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Pathogenesis and pathophysiology of endometriosis

2012; Elsevier BV; Volume: 98; Issue: 3 Linguagem: Inglês

10.1016/j.fertnstert.2012.06.029

1556-5653

Richard O. Burney, Linda C. Giudice,

Reproductive System and Pregnancy

Originally described over three hundred years ago, endometriosis is classically defined by the presence of endometrial glands and stroma in extrauterine locations. Endometriosis is an inflammatory, estrogen-dependent condition associated with pelvic pain and infertility. This work reviews the disease process from theories regarding origin to the molecular basis for disease sequelae. A thorough understanding of the histopathogenesis and pathophysiology of endometriosis is essential to the development of novel diagnostic and treatment approaches for this debilitating condition. Originally described over three hundred years ago, endometriosis is classically defined by the presence of endometrial glands and stroma in extrauterine locations. Endometriosis is an inflammatory, estrogen-dependent condition associated with pelvic pain and infertility. This work reviews the disease process from theories regarding origin to the molecular basis for disease sequelae. A thorough understanding of the histopathogenesis and pathophysiology of endometriosis is essential to the development of novel diagnostic and treatment approaches for this debilitating condition. Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/burneyro-pathogenesis-pathophysiology-endometriosis/ Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/burneyro-pathogenesis-pathophysiology-endometriosis/ Endometriosis is classically defined as the presence of endometrial glands and stroma in ectopic locations, primarily the pelvic peritoneum, ovaries, and rectovaginal septum. Affecting 6%–10% of women of reproductive age, the stigmata of endometriosis include dysmenorrhea, dyspareunia, chronic pelvic pain, irregular uterine bleeding, and/or infertility (1Eskenazi B. Warner M.L. Epidemiology of endometriosis.Obstet Gynecol Clin North Am. 1997; 24: 235-258Abstract Full Text Full Text PDF PubMed Scopus (1204) Google Scholar). The prevalence of this condition in women experiencing pain, infertility, or both is as high as 35%–50% (2Meuleman C. Vandenabeele B. Fieuws S. Spiessens C. Timmerman D. D'Hooghe T. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners.Fertil Steril. 2009; 92: 68-74Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar). Yet endometriosis is underdiagnosed and associated with a 6.7-year mean latency from onset of symptoms to definitive diagnosis (3Nnoaham K.E. Hummelshoj L. Webster P. d'Hooghe T. de Cicco Nardone F. de Cicco Nardone C. et al.Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries.Fertil Steril. 2011; 96 (366–73.e8)Abstract Full Text Full Text PDF PubMed Scopus (848) Google Scholar), in part owing to the requirement for surgical diagnosis. Endometriosis is a debilitating condition, posing significant quality-of-life issues for the individual patient (4Berkley K.J. Rapkin A.J. Papka R.E. The pains of endometriosis.Science. 2005; 308: 1587-1589Crossref PubMed Scopus (356) Google Scholar). The disorder represents a major cause of hysterectomy and hospitalization in the United States, with total annual societal costs estimated at $69.4 billion in 2009 (5Simoens S. Dunselman G. Dirksen C. Hummelshoj L. Bokor A. Brandes I. et al.The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres.Hum Reprod. 2012; 27: 1292-1299Crossref PubMed Scopus (611) Google Scholar). The significant individual and public health concerns associated with endometriosis underscore the importance of understanding its pathogenesis and pathophysiology toward prevention and the development of sensitive nonsurgical diagnostic assays and effective treatments. The past several decades have witnessed substantial progress toward unraveling the enigma associated with this disorder. Herein we outline the current understanding of the pathogenesis and pathophysiology of endometriosis. A unifying theory regarding the origin of endometriosis has remained