Endometriosis: Pathogenesis and Treatment 2014 Ed.

2. Pathological Aspect and Pathogenesis of Endometriosis

Ritsuo Honda  and Hidetaka Katabuchi1


Department of Obstetrics and Gynecology, Faculty of life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

Ritsuo Honda

Email: ritz@kuamoto-u.ac.jp


Historically, endometriosis was first described in Egyptian scrolls in the sixteenth century BC. The first scientific description of endometriosis was published by Carl Freiherr von Rokitansky in 1860. At this time, the concept of endometriosis as a disease entity was not established and it was assumed to be an enigmatic disease with an unknown pathology. Although extensive basic and clinical research has been carried from the last century until present, the pathogenesis of endometriosis is still controversial. Major theories on the pathogenesis of endometriosis are (1) metastases of endometrial tissues to an ectopic location (transplantation theory), (2) metaplastic development of endometrial tissue on the ectopic site (metaplastic theory), and (3) changes of the embryonic duct remnant epithelium into endometrial epithelium (müllerian remnants theory). A comprehensive understanding of the histopathogenesis of endometriosis is essential to the novel clinical approaches for the enigmatic disease.



2.1 Introduction

Endometriosis is a common gynecological disease of unknown etiology which affects an estimated 10–45 % in infertile females. Endometriosis is defined as the presence of endometrial tissue, consisting of both glandular epithelium and stroma, in ectopic locations. Clinically, it can be associated with many distressing and debilitating symptoms, such as pelvic pain, severe dysmenorrhea, dyspareunia, and infertility, or it may be asymptomatic and incidentally discovered at laparoscopic surgery.

In 1860, the first histological description of endometriosis was given by von Rokitansky [1]. In 1896, Cullen suggested that adenomyoma, as he called it, resembled the histological features of normal endometrial epithelium and stroma [2]. The term “endometriosis” was first described by Sampson in 1925 [3] and his studies became a pioneering figure of research on the pathogenesis of endometriosis [35]. Endometriosis is believed a benign disease, but it has been confirmed that it may lead to recurrence and metastasis and be secondary ovarian cancer from chocolate cysts. Because of the different locations of the disease, its pathogenesis also has been attributed either to transplantation of viable endometrial cell fragments, to coelomic metaplasia, or to embryonic remnants, and several contributing factors are also involved, including retrograde menstruation, disturbances of hormonal conditions, or familial and genetic factors.

2.2 Sites of Endometriosis

Endometriosis is defined as a pathological disease caused by the presence and proliferation of ectopic endometrial tissue in sites other than the endometrial cavity. Endometriosis often develops in the ovary, pouch of Douglas, and uterosacral ligaments and sometimes in the fallopian tubes, uterine cervix, vagina, colon and rectum, vermiform appendix, urinary bladder and tract, and others, that is, mostly in the peritoneum of the pelvic cavity and associated deep tissue [6].

Endometriosis is also occasionally observed in remote organs such as lymph nodes, pudendum, umbilicus, and lung [6]. Cases of endometriosis can occur in tissues beyond the pelvis and have diverse symptoms that depend on the site of development, including pain and/or bleeding, associated with the menstrual cycle. Rarely, endometriosis has been reported in males. However, they were all older men suffering from prostate cancer, who were treated with high doses of estrogens. In these cases, a hypertrophic change of the müllerian remnants was observed in the prostate [7].

2.3 The Theory of Secondary Müllerian System

The term “secondary müllerian system” was first described by Lauchlan in 1972 [8]. He noted the propensity of the peritoneum which covers the surface of the ovary and the peritoneal cavity to müllerian differentiation. The surface mesothelial and the submesothelial stroma of peritoneum exhibit a full spectrum of müllerian differentiation from benign to malignant. Many lesions of secondary müllerian system are described, which are benign, such as endosalpingiosis, of the low grade of malignancy, serous and mucinous and malignant, described as extraovarian peritoneal serous and mucinous carcinomas, and endometriosis is considered as the main lesson of the secondary müllerian system [9]. It is proposed that the development of peritoneal müllerian lesions may be secondary to the proximity of pelvic peritoneum to tubal fimbria and the exposure of the peritoneal surfaces to external agents, such as talc and asbestos, that stimulate the peritoneal müllerian differentiation [10].

2.4 Microscopic Findings of Endometriosis

The focus of endometriosis is basically formed of three components: the endometrial glandular epithelium, an endometrium-specific stroma, and a stroma with fibrosis that forms the lesion in regions of chronic inflammation associated with endometriosis. Findings of fibrosis are associated with infiltration of inflammatory cells such as macrophages, mast cells, monocytes, eosinophil granulocytes, and basophil granulocytes; proliferation of fibroblasts; and smooth muscle metaplasia, angiogenesis, and innervation. Similar to the original endometrium, the ectopic glandular and stromal cells also express estrogen and progesterone receptors. In response to the expression of the sex steroid receptors, stromal cells show a decidual reaction in the pregnant women.

The cell morphology of glandular epithelium may change to that of the epithelium of müllerian ducts; epithelial cells of the fallopian tubes [11], the glandular epithelium of the endocervical canal (Fig. 2.1b), with apocrine-like cells (Fig. 2.1c) and intestinal epithelium (Fig. 2.1d). These changes usually may occur in response to inflammation and others, and it enables epithelial cells to change to their surrounding circumstances to better adapt to their environment [12].


Fig. 2.1

Metaplasia of epithelial cells involved in endometriosis. (a) Metaplasia of tubal epithelial cells. (b) Metaplasia of endocervical canal glandular cells. (c) Apocrine metaplasia. (d) Intestinal metaplasia. Hematoxylin–eosin stain, (ad) ×200 (Reprinted from Okamura and Katabuchi [12] with permission of Int Rev Cytol.)

2.5 Theories on the Pathogenesis of Endometriosis

Because of the different locations, possible organs, appearances, and hormone responsiveness, many theories on the pathogenesis of endometriosis have been proposed over about one century. However, no single theory is sufficient to explain the development of this enigmatic disease.

2.5.1 Transplantation

The theory of transplantation implies that the endometrium is replaced from the uterus to another location inside the body. Many different ways of dissemination of endometrial tissue are involved in this concept. Iatrogenic, lymphogenic, and hematogenic spread account for uncommon, extraperitoneal lesion of endometriosis [1314]. The most easily understood, scientifically supported, and widely accepted mechanism for the histogenesis of endometriosis is that, at menstruation, some effluent flows retrograde through the lumen of fallopian tubes into the peritoneal cavity (Fig. 2.2). Indeed, the high frequency of this phenomenon is supported by the finding of menstrual blood in the peritoneal fluid of up to 90 % of women with patent fallopian tubes undergoing laparoscopy during the perimenstrual period [16]. 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 the immune clearance system, during the courses of attachment to the ovarian surface epithelium and peritoneal mesothelium, invasion of the epithelium, establishment of local neurovascularity, and continued growth and survival are necessary if endometriosis is to develop from retrograde passage of the endometrium.


Fig. 2.2

Histogenesis of endometriosis. (a) Exfoliated endometrial tissue (left arrow) floating in the tubal cavity. (b) Endometrial tissue (left arrow) adhering to the peritoneum. Hematoxylin–eosin stain, (a) ×40, (b) ×100 (Reprinted from Katabuchi [15] with permission of J Japan Societ Endo.)

2.5.2 Coelomic Metaplasia

The theory of coelomic metaplasia suggests that the mesothelium of the peritoneum including ovarian surface epithelium (OSE) can be transformed into endometrium by metaplasia. The müllerian ducts, which constitute the primordial uterus, are generated through intrusion of the coelomic epithelium in the antenatal stage. For this reason, it has been proposed secondary müllerian system; the organs derived from müllerian duct are generated from the same origin as that of the peritoneal mesothelium and OSE [817]. The peritoneal mesothelium and OSE may undergo metaplasia into the endometrial epithelium and stroma, thereby inducing endometriosis. We rarely come across the histological evidence for this metaplastic progression in the ovarian surface as shown in Fig. 2.3 [17]. Moreover, in the observation of morphological changes in a collagen-embedded culture system of the human OSE [18], the OSE and the coculture of OSE with endometrial stromal cells (ES) showed a luminal structure with estradiol (E2) supplementary (Fig. 2.4a–c), and, in the OSE/ES coculture, the nuclear position was deviated toward the basal side and the appearance of cilia was observed [19]. The OSE/ES coculture was positive for epithelial membrane antigen (EMA) and cytokeratin, indicating differentiation into glandular cells, while the epithelium of the OSE culture was negative for EMA. These findings suggest that the OSE can differentiate into glandular cells and that E2 and endometrial stromal cells are involved in this process. Thus, flow of endometrial stromal cells in the menstrual blood back through the fallopian tube may be an important factor in the development of endometriosis [1820].


Fig. 2.3

Progression of a cyst enclosed in the ovary to endometriosis. Single layer of the surface epithelium in the cortex of the ovary, which formed the cyst, moved to the glandular epithelium of the endometrium (right arrow). Hematoxylin-eosin stain, ×150 (Reprinted from Okamura and Katabuchi [17] with permission of Ital J Anat Embryol.)


Fig. 2.4

Three-dimensional collagen gel-embedded cultures of the ovarian surface epithelium (OSE). (a) In the OSE culture, a cavity formed after addition of estradiol 17β (10 ng/mL). (bc) In a coculture of OSE with the endometrial stoma, an epithelium-stoma structure formed, the surface epithelium formed a cavity with a three–dimensional structure, the position of the nucleus was biased toward the basal side, and cilia appeared. Hematoxylin–eosin stain, (a) ×200, (b) ×400; Uranyl acetate-lead citrate stain, (c) ×17,000 (Reprinted from Ohtake et al. [19] with permission of Fertil Steril.)

2.5.3 Müllerian Ducts Remnants

In the antenatal phase, the coelomic epithelium gives rise to the müllerian ducts, which constitute the fallopian tubes and the uterus and the upper portion of the vagina. During the course of differentiation and migration of the müllerian ducts and fetal organogenesis, some primordial cells might spread in the posterior pelvic floor. This might explain the findings that endometriosis is frequently found in the pouch of Douglas, uterosacral ligaments, and rectovaginal septum and even the presence of endometriosis among young women with Mayer–Rokitansky–Küster–Hauser syndrome.

2.6 The Factors Affecting the Development of Endometriosis

2.6.1 Disturbances of Hormonal Conditions

Hormonal alterations may influence the ability of endometrial cells to proliferate, attach to the mesothelium, and/or evade immune-mediated clearance [11]. Sex steroids including estradiol (E2) are found intracellularly in patients with endometriosis. Aromatase is specifically expressed in endometrial tissue and converts androstenedione to estrone (E1), which in turn is converted to E2 by 17β-hydroxysteroid dehydrogenase (17β-HSD) type 1. 17β-HSD type 2, which converts E2 to E1 for regulation of E2 activity, is found in the normal endometrium, but seems not to be expressed in the tissue of patients with endometriosis, with a consequent increase in the local concentration of E2[21]. In addition to estrogen dependence, there is increasing evidence to support a profile of P resistance in the pathophysiology of endometriosis [22]. Endometriotic lesions exhibit an overall reduction in P receptor expression relative to eutopic endometrium and absence of P receptor-B [23]. Additionally, endometrial expression profiling has documented dysregulation of P-responsive genes in the luteal phase [24]. An incomplete transition of endometrium from the proliferative to a secretory phase has significant molecular implantation of refluxed endometrial cells.

2.6.2 Familial and Genetic Factors

The upregulation of the antiapoptotic gene BCL-2 in eutopic and ectopic endometrium from women with endometriosis is reported, and a genetic alteration of endometrial cells influencing their tendency to implant may be hereditary [25]. Linkage analysis has elucidated candidate genes with biological plausibility. The largest of these involved over 1,000 families more than two affected sib pairs and established significance for a susceptibility locus in the regions of chromosome 10q26 and 7p15 [2627].

2.6.3 Inflammation

From the studies of macrophages in the female reproductive organ since the 1980s [2829], the conceptualization of endometriosis as a pelvic inflammatory condition is established. In patients with endometriosis, the peritoneal fluid is remarkable for an increased number of activated macrophages and important differences in the cytokine/chemokine profile. Macrophages produce and secrete diverse physiologically active substances including cytokines, coagulation factors, fibrinolytic factