Prostaglandin Receptor Signalling and Function in Human Endometrial Pathology

Review TRENDS in Endocrinology and Metabolism Vol.15 No.8 October 2004

Prostaglandin receptor signalling and function in human endometrial pathology

H.N. Jabbour and K.J. Sales

MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The University of Edinburgh Academic Centre, 49 Little France Crescent, Edinburgh, EH16 4SB, UK

Prostaglandins are bioactive lipids that exert an auto- prostaglandin, prostaglandin H2 (PGH2), by COX crine or paracrine function by binding to specific enzymes. This intermediate serves as the substrate for G-protein-coupled receptors (GPCRs) to activate intra- terminal enzymes in the prostanoid biosynthetic pathway. cellular signalling and gene transcription. Prostaglan- These enzymes are named according to the prostanoid dins are key regulators of reproductive processes, that they produce, such that PGD2 is synthesized by including ovulation, implantation and menstruation. prostaglandin D synthase (PGDS), PGF2a by PGFS, PGI2 Prostaglandins have been ascertained to have a role in (also known as prostacyclin) by PGIS, thromboxane various pathological changes of the reproductive tract (TXA2) by thromboxane synthase (TXS), and PGE2 by including menorrhagia, dysmenorrhea, endometriosis PGES [3] (Figure 1). and cancer. Although the mechanism by which prosta- At least four isoforms of PGES have been described: two glandins modulate these changes remains unclear, membrane-bound isoforms, mPGES-1 and mPGES-2; a much evidence suggests that prostaglandins and their cytosolic isoform, cPGES; and a glutathione S-transferase receptors and downstream signalling pathways are isoform, GST-m [4]. cPGES preferentially converts COX-1- involved in angiogenesis and in alterations in cell derived PGH2 to PGE2 and is associated with immediate adhesion, morphology, motility, invasion and metastases. prostaglandin biosynthesis. The inducible membrane- The potential role of prostaglandin receptors in patho- associated form, mPGES-1, is preferentially associated logical changes of the endometrium has significance for with COX-2 under conditions of limited AA supply (but the future development of therapeutic interventions. can couple to COX-1 under conditions where AA is available) and is associated with delayed biosynthesis Prostaglandins, thromboxanes and leukotrienes, collec- of PGE2 [5]. mPGES-2 is structurally distinct from tively referred to as ‘eicosanoids’, are the cyclooxygenase mPGES-1 and seems to be expressed in tissues where (COX) and lipooxygenase metabolites of arachidonic acid biosynthesis of mPGES-1 is low. mPGES-2 can couple (AA). Over the past decade, much effort has gone into with both COX-1 and COX-2. The GST-m isoform of elucidating the roles of the COX enzymes in health and PGES has been described recently; however, its speci- disease, and into creating selective COX enzyme inhibitors ficity for coupling with either COX isoform remains to as a means of therapy. Only recently has the focus turned be determined [4]. towards elucidating the function of specific prostanoid COX-1 has been long considered to be a constitutively receptors and their signalling pathways in pathology. expressed enzyme involved in normal physiological func- In this short review, we outline the role of prosta- tions, but more recently it has been shown to be glandins, their receptors and signalling pathways in upregulated in various carcinomas [6–9] and to have a pathological changes of the endometrium and explore central role in tumorigenesis [10–12].COX-2isthe the potential phenotypic effects that they might mediate product of an immediate early gene that is rapidly induced in target cells. by growth factors, oncogenes, carcinogens and tumour- promoting phorbol esters, and its involvement in rheu- matic disease, inflammation and tumorigenesis has been Cyclooxygenase enzymes demonstrated [1]. In vitro model systems of cell lines So far, three isoforms of the COX enzyme (COX-1, COX-2 overexpressing COX-2 have shown that the upregulation and COX-3) have been reported to catalyse the committed of this enzyme, coupled with the consequent increase in step in the biosynthesis of prostaglandin and thrombox- PGE2 biosynthesis, promotes angiogenesis [13], inhibits ane (collectively termed ‘prostanoids’) [1,2]. After the apoptosis [14] and increases the proliferation and meta- activation of phospholipase A2 (PLA2), AA is released static potential of epithelial cells [15]. A role for a func- from plasma membrane phospholipids or dietary fats, and is tional COX-3 isoform in human physiology and cyclized, oxygenated and reduced to the intermediary pathophysiology remains to be established.