mystifyingly elusive. Instead, several theories (Fig. 1) have arisen to account for the disparate observations regarding pathogenesis, and these can generally be categorized as those proposing that implants originate from uterine endometrium and those proposing that implants arise from tissues other than the uterus. Intrinsic to these theories are inciting factors and genetic susceptibilities whose roles are beginning to be delineated, although they are insufficiently established to confirm cause and effect and subsequent development of endometriosis. For example, reports linking endocrine disrupting chemicals (EDCs) with endometriosis (6Crain D.A. Janssen S.J. Edwards T.M. Heindel J. Ho S.M. Hunt P. et al.Female reproductive disorders: the roles of endocrine-disrupting compounds and developmental timing.Fertil Steril. 2008; 90: 911-940Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar) suggest these, and endogenous/exogenous estrogens, as potential transforming/inductive/stimulant candidates in theories of endometriosis pathogenesis. The developmental timing of action of such agents and their roles in influencing other systems that predispose to endometriosis (endocrine, immune, stem/progenitor cells, epigenetic modifications) must be considered in the context of genetic background as well as stimulus-driven reprogramming of the female reproductive tract (7Bulun S.E. Endometriosis.N Engl J Med. 2009; 360: 268-279Crossref PubMed Scopus (1531) Google Scholar). Among theories proposing a nonuterine origin of disease, coelomic metaplasia involves the transformation of normal peritoneal tissue to ectopic endometrial tissue (8Iwanoff N. Dusiges cystenhaltiges uterusfibromyom compliciert durch sarcom und carcinom. (Adenofibromyoma cysticum sarcomatodes carcinomatosum).Monatsch Geburtshilfe Gynakol. 1898; 7: 295-300Google Scholar). Agents responsible for such transformation remain poorly defined, although EDCs may be candidates. The closely related induction theory holds that an endogenous inductive stimulus, such as a hormonal or immunologic factor, promotes the differentiation of cells in the peritoneal lining to endometrial cells (9Levander G. Normann P. The pathogenesis of endometriosis; an experimental study.Acta Obstet Gynecol Scand. 1955; 34: 366-398Crossref PubMed Scopus (78) Google Scholar, 10Merrill J.A. Endometrial induction of endometriosis across Millipore filters.Am J Obstet Gynecol. 1966; 94: 780-790PubMed Google Scholar). Finally, the theory of embryonic Müllerian rests, or müllerianosis, purports that cells residual from embryologic Müllerian duct migration maintain the capacity to develop into endometriotic lesions under the influence of estrogen beginning at puberty (11Russell W. Aberrant portions of the mullerian duct found in an ovary. Ovarian cysts of mullerian origin.Bull Johns Hopkins Hosp. 1899; 10: 8Google Scholar) or perhaps in response to estrogen mimetics. These theories find support in epidemiological studies reporting a twofold increased risk of endometriosis in women exposed to diethylstilbestrol in utero (12Missmer S.A. Hankinson S.E. Spiegelman D. Barbieri R.L. Michels K.B. Hunter D.J. In utero exposures and the incidence of endometriosis.Fertil Steril. 2004; 82: 1501-1508Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). A more recent proposal suggests that extrauterine stem/progenitor cells originating from bone marrow may differentiate into endometriotic tissue (13Sasson I.E. Taylor H.S. Stem cells and the pathogenesis of endometriosis.Ann N Y Acad Sci. 2008; 1127: 106-115Crossref PubMed Scopus (275) Google Scholar). Candidate cell lineages include bone marrow mesenchymal stem progenitors and endothelial progenitors, and this represents an active area of investigation. Support for theories advocating a nonendometrial origin for endometriosis is derived from clinical accounts of histologically confirmed endometriotic tissue in patients without menstrual endometrium, such as individuals with Rokitansky-Kuster-Hauser syndrome (14Rosenfeld D.L. Lecher B.D. Endometriosis in a patient with Rokitansky-Kuster-Hauser syndrome.Am J Obstet Gynecol. 