Elsevier

Fertility and Sterility

Volume 98, Issue 3, September 2012, Pages 511-519
Fertility and Sterility

Views and reviews
Pathogenesis and pathophysiology of endometriosis

https://doi.org/10.1016/j.fertnstert.2012.06.029Get rights and content

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.

Section snippets

Histopathogenesis

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

Endometrial cell survival

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 (31). In addition to decreased apoptosis, enhanced proliferation may confer a

Altered hormonal milieu: estrogen dependence and P resistance

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 (46). 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 (47).

Evasion from immune clearance

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 (52). Additionally, the

Endometrial cell attachment and invasion

Although endometriosis is a benign disorder, the process by which endometrial cells attach and invade surfaces shares features of malignancy. The ESC fraction is primarily involved in the interaction of endometrial tissue with the mesothelial cell lining of the peritoneum. A study using ESCs and peritoneal mesothelial cells from a variety of sources in an in vitro binding assay demonstrated that the source of the ESCs rather than the source of the peritoneal cells had the greatest impact on the

Lesional neuroangiogenesis/vasculogenesis and growth

A rich vascular supply is necessary for the development and sustenance of endometriotic lesions, particularly in the peritoneal microenvironment, which is relatively avascular compared with the eutopic endometrium. Neoangiogenesis and capillary recruitment are visibly associated with endometriotic lesions at laparoscopy, most notably in the context of the red vesicular phenotype (Fig. 2). In addition, nerves frequently accompany angiogenesis (neuroangiogensis), likely contributing to the pain

Inflammation

Increasing evidence supports the conceptualization of endometriosis as a pelvic inflammatory condition. In women with endometriosis, the peritoneal fluid is remarkable for an increased number of activated macrophages and important differences in the cytokine/chemokine profile (78). A proteomics approach identified a unique protein structurally similar to haptoglobin in the peritoneal fluid of patients with endometriosis (79). This protein was subsequently found to bind to macrophages, reduce

Lesional progression and sequelae

Clinical and molecular lines of evidence converge to support a stagewise phenotypic progression associated with peritoneal endometriotic lesions. These stages include red vesicular, black powder-burn, and fibrotic lesional phenotypes. Longitudinal placebo-controlled trials with second-look laparoscopy have demonstrated that 71%–83% of untreated lesions will progress or remain stable over a 12-month period 92, 93. The earliest lesion is the red vesicular subtype (Fig. 4A). Red vesicular lesions

Conclusion

Since the original clinical description of endometriosis, much has been accomplished in furthering our understanding of this debilitating disease. Although no theory of pathogenesis can account for all of the described manifestations of endometriosis, the retrograde menstruation theory has gained widespread acceptance as an explanation for the dissemination of endometrial cells. The exact factor or factors that orchestrate the survival and subsequent implantation of the displaced endometrium

References (105)

  • R.L. Barbieri

    Stenosis of the external cervical os: an association with endometriosis in women with chronic pelvic pain

    Fertil Steril

    (1998)
  • H. Al-Fozan et al.

    Left lateral predisposition of endometriosis and endometrioma

    Obstet Gynecol

    (2003)
  • M. Wingfield et al.

    Cell proliferation is increased in the endometrium of women with endometriosis

    Fertil Steril

    (1995)
  • J.L. Simpson et al.

    Heritable aspects of endometriosis. I. Genetic studies

    Am J Obstet Gynecol

    (1980)
  • R.M. Hadfield et al.

    Endometriosis in monozygotic twins

    Fertil Steril

    (1997)
  • S.A. Treloar 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)
  • S.W. Guo et al.

    Genomic alterations in the endometrium may be a proximate cause for endometriosis

    Eur J Obstet Gynecol Reprod Biol

    (2004)
  • J. Kitawaki et al.

    Endometriosis: the pathophysiology as an estrogen-dependent disease

    J Steroid Biochem Mol Biol

    (2002)
  • S.E. Bulun et al.

    Progesterone resistance in endometriosis: link to failure to metabolize estradiol

    Mol Cell Endocrinol

    (2006)
  • D.J. Oosterlynck et al.

    Women with endometriosis show a defect in natural killer activity resulting in a decreased cytotoxicity to autologous endometrium

    Fertil Steril

    (1991)
  • B.J. Van Voorhis et al.

    Autoantibodies and infertility: a review of the literature

    J Reprod Immunol

    (1997)
  • R.S. Lucidi et al.

    A novel in vitro model of the early endometriotic lesion demonstrates that attachment of endometrial cells to mesothelial cells is dependent on the source of endometrial cells

    Fertil Steril

    (2005)
  • C.M. Kyama et al.