Corresponding author: H.N. Jabbour ([email protected]). The importance of COX-1 and COX-2 in reproduction has been observed from studies in knockout mice. Mice deﬁcient www.sciencedirect.com 1043-2760/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2004.08.006 Review TRENDS in Endocrinology and Metabolism Vol.15 No.8 October 2004 399

PGE2 PGI2 PGF2α PGD2 TXA2 EP1 EP2 EP3 EP4 IPFP DP TP

PGT PLA2 α α α α α α α α q s i/s/q s s/q q s i/s/q

↑↓ ↑ cAMP cAMP ↑ 2+ ↑↓ cAMP IP3/Ca ↑ 2+ IP3/Ca ↑ cAMP PGE2 AA PGI2 PGF ↑ 2+ 2α ↑ cAMP IP3/Ca PGD2 TXA2 ↑

↑ 2+ ↑ COX IP3/Ca cAMP PGES ↑ 2+ IP3/Ca PGFS PGDS PGIS TXS

Figure 1. The cyclooxygenase (COX) and prostanoid biosynthetic and signalling pathways. Arachidonic acid (AA) is released from plasma membrane phospholipids by phospholipase A2 (PLA2) and used by COX enzymes and speciﬁc synthase enzymes, such as prostaglandin D synthase (PGDS), PGES, PGFS, PGIS thromboxane synthase

(TXS), to form prostaglandin D2 (PGD2), PGE2, PGF2a, PGI2 and thromboxane A2 (TXA2), respectively. These molecules are actively transported out of the cell by means of a prostaglandin transporter (PGT), where they exert an autocrine or paracrine effect by coupling to their respective heptahelical transmembrane receptors, DP, EP1–EP4, FP, IP and TP, to activate second messengers, such as cyclic AMP (cAMP) and inositol (1,4,5)-trisphosphate (IP3), and intracellular signalling cascades.

in COX-1 show longer gestation periods and protracted respectively,the DP,EP,FP,IP and TP prostanoid receptors. parturition and deliver fewer live young as compared with There are four subtypes of EP receptor (EP1–EP4), which wild-type mice [16,17]. This effect is predominantly caused are encoded by four separate genes [3] (Figure 1). In by abolition of the luteolytic role of PGF2a in parturition. addition, there are several splice variants of the EP3, FP Ablation of the gene encoding COX-2 in mice results in and TP receptors, which differ only in their carboxy- multiple reproductive failures, including in ovulation, terminal tails. In general, prostanoid receptor isoforms fertilization, implantation and decidualization, confirming show similar ligand binding but differ in their signalling that the prostaglandins produced by COX-2 have a crucial pathways, their sensitivity to agonist-induced desensitiza- role in these processes [18,19]. tion, and their tendency towards constitutive activity. Phylogenetic analyses indicate that receptors shar- Prostaglandin receptors ing a common signal pathway have higher sequence After biosynthesis, prostanoids are rapidly transported homology than do receptors sharing a common prostan- out of the cell by means of a prostaglandin transporter oid as their preferential ligand. Among the different (PGT), a protein belonging to a superfamily of 12-trans- receptors, the IP, DP, EP2 and EP4 receptors increase membrane organic anion-transporting polypeptides [20,21]. the accumulation of intracellular cyclic (cAMP) via Gas PGT is responsible for the efflux of newly synthesized and have been termed ‘relaxant’ receptors because they prostaglandins [20]. Expression of PGT has not been induce smooth muscle relaxation. The TP, FP and EP1 2C verified in the human endometrium, but PGT has been receptors induce Ca mobilization via Gaq and constitute shown to be involved in the transport of various a ‘contractile’ receptor group because they cause smooth prostaglandins in the bovine endometrium [22]. muscle contraction. The remaining receptor, EP3, is Once released outside the cell, prostaglandins act in an generally associated with a decline in cAMP. This autocrine or paracrine manner on their cognate hepta- ‘inhibitory’ receptor usually stimulates smooth muscle helical transmembrane GPCRs in the vicinity of their sites contraction; depending on the splice variant and cell type, however, the EP3 receptor can also increase intracellular of production. PGD2, PGE2, PGF2a, PGI2 and TXA2 exert their biological function through interactions with, cAMP and mobilize Ca2C [3]. www.sciencedirect.com 400 Review TRENDS in Endocrinology and Metabolism Vol.15 No.8 October 2004