1981; 139: 105PubMed Scopus (38) Google Scholar) and men with prostate cancer undergoing high-dose estrogen treatment (15Schrodt G.R. Alcorn M.O. Ibanez J. Endometriosis of the male urinary system: a case report.J Urol. 1980; 124: 722-723PubMed Google Scholar). The theory of benign metastasis holds that ectopic endometrial implants are the result of lymphatic or hematogenous dissemination of endometrial cells (16Halban J. Metastatic hysteroadenosis.Wien klin Wochenschr. 1924; 37: 1205-1206Google Scholar, 17Sampson J.A. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation.Am J Pathol. 1927; 3: 93-110PubMed Google Scholar). Microvascular studies demonstrated flow of lymph from the uterine body into the ovary, rendering possible a role for the lymphatic system in the etiology of ovarian endometriosis. Endometriosis within lymph nodes has been documented in a baboon model of induced endometriosis (18Hey-Cunningham A.J. Fazleabas A.T. Braundmeier A.G. Markham R. Fraser I.S. Berbic M. Endometrial stromal cells and immune cell populations within lymph nodes in a nonhuman primate model of endometriosis.Reprod Sci. 2011; 18: 747-754Crossref PubMed Scopus (24) Google Scholar) and in 6%–7% of women at lymphadenectomy (19Javert C.T. The spread of benign and malignant endometrium in the lymphatic system with a note on coexisting vascular involvement.Am J Obstet Gynecol. 1952; 64: 780-806PubMed Scopus (91) Google Scholar). The strongest evidence for the theory of benign metastasis is derived from reports of histologically proven endometriotic lesions occurring in sites distant from the uterus, including bone, lung, and brain (20Jubanyik K.J. Comite F. Extrapelvic endometriosis.Obstet Gynecol Clin North Am. 1997; 24: 411-440Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). Initially proposed by Sampson in the 1920s, the theory of retrograde menstruation is both intuitively attractive and supported by multiple lines of scientific evidence (21Sampson J.A. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity.Am J Obstet Gynecol. 1927; 14: 442-469Abstract Full Text PDF Google Scholar). According to this theory, eutopic endometrium is sloughed via patent fallopian tubes into the peritoneal cavity during menstruation. Indeed, the universality of this phenomenon is supported by the finding of menstrual blood in the peritoneal fluid of up to 90% of healthy women with patent fallopian tubes undergoing laparoscopy during the perimenstrual time of the cycle (22Halme J. Hammond M.G. Hulka J.F. Raj S.G. Talbert L.M. Retrograde menstruation in healthy women and in patients with endometriosis.Obstet Gynecol. 1984; 64: 151-154PubMed Google Scholar). Further support for this etiology is derived from studies of obstructed or compromised outflow tracts. In adolescent girls with congenital outflow obstruction, the prevalence of endometriosis is high (23Sanfilippo J.S. Wakim N.G. Schikler K.N. Yussman M.A. Endometriosis in association with uterine anomaly.Am J Obstet Gynecol. 1986; 154: 39-43Abstract Full Text PDF PubMed Scopus (115) Google Scholar). Likewise, iatrogenic obstruction of the outflow tract in a nonhuman primate model results in endometriotic lesions within the peritoneal cavity (24D'Hooghe T.M. Bambra C.S. Suleman M.A. Dunselman G.A. Evers H.L. Koninckx P.R. Development of a model of retrograde menstruation in baboons (Papio anubis).Fertil Steril. 1994; 62: 635-638PubMed Google Scholar). Even subtle compromise of antegrade menstruation may predispose to endometriosis, as evidenced by the higher prevalence of endometriosis in women with a uterine septum (25Nawroth F. Rahimi G. Nawroth C. Foth D. Ludwig M. Schmidt T. Is there an association between septate uterus and endometriosis?.Hum Reprod. 2006; 21: 542-544Crossref PubMed Scopus (51) Google Scholar) and cervical stenosis (26Barbieri R.L. Stenosis of the external cervical os: an association with endometriosis in women with chronic pelvic pain.Fertil Steril. 1998; 70: 571-573Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). The anatomic distribution of endometriotic lesions also favors the retrograde menstruation theory. Superficial implants are more often located in the posterior compartment of the pelvis (27Dmowski W.P. Radwanska E. Current concepts on pathology, histogenesis and etiology of endometriosis.Acta Obstet Gynecol Scand Suppl. 1984; 123: 29-33Crossref PubMed Scopus (38) Google Scholar) and in the left hemipelvis (28Al-Fozan H. Tulandi T. Left lateral predisposition of endometriosis and endometrioma.Obstet Gynecol. 2003; 101: 164-166Crossref PubMed Scopus (85) Google Scholar). The propensity for lesions to implant in the posterior cul de sac is explained by the accumulation of regurgitated menstrual effluent in this most dependent portion of the peritoneal cavity under the influence of gravity. In allowing flow from the anterior to posterior compartment in the upright or supine position, a retroverted uterine position is correlated with the finding of endometriosis (29Jenkins S. Olive D.L. Haney A.F. Endometriosis: pathogenetic implications of the anatomic distribution.Obstet Gynecol. 1986; 67: 335-338PubMed Google Scholar). By acting as an obstacle to the diffusion of menstrual effluent from the left fallopian tube, the sigmoid colon promotes stasis of this effluent, thereby extending the interval for refluxed endometrial fragments to implant in the left hemipelvis. A murine model of endometriosis has provided insight into the pathogenesis of peritoneal endometriosis (30Dinulescu D.M. Ince T.A. Quade B.J. Shafer S.A. Crowley D. Jacks T. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer.Nat Med. 2005; 11: 63-70Crossref PubMed Scopus (500) Google Scholar). The conditional activation of the K-ras oncogene in endometrial cells deposited into the peritoneum resulted in histologically confirmed peritoneal endometriotic implants in nearly 50% of mice within 8 months. On the other hand, similar activation of the K-ras oncogene in peritoneal cells showed no progression to endometriosis. These preclinical observations favor an endometrial origin of the development of peritoneal lesions. Although retrograde menstruation explains the physical displacement of endometrial fragments into the peritoneal cavity, additional steps are necessary for the development of endometriotic implants. Escape from immune clearance, attachment to peritoneal epithelium, invasion of the epithelium, establishment of local neurovascularity, and continued growth and survival are necessary if endometriosis is to develop from retrograde passage of endometrium. Collectively, investigations involving the pathophysiology of endometriosis have revealed several well supported molecular hallmarks of this disease: genetic predisposition, estrogen dependence, P resistance, and inflammation. It is the propensity for implantation that best accounts for the discrepancy between the 90% prevalence of retrograde menstruation and the nearly 10% prevalence of the disease. Hereditary or acquired properties of the endometrium, hereditary or acquired defects of the peritoneal epithelium, and/or defective immune clearance of sloughed endometrium are areas of active investigation in the search for the factor or factors that influence a predisposition toward implantation of the displaced endometrial cells—a necessary correlate to theories proposing an endometrial origin to disease pathogenesis. The evidence for an innate or acquired condition of the endometrial cells as the predisposing factor toward implantation is compelling. The eutopic endometrium from women with endometriosis shares certain alterations with ectopic lesions that are not observed in the endometrium from healthy women. Up-regulation of the antiapoptotic gene BCL-2 has been shown in both eutopic and ectopic endometrium from affected women (31Jones R.K. Searle R.F. Bulmer J.N. Apoptosis and bcl-2 expression in normal human endometrium, endometriosis and adenomyosis.Hum Reprod. 1998; 13: 3496-3502Crossref PubMed Scopus (142) Google Scholar). In addition to decreased apoptosis, enhanced proliferation may confer a selective survival advantage to the endometrium of women predisposed to endometriosis (32Wingfield M. Macpherson A. Healy D.L. Rogers P.A. Cell proliferation is increased in the endometrium of women with endometriosis.Fertil Steril. 1995; 64: 340-346PubMed Google Scholar). A genetic alteration of the endometrial cells influencing their tendency to implant may be hereditary, as a heritable component to the disease has been established. The risk for first-degree relatives of women with severe endometriosis is 6 times higher than that for relatives of unaffected women (33Simpson J.L. Elias S. Malinak L.R. Buttram Jr., V.C. Heritable aspects of endometriosis. I. Genetic studies.Am J Obstet Gynecol. 1980; 137: 327-331Abstract Full Text PDF PubMed Scopus (381) Google Scholar). Studies of monozygotic twins demonstrate high concordance rates for histologically confirmed endometriosis (34Hadfield R.M. Mardon H.J. Barlow D.H. Kennedy S.H. Endometriosis in monozygotic twins.Fertil Steril. 1997; 68: 941-942Abstract Full Text PDF PubMed Scopus (142) Google Scholar). Linkage analysis has elucidated candidate genes with biological plausibility. The largest of these involved over 1,100 families with two or more affected sib pairs, and established significance for a susceptibility locus in the regions of chromosome 10q26 and 7p15 (35Treloar S.A. Wicks J. Nyholt D.R. Montgomery G.W. Bahlo M. Smith V. et al.Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26.Am J Hum Genet. 2005; 77: 365-376Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 36Painter J.N. Anderson C.A. Nyholt D.R. Macgregor S. Lin J. Lee S.H. et al.Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis.Nat Genet. 2011; 43: 51-54Crossref PubMed Scopus (256) Google Scholar). Acquired genomic alterations represent a potential source for a conferred survival advantage to sloughed endometrial cells in the establishment of endometriotic implants. The endometrium is a setting of extraordinary cell turnover and, consequently, is vulnerable to errors of genetic recombination. The occurrence of genomic alteration in eutopic endometrium is well documented and may be consequent to epigenetic factors or oxidative stress (37Guo S.W. Wu Y. Strawn E. Basir Z. Wang Y. Halverson G. et al.Genomic alterations in the endometrium may be a proximate cause for endometriosis.Eur J Obstet Gynecol Reprod Biol. 2004; 116: 89-99Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Loss of heterozygosity and somatic mutation of the tumor suppressor gene PTEN has been documented in 56% and 21% of solitary endometrial cysts of the ovary, respectively (38Sato N. Tsunoda H. Nishida M. Morishita Y. Takimoto Y. Kubo T. et al.Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary.Cancer Res. 2000; 60: 7052-7056PubMed Google Scholar). Genomic alterations within endometriotic implants have been described using comparative genomic hybridization (CGH) microarrays (39Wu Y. Strawn E. Basir Z. Wang Y. Halverson G. Jailwala P. et al.Genomic alterations in ectopic and eutopic endometria of women with endometriosis.Gynecol Obstet Invest. 2006; 62: 148-159Crossref PubMed Scopus (45) Google Scholar). Interestingly, the CGH profiles (chromosome loss or gain) clustered by anatomic location of the implant as peritoneal or ovarian. Finally, increasing evidence supports epigenetic regulation of steroid hormone action in the endometrium (40Zhang X. Ho S.M. Epigenetics meets endocrinology.J Mol Endocrinol. 2011; 46: R11-32Crossref PubMed Scopus (186) Google Scholar) and dysregulation in women with endometriosis (41Houshdaran S. Zelenko Z. Tamaresis J.S. Irwin J.C. Giudice L.C. Abnormal epigenetic signature in eutopic endometrium of subjects with severe endometriosis.Reprod Sci. 2011; 18: 191AGoogle Scholar). In particular, aberrant DNA methylation of promoters of genes whose products are critical for normal endometrial P response have been reported in endometriosis and animal models of the disease, with resulting P resistance (42Guo S.W. Epigenetics of endometriosis.Mol Hum Reprod. 