    Increased peritoneal and endometrial gene expression of biologically relevant cytokines and growth factors during the menstrual phase in women with endometriosis

    Fertil Steril

    (2006)
  • N. Suzumori et al.

    Elevated angiogenin levels in the peritoneal fluid of women with endometriosis correlate with the extent of the disorder

    Fertil Steril

    (2004)
  • J. Sugawara et al.

    Increased secretion of hepatocyte growth factor by eutopic endometrial stromal cells in women with endometriosis

    Fertil Steril

    (1997)
  • J.C. Huang et al.

    Epidermal growth factor and basic fibroblast growth factor in peritoneal fluid of women with endometriosis

    Fertil Steril

    (1996)
  • N. Rana et al.

    Basal and stimulated secretion of cytokines by peritoneal macrophages in women with endometriosis

    Fertil Steril

    (1996)
  • R. Kats et al.

    Marked elevation of macrophage migration inhibitory factor in the peritoneal fluid of women with endometriosis

    Fertil Steril

    (2002)
  • J. Eisermann et al.

    Tumor necrosis factor in peritoneal fluid of women undergoing laparoscopic surgery

    Fertil Steril

    (1988)
  • T. Harada et al.

    Increased interleukin-6 levels in peritoneal fluid of infertile patients with active endometriosis

    Am J Obstet Gynecol

    (1997)
  • S.E. Bulun et al.

    Role of aromatase in endometrial disease

    J Steroid Biochem Mol Biol

    (2001)
  • C.J. Sutton et al.

    Prospective, randomized, double-blind, controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild, and moderate endometriosis

    Fertil Steril

    (1994)
  • J. Donnez et al.

    Three-dimensional architectures of peritoneal endometriosis

    Fertil Steril

    (1992)
  • M.W. Vernon et al.

    Classification of endometriotic implants by morphologic appearance and capacity to synthesize prostaglandin F

    Fertil Steril

    (1986)
  • R.O. Burney et al.

    Menstrual bleeding from an endometriotic lesion

    Fertil Steril

    (2009)
  • I. Kokorine et al.

    Expression of interstitial collagenase (matrix metalloproteinase-1) is related to the activity of human endometriotic lesions

    Fertil Steril

    (1997)
  • M.N. Vipond et al.

    Peritoneal fibrinolytic activity and intra-abdominal adhesions

    Lancet

    (1990)
  • P.R. Koninckx et al.

    Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain

    Fertil Steril

    (1991)
  • K.E. Nnoaham et al.

    Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries

    Fertil Steril

    (2011)
  • K.J. Berkley et al.

    The pains of endometriosis

    Science

    (2005)
  • S. Simoens et al.

    The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres

    Hum Reprod

    (2012)
  • S.E. Bulun

    Endometriosis

    N Engl J Med

    (2009)
  • N. Iwanoff

    Dusiges cystenhaltiges uterusfibromyom compliciert durch sarcom und carcinom. (Adenofibromyoma cysticum sarcomatodes carcinomatosum)

    Monatsch Geburtshilfe Gynakol

    (1898)
  • G. Levander et al.

    The pathogenesis of endometriosis; an experimental study

    Acta Obstet Gynecol Scand

    (1955)
  • J.A. Merrill

    Endometrial induction of endometriosis across Millipore filters

    Am J Obstet Gynecol

    (1966)
  • W. Russell

    Aberrant portions of the mullerian duct found in an ovary. Ovarian cysts of mullerian origin

    Bull Johns Hopkins Hosp

    (1899)
  • I.E. Sasson et al.

    Stem cells and the pathogenesis of endometriosis

    Ann N Y Acad Sci

    (2008)
  • J. Halban

    Metastatic hysteroadenosis

    Wien klin Wochenschr

    (1924)
  • J.A. Sampson

    Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation

    Am J Pathol

    (1927)
  • A.J. Hey-Cunningham et al.

    Endometrial stromal cells and immune cell populations within lymph nodes in a nonhuman primate model of endometriosis

    Reprod Sci

    (2011)
  • Cited by (1069)

    • Research progress of dydrogesterone in the treatment of endometriosis

      2024, European Journal of Obstetrics and Gynecology and Reproductive Biology
    • Robotic assisted laparoscopy for deep infiltrating endometriosis

      2024, Best Practice and Research: Clinical Obstetrics and Gynaecology
    • Endometriosis

      2024, FMC Formacion Medica Continuada en Atencion Primaria
    View all citing articles on Scopus

    R.O.B. has nothing to disclose. L.C.G. has nothing to disclose.

    Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health (NICHD/NIH) through cooperative agreement U54HD055764-06 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research (L.C.G.).

    View full text