Prostaglandin receptor cross-communication heparin-binding EGF (HB–EGF) from its latent mem- Recent studies have shown that prostanoid receptor brane-spanning precursor in the plasma membrane. Once signalling (via EP2 and FP) to downstream signalling cleaved, the HB–EGF ligand can associate with and pathways involves productive cross-communication with activate the EGFR, and thereby induce downstream the epidermal growth factor receptor (EGFR) [23,24]. signalling events such as phosphorylation of the MAPK These data are supported by several studies providing extracellular-signal-regulated kinases 1 and 2 (ERK1/2). evidence that prostanoid GPCRs activate receptor tyro- In addition, several studies have shown that activation of sine kinases (RTKs) [23–28]. This cross-communication the c-Src family of non-receptor tyrosine kinases is results in increased autophosphorylation and dimeriza- involved in GPCR-mediated transactivation of the EGFR tion of RTKs such as the EGFR and platelet-derived [29,30,32]. The latter observation is supported by our growth factor receptor, culminating in the activation of recent findings in endometrial epithelial cells, in which mitogen-activated protein kinase (MAPK) or phospha- PGE2 activation of the EP2 receptor increases ERK1/2 tidylinositol 3-kinase (PI3K) signalling [23–28] (Figure 2). signalling via c-Src-mediated transactivation of the The diversity of RTK activation by prostanoid receptors, EGFR [24] (Figure 2). the exact intracellular mechanisms of the activation, and the physiological or pathological significance of this cross- Prostaglandin synthesis and receptor expression in communication are not, however, fully elucidated. endometrial pathology Several mechanisms have been proposed for the Over the past decade, many epidemiological, pharmaco- transactivation of EGFR by GPCRs [29–31].Oneof logical and laboratory studies using gene disruption and these mechanisms involves activation of transmembrane overexpression systems have provided conclusive evi- matrix metalloproteinases and extracellular release of dence in support of a role for COX enzymes and prostanoids in pathophysiology [11]. Similar observations have been made in recent years implicating COX enzymes Seminal plasma PG and prostaglandins in benign and neoplastic pathologies PG HBÐEGF of the endometrium including menorrhagia (heavy men- RTK(EGFR) HBÐEGF strual blood loss), endometriosis, dysmenorrhea (painful MMPs periods) and cancer [33]. Collectively, these disorders α G i/s/q -p place a heavy burden on health service resources and are cSrc -p major contributors to morbidity in reproductive health. ↑↓cAMP PKA The potential role of COX enzymes, their prostanoids PGT ↑IP3 /Ca2+ PKC and their receptors in benign uterine pathologies such as COX menorrhagia, endometriosis and dysmenorrhea is well MAPK recognized. Synthesis of PGE and the number of PI3K/Akt 2 PLA2 AA PGE-binding sites are greater in the uterine tissues of women with menorrhagia than in the tissues of normal ATG women and correlate directly with menstrual blood loss. Target gene Levels of PGI2 and nitric oxide are also increased in transcription menstrual blood collected from women presenting with excessive menstrual bleeding. This suggests that the degree or duration of menstrual bleeding in women diagnosed with menorrhagia might be augmented after an increase in vasodilatory factors [33]. The increased biosynthesis of prostanoids present in the endometrium of Adhesion women with menorrhagia has led to the administration of Vascular function Migration COX enzyme inhibitors as a means of therapy. Inhibitors Vascular tone Cell proliferation Metastasis of COX have been shown to reduce menstrual blood loss in TRENDS in Endocrinology & Metabolism women with menorrhagia [33]. As with heavy menses, recent evidence suggests that Figure 2. Autocrine or paracrine regulation of prostanoid receptor signalling and the downstream effects on biological function. Prostaglandin (PG), either produced the pathology of endometriosis is associated with aberrant intracellularly via the cyclooxygenase (COX) enzyme biosynthetic pathway biosynthesis of COX enzymes and prostaglandins. (Figure 1) or present in seminal plasma, activates specific prostanoid receptors, Immunohistochemical studies have shown that COX-2 initiating production of the second messengers cyclic AMP (cAMP) and inositol

(1,4,5)-trisphosphate (IP3). Activation of these second messenger systems can then protein is upregulated in endometriotic endometrium [34]. initiate kinase signalling by the mitogen-activated protein kinase (MAPK) and Moreover, increases in prostaglandins have been reported phosphatidylinositol 3-kinase (PI3K) pathways and target gene transcription. Recent in the peritoneal fluid of infertile women with endo- data suggest that target gene transcription can occur via prostanoid-receptor- mediated transactivation of receptor tyrosine kinases (RTKs) such as the epidermal metriosis, suggesting that ectopic endometrium directly growth factor receptor (EGFR), either via the release of a heparin-bound EGF-like synthesizes and releases prostanoids into the peritoneal molecule (HB–EGF) to activate the RTK directly or by intracellular mechanisms fluid [35]. This release could have an adverse impact on involving non-receptor tyrosine kinases such as c-Src. In turn, the activation of target genes by prostanoid receptor signalling can promote angiogenesis (by modulating tubal function and on spermatozoa, oocyte and embryo vascular function and vascular tone), cellular proliferation, and cellular adhesion, transport, thereby reducing the likelihood of conception migration or metastasis. Abbreviations: AA, arachidonic acid; MMPs, matrix metalloproteinases; PLA2, phospholipase A2; PG, prostaglandin; PGT, prostaglandin [35]. Prostanoids in peritoneal fluid might also act in a transporter; PKA, protein kinase A; PKC, protein kinase C. paracrine manner on surrounding tissues to sustain the www.sciencedirect.com Review TRENDS in Endocrinology and Metabolism Vol.15 No.8 October 2004 401 state of endometriosis or to facilitate further dysfunction human endometrium, the E and F series of prostanoids of the reproductive tract. are the principal eicosanoids produced, and PGD2, TXA2 Little is known about the endocrine and local factors and PGI2 are present in lesser amounts. The effect of the that might result in primary dysmenorrhea (painful divergence of intracellular signalling via the respective periods in the absence of an anatomical cause); however, prostanoid receptors on target gene transcription and many researchers have suggested that dysmenorrhea is regulation of reproductive function remains to be fully associated with local disturbances in the expression and elucidated. synthesis of inflammatory mediators. Primary candidates In the normal human endometrium, PGE2 activation of that have been described include COX enzymes and their the EP receptors [45] and PGI2 activation of the IP prostanoid products. The hyperalgesic effects of PGE2 and receptor [46] result in an increase in the accumulation of

PGF2a have been described in several inflammatory intracellular cAMP, whereas PGF2a–FP receptor coupling models of nociception (reviewed in Ref. [36]). An increase mobilizes inositol trisphosphates and intracellular Ca2C in the synthesis of prostanoids such as PGE2 and PGF2a [44]. Activation of these second messenger systems is has been demonstrated in the menstrual fluid of women greatest during the middle-to-late proliferative phase of with dysmenorrhoea as compared with the menstrual the menstrual cycle, when levels of the prostanoid fluid of women with painless periods [33]. In vitro studies receptors are highest, and is increased even further in have shown that endometrial explants from dysmenor- endometrial adenocarcinomas as compared with normal rhoeic women produce more prostanoids in response to endometrium [23,38]. The second messenger systems and AA than do endometrial explants from pain-free women, cell signalling pathways that are activated in other suggesting that they express a higher level of COX uterine disorders remain to be fully elucidated. enzymes and specific prostanoid synthase enzymes. This Because the number of PGE2-binding sites is higher in observation has prompted the use of COX enzyme inhi- the endometrium of women with menorrhagia than in bitors in therapeutic regimens for managing this disorder, normal endometrium [33], it is possible that the activation with treatment being administered either during men- of second messenger systems in the menorrhagic endo- struation or before its onset [33]. metrium might be also increased as compared with The biosynthesis of COX-1 and/or COX-2 is also normal endometrium. Increases in the biosynthesis and upregulated in cancers of the endometrium [6,37–39]. signalling of other prostanoid receptors might similarly This finding has led to the suggestion that COX enzyme exacerbate the prevailing endometrial pathology. Once inhibitors might be of potential benefit in the treatment of activated, second messenger systems can mediate down- uterine carcinomas, as has been recommended for other stream signalling, including the activation of MAPK types of carcinoma that express high levels of COX cascades such as ERK, Jun amino-terminal kinase enzymes [40]. Upregulated expression of COX enzymes (JNK), p38 and ERK5 (also known as BMK) [23,44,47,48]. in endometrial carcinomas coincides with increased Further investigation into the diversity of signalling events synthesis and secretion of PGE2 and increased expression triggered by one or multiple prostanoid receptors is needed and signalling of EP receptors [37,38]. Although much to define the roles of prostanoid receptor signalling path- emphasis has been placed on the potential role of PGE2 in ways in reproductive function and pathology. regulating neoplastic cell function [41–43], other prostanoids using the same or alternative signal transduction Activation of prostaglandin receptors by seminal plasma pathways might similarly enhance or contribute towards In addition to their endogenously synthesized prosta- the neoplastic state. Recent data have outlined a marked noids, sexually active women come into contact with PGE2 upregulation in synthesis and signalling of the FP receptor that is present in seminal plasma. Prostaglandin levels in endometrial adenocarcinomas [23], and its potential role are 10 000 times higher in seminal plasma than at a site of in enhancing the proliferation of epithelial cells [44]. inflammation, and PGE2 is one of the predominant types Interestingly, many of the phenotypic changes that are of prostaglandin detected in seminal plasma [49]. Little is required for promoting the above-named pathologies, such known about the effect of seminal plasma prostaglandins as cell adhesion, cell invasion, cellular proliferation, on the physiology and pathology of the uterus; however, vascular permeability and angiogenesis, have been associ- recent evidence suggests that seminal plasma is trans- ated with COX enzymes and their prostanoid products [33]. ported into the uterine cavity in humans. Research using However, the potential role of the prostanoid receptors and labelled albumin macrospheres deposited at the external their signalling pathways in benign and neoplastic endo- cervical opening has shown that these spheres can travel metrial pathologies remain largely unexplored. into the uterine cavity within minutes of deposition. The proportion of spheres entering the uterine cavity goes up Prostaglandin receptor signalling in human with the increasing intensity of uterine contractions endometrium during the menstrual cycle [50]. Agonist stimulation of prostanoid GPCRs leads to receptor More recently, seminal plasma has been shown to activation and dissociation of the heterotrimeric G-protein influence the expression of genes in endometrial epithelial complex. This action generates various soluble second and stromal cells. The synthesis of several proinflamma- messengers (cAMP, inositol [1,4,5]-trisphosphate and tory mediators such as interleukins (IL-1b and IL-8) is Ca2C) by effector enzymes, depending on the hetero- increased after treatment with seminal plasma [51]. trimeric subtypes (Gas,Gai or Gaq; Figure 1), leading to Research in our laboratory has demonstrated that seminal the activation of divergent signalling cascades. In the plasma prostaglandins can activate the intracellular www.sciencedirect.com 402 Review TRENDS in Endocrinology and Metabolism Vol.15 No.8 October 2004 signalling and biosynthesis of proinflammatory mediators xenografts have been implanted subcutaneously in nude via specific prostanoid receptors such as EP2 and EP4 mice have demonstrated that reduced tumour prolifer- [52]. Thus, it is envisaged that seminal plasma prosta- ation, invasiveness and metastatic nodules occur coin- glandins might exacerbate endometrial pathologies that cidently with the inhibition of prostanoid production with are associated with an increase in prostaglandin receptors COX inhibitors [60,61]. More recent findings have shown in the plasma membrane compartment, especially those of that alterations in cellular adhesion, morphology and the prostaglandin E series. proliferation can occur after the binding of ligands to specific prostanoid receptors (namely, the EP4, FP and Uterine effects mediated by prostaglandin receptors TP receptors) and the activation of downstream sig- Many of the phenotypic effects associated with the nalling pathways such as the MAPK and PI3K pathways expression and activation of prostanoid receptors have [23,43,62,63] (Figure 2). Thus, it is predicted that the been derived from studies involving the genetic or aberrant biosynthesis and signalling of prostanoid recep- pharmacological manipulation of prostanoid receptors in tors in the endometrium [23,38] might promote uterine animal models or in vitro cell culture. Some of the known pathologies such as carcinoma and endometriosis by effects of prostanoid signalling include angiogenesis, stimulating unregulated cellular proliferation and dif- proliferation, adhesion, alterations in cellular morphology, ferentiation and downregulating cell-surface adhesion motility, invasion [33,48] and pain perception [53,54]. molecules, such as E-cadherin [14,64], to facilitate cell In the human endometrium, the COX–prostanoid motility, invasion and metastases. biosynthetic pathway plays a role in vascular function– Prostanoid receptors are also involved in the pathology dysfunction by promoting the transcription of angiogenic of dysmenorrhea. Current data investigating pain per- factors or by reducing the expression of anti-angiogenic ception in mice lacking individual prostaglandin recep- factors [55,56]. Vascular endothelial growth factor (VEGF) tors strongly suggest that EP3 and IP are the principal is known to be the progenitor angiogenic factor in the receptors that mediate pain perception [53,54].Inan formation of new blood vessels [57], and it promotes in vivo model system, IP and EP3 receptor knockout mice angiogenesis by recruiting endothelial cells from the pre- that were treated with lipopolysaccharide to induce COX existing vasculature to form vascular tubes [57]. Other enzyme and prostanoid biosynthesis showed a significant angiogenic factors have been proposed to act in parallel reduction in pain perception; by contrast, the response in or synergistically with VEGF to stabilize endothelial mice deficient in EP1, EP2 or EP4 was similar to that in cells and to promote their proliferation and arrangement wild-type mice [53]. Together with the significant increase into tubular structures to form new blood vessels. This in synthesis and signalling of the IP receptor observed not only serves to provide a blood supply and nutrients during menstruation [46], these findings indicate that this to encourage tissue repair, growth and differentiation, receptor has a potential role in regulating pain perception but can also promote receptivity in the uterus that in menstrual disorders associated with intensely painful prepares the endometrium for implantation in the next menstrual cramps, such as dysmenorrhoea. menstrual cycle. Recent in vivo work in knockout mice and in vitro Conclusion studies manipulating the expression and signalling of Over the past few years, much effort has gone into the prostanoid receptors have shown that prostanoids pro- discovery and implementation of specific COX enzyme mote angiogenesis by coupling to target receptors that inhibitors as a therapeutic regimen for diseases associated might be specific to the cell or tissue type. For example, with increased synthesis of endogenous COX enzymes and PGE2 coupling to the EP2 receptor induces the expression prostaglandins. In these disorders, treatment with COX of VEGF in pancreatic cancer cells and endometrial enzyme inhibitors will suppress only the production of adenocarcinoma cells [24,58], whereas the EP3 receptor endogenous prostaglandins. In sexually active women, regulates vascular function–dysfunction in ocular tissues however, any increase in prostanoid receptor activation and promotes vitreal neovascular diseases such as can be further enhanced by seminal plasma prosta- ischaemic retinopathies [59]. Although little is known of glandins. Furthermore, from the observations reported the angiogenic potential of other prostanoid receptors, herein, it is envisaged that an understanding of the role of increased levels of the EP4 and FP receptor have been the specific prostanoid receptors, their signalling path- reported in perivascular cells in endometrial adenocarcin- ways and their phenotypic effects in the female reproduc- omas [23,38]. It is therefore predicted that dysregulated tive tract might result ultimately in the development biosynthesis and signalling of prostanoid receptors can and implementation of more efficacious interventions in promote aberrant neovascularization in endometrial the clinic. pathologies, thereby promoting dysfunctional uterine Of particular significance is the involvement of RTKs in bleeding and the growth of endometrial cells in pathol- transducing the signal from the prostanoid receptor. The ogies such as cancer and endometriosis. trans-phosphorylation of RTKs by prostanoid receptors In addition to the role of prostanoids in promoting might have a crucial role in endometrial function– vascular function–dysfunction and vascular tone, in vitro dysfunction and consequently have important impli- model systems have shown that prostaglandins can cations for drug development. Recent data suggest that downregulate cell-surface adhesion molecules and stimu- combinational therapies such as a COX enzyme inhibitor late cell motility, invasiveness and metastasis [15,26] coupled with a selective inhibitor of an RTK, such as the (Figure 2). In vivo model systems in which cancer cell EGFR, can be more effective therapeutically than either www.sciencedirect.com Review TRENDS in Endocrinology and Metabolism Vol.15 No.8 October 2004 403 compound administered alone [65]. In light of these 18 Langenbach, R. et al. (1999) Cyclooxygenase-deficient mice. A studies, the combination of a prostanoid receptor antag- summary of their characteristics and susceptibilities to inflammation onist and an RTK inhibitor might be an efficacious therapy and carcinogenesis. Ann. N. Y. Acad. Sci. 889, 52–61 19 Lim, H. et al. (1997) Multiple female reproductive failures in for endometrial pathologies that are regulated by prosta- cyclooxygenase 2-deficient mice. 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Free journals for developing countries

The WHO and six medical journal publishers have launched the Access to Research Initiative, which enables nearly 70 of the world’s poorest countries to gain free access to biomedical literature through the Internet.

The science publishers, Blackwell, Elsevier, the Harcourt Worldwide STM group, Wolters Kluwer International Health and Science, Springer-Verlag and John Wiley, were approached by the WHO and the British Medical Journal in 2001. Initially, more than 1000 journals will be available for free or at signiﬁcantly reduced prices to universities, medical schools, research and public institutions in developing countries. The second stage involves extending this initiative to institutions in other countries.

Gro Harlem Brundtland, director-general for the WHO, said that this initiative was ’perhaps the biggest step ever taken towards reducing the health information gap between rich and poor countries’.

See http://www.healthinternetwork.net for more information. www.sciencedirect.com