2009; 15: 587-607Crossref PubMed Scopus (252) Google Scholar). MicroRNAs (miRNAs) are short noncoding RNAs that generally repress gene expression through mRNA degradation. Differential and ovarian steroid-dependent expression of miRNAs in eutopic endometrium from women with and without endometriosis has been demonstrated (43Pan Q. Luo X. Toloubeydokhti T. Chegini N. The expression profile of micro-RNA in endometrium and endometriosis and the influence of ovarian steroids on their expression.Mol Hum Reprod. 2007; 13: 797-806Crossref PubMed Scopus (242) Google Scholar). The search for an innate or acquired survival advantage of eutopic endometrium toward ectopic implantation has fueled a number of studies comparing eutopic endometrium from women with and without endometriosis. Collectively, these studies reveal striking differences in gene and protein expression that may predispose to disease development, and these have been nicely synopsized recently (44May K.E. Villar J. Kirtley S. Kennedy S.H. Becker C.M. Endometrial alterations in endometriosis: a systematic review of putative biomarkers.Hum Reprod Update. 2011; 17: 637-653Crossref PubMed Scopus (175) Google Scholar). A partial list of promising candidates is provided in Table 1. Validation of these genes/proteins requires temporally controlled experiments that can only be conducted using preclinical models such as the nonhuman primate, the only other species documented to spontaneously develop endometriosis (45D'Hooghe T.M. Kyama C.M. Chai D. Fassbender A. Vodolazkaia A. Bokor A. et al.Nonhuman primate models for translational research in endometriosis.Reprod Sci. 2009; 16: 152-161Crossref PubMed Scopus (100) Google Scholar).Table 1Candidate factors implicated in the pathophysiology of endometriosis.GeneFunctionReference17β-HSD-2Hydroxysteroid dehydrogenase47Zeitoun K. Takayama K. Sasano H. Suzuki T. Moghrabi N. Andersson S. et al.Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol.J Clin Endocrinol Metab. 1998; 83: 4474-4480Crossref PubMed Google ScholarBCL-2Antiapoptosis31Jones R.K. Searle R.F. Bulmer J.N. Apoptosis and bcl-2 expression in normal human endometrium, endometriosis and adenomyosis.Hum Reprod. 1998; 13: 3496-3502Crossref PubMed Scopus (142) Google ScholarCYP19Aromatase enzyme102Noble L.S. Simpson E.R. Johns A. Bulun S.E. Aromatase expression in endometriosis.J Clin Endocrinol Metab. 1996; 81: 174-179Crossref PubMed Scopus (522) Google ScholarHOXA10Transcription factor103Taylor H.S. Bagot C. Kardana A. Olive D. Arici A. HOX gene expression is altered in the endometrium of women with endometriosis.Hum Reprod. 1999; 14: 1328-1331Crossref PubMed Scopus (353) Google ScholarIL-6Cytokine82Harada T. Yoshioka H. Yoshida S. Iwabe T. Onohara Y. Tanikawa M. et al.Increased interleukin-6 levels in peritoneal fluid of infertile patients with active endometriosis.Am J Obstet Gynecol. 1997; 176: 593-597Abstract Full Text Full Text PDF PubMed Scopus (215) Google ScholarKRASOncogene30Dinulescu D.M. Ince T.A. Quade B.J. Shafer S.A. Crowley D. Jacks T. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer.Nat Med. 2005; 11: 63-70Crossref PubMed Scopus (500) Google ScholarMMP 3,7Matrix metalloproteinases65Bruner-Tran K.L. Eisenberg E. Yeaman G.R. Anderson T.A. McBean J. Osteen K.G. Steroid and cytokine regulation of matrix metalloproteinase expression in endometriosis and the establishment of experimental endometriosis in nude mice.J Clin Endocrinol Metab. 2002; 87: 4782-4791Crossref PubMed Scopus (164) Google ScholarNF-KBTranscription factor104Gonzalez-Ramos R. Van Langendonckt A. Defrere S. Lousse J.C. Colette S. Devoto L. et al.Involvement of the nuclear factor-kappaB pathway in the pathogenesis of endometriosis.Fertil Steril. 2010; 94: 1985-1994Abstract Full Text Full Text PDF PubMed Scopus (144) Google ScholarPGE2Prostaglandin105Badawy S.Z. Cuenca V. Marshall L. Munchback R. Rinas A.C. Coble D.A. Cellular components in peritoneal fluid in infertile patients with and without endometriosis.Fertil Steril. 1984; 42: 704-708Abstract Full Text PDF PubMed Google ScholarPTENTumor suppressor gene30Dinulescu D.M. Ince T.A. Quade B.J. Shafer S.A. Crowley D. Jacks T. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer.Nat Med. 2005; 11: 63-70Crossref PubMed Scopus (500) Google ScholarTGF-BCytokine61Oosterlynck D.J. Meuleman C. Waer M. Koninckx P.R. Transforming growth factor-beta activity is increased in peritoneal fluid from women with endometriosis.Obstet Gynecol. 1994; 83: 287-292PubMed Google ScholarTNF-αCytokine81Eisermann J. Gast M.J. Pineda J. Odem R.R. Collins J.L. Tumor necrosis factor in peritoneal fluid of women undergoing laparoscopic surgery.Fertil Steril. 1988; 50: 573-579Abstract Full Text PDF PubMed Scopus (261) Google Scholar Open table in a new tab Hormonal alterations may influence the ability of endometrial cells to proliferate, attach to the mesothelium, and/or evade immune-mediated clearance. Long appreciated clinically, the concept of endometriosis as an estrogen-dependent disorder is well supported by molecular evidence (46Kitawaki J. Kado N. Ishihara H. Koshiba H. Kitaoka Y. Honjo H. Endometriosis: the pathophysiology as an estrogen-dependent disease.J Steroid Biochem Mol Biol. 2002; 83: 149-155Crossref PubMed Scopus (293) Google Scholar). A striking finding in endometriotic tissue relative to eutopic endometrium is the increased expression of the aromatase enzyme and decreased expression of 17β-hydroxysteroid dehydrogenase (17β-HSD) type 2 (47Zeitoun K. Takayama K. Sasano H. Suzuki T. Moghrabi N. Andersson S. et al.Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol.J Clin Endocrinol Metab. 1998; 83: 4474-4480Crossref PubMed Google Scholar). The sum consequence of this differential expression profile is a marked increase in the locally bioavailable E2 concentration. E2 stimulates the production of prostaglandin E2, (PGE2) which further stimulates aromatase activity (48Noble L.S. Takayama K. Zeitoun K.M. Putman J.M. Johns D.A. Hinshelwood M.M. et al.Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells.J Clin Endocrinol Metab. 1997; 82: 600-606Crossref PubMed Scopus (409) Google Scholar). These findings support the capacity of endometriotic lesions for E2 biosynthesis and substantiate treatments aimed at promoting a hypoestrogenic peritoneal microenvironment. In addition to estrogen dependence, there is increasing evidence to support a profile of P resistance in the pathophysiology of endometriosis (49Bulun S.E. Cheng Y.H. Yin P. Imir G. Utsunomiya H. Attar E. et al.Progesterone resistance in endometriosis: link to failure to metabolize estradiol.Mol Cell Endocrinol. 2006; 248: 94-103Crossref PubMed Scopus (323) Google Scholar). Endometriotic lesions exhibit an overall reduction in P receptor expression relative to eutopic endometrium and an absence of P receptor-B (50Attia G.R. Zeitoun K. Edwards D. Johns A. Carr B.R. Bulun S.E. Progesterone receptor isoform A but not B is expressed in endometriosis.J Clin Endocrinol Metab. 2000; 85: 2897-2902Crossref PubMed Scopus (429) Google Scholar). Additionally, endometrial expression profiling has documented dysregulation of P-responsive genes in the luteal phase (51Burney R.O. Talbi S. Hamilton A.E. Vo K.C. Nyegaard M. Nezhat C.R. et al.Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis.Endocrinology. 2007; 148: 3814-3826Crossref PubMed Scopus (601) Google Scholar). An incomplete transition of endometrium from the proliferative to secretory phase has significant molecular implications toward enhancing the survival and implantation of refluxed endometrium. Normally, refluxed endometrial tissue is cleared from the peritoneum by the immune system, and the dysregulation of this clearance mechanism has been implicated in the predisposition to implantation and growth of endometrial cells. Interestingly, larger tissue fragments as opposed to individual cells demonstrate an increased capacity to implant, presumably owing to the protection from immune clearance afforded the cells residing on the inner aspects of such fragments (52Nap A.W. Groothuis P.G. Demir A.Y. Maas J.W. Dunselman G.A. de Goeij A.F. et al.Tissue integrity is essential for ectopic implantation of human endometrium in the chicken chorioallantoic membrane.Hum Reprod. 2003; 18: 30-34Crossref PubMed Scopus (37) Google Scholar). Additionally, the eutopic endometrium from women with endometriosis was found to be more resistant to lysis by natural killer (NK) cells than the eutopic endometrium from