal autonomy and many cancer cells acquire the ability to synthesise mitogenic growth factors to which they are responsive, forming an autocrine positive feedback loop to enhance mitogenesis and proliferation. Examples of this are demonstrated in glioblastomas and sarcomas, where cancer tissue produces platelet-derived growth factor (PDGF) and tumour growth factor alpha (TGF␣) to enhance tumorigenesis in an autocrine manner [157]. In various model systems COX enzymes mediate a role in mitogenesis and cell proliferation in response to stimulation with mitogens, cytokines and tumour promoters. In in vitro model systems of rat intestinal epithelial cells and mouse colon carcinoma cells, selective inhibition of COX-2 results in a decrease in serum-induced cell proliferation [158]. Similar model systems have demonstrated that epidermal growth factor (EGF) stimulation of COX-2 expression enhances mitogenesis of colon cancer cells. Blockade of COX-2 up-regulation by epidermal growth factor receptor antagonists or selective inhibition of COX-2 causes a dose-dependant decrease in mitogenesis [159]. Further studies in COX-2 overexpressing colon cancer cell lines have demonstrated that proliferation is inhibited by administration of selective COX-2 inhibitors [160]. In the reproductive tract COX enzymes and PGE2 may act similarly to enhance proliferation of the endometrium during the menstrual cycle as well as promote endometrial pathologies such as endometriosis and reproductive tract cancer. 6.4. Tissue invasion and metastasis Tissue invasion and metastasis are the terms used to describe the proliferation and movement of primary cells from their site of origin to distant sites where new colonies are formed. Metastasis is the cause of 90% of cancer related death [161]. An essential feature of tumour formation is local invasion of surrounding tissues. This is accomplished via the degradation of the extracellular matrix by matrix metalloproteinases, a family of proteolytic enzymes produced by both stromal and tumour cells. An increase

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in invasive and metastatic ability is mediated via up-regulation of protease genes, resulting in an increase in protease and matrix-degrading proteases and a decrease in cell surface interactions between adjacent cells, allowing increased metastasis and invasion [157,162]. Under pathological conditions, COX enzymes and prostaglandins promote tumorigenesis by enhancing the metastatic potential and promoting invasion of surrounding tissues. In vitro model systems of colon cancer cells overexpressing COX-2 have demonstrated that COX-2 promotes invasiveness and elevates MMP expression [151]. MMP and COX-2 expression are up-regulated in invasive carcinomas, further supporting the idea that COX enzymes promote tumorigenesis by facilitating matrix and basement membrane degradation [163–167]. In order for tumour cells to become mobile to invade distant parts of the body where space and nutrients are not limiting, changes in cell surface adhesion molecules (CAMs), members of the immunoglobulin and calcium-dependent cadherin families are needed. The most widely observed alteration in CAMs is that involving E-cadherin, ubiquitously expressed in epithelial cells [168]. Anti-growth signals are triggered when adjacent cells are coupled via E-cadherin. E-cadherin function is lost in many epithelial cancers—either by mutational inactivation or transcriptional repression or down-regulation [169]. More than 80% of poorly differentiated tumours lack expression of E-cadherin. Expression of E-cadherin is down regulated in a number of solid tumours and is closely and inversely related to enhanced invasion of neoplastically transformed cells [170,171]. Model systems overexpressing E-cadherin have demonstrated a reduction in cell invasiveness and metastasis, further supporting the idea that E-cadherin acts as a suppressor of invasion and metastasis in epithelial cancers and that down-regulation of E-cadherin expression is associated with local invasion of tumour cells [157,169,172]. Further studies have demonstrated a link between COX enzymes and loss of cell surface adhesion molecules. In an in vitro model system, rat intestinal epithelial cells overexpressing COX-2 showed down-regulation of E-cadherin compared with wild-type and COX-2 antisense cells suggesting that COX-2 up-regulation promotes cell invasion and metastasis by down regulating cell adhesion molecules [150]. Similar cellular mechanisms may be at play in solid reproductive tract tumours and endometriosis where COX enzyme expression is elevated.

7. Conclusion In this review, we highlighted several aspects of the COX/PGE biosynthetic pathway and its function in physiology and pathology of the reproductive tract and have showed that in contrast to classical dogma, COX-1 may function not merely as a housekeeping gene, but may also potentiate dysfunction by up-regulating cellular machinery involved in signal transduction and gene transcription. Furthermore, since both COX isoforms are involved in certain reproductive tract pathologies, the use of selective COX inhibitors as proposed for the treatment of colorectal disease may be only of partial therapeutic benefit. In light of the evidence for a role of the EP receptors in regulating tumour growth, the use of selective receptor antagonists and modulators of signal transduction may thus be of more benefit as therapeutic regimens for treatment of reproductive tract dysfunction. Future studies to elucidate the divergent prostanoid signal transduction pathways culminating in

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the transcription of target genes associated with aberrant vascular growth, cell adhesion, cell proliferation and survival may lead to improved female reproductive health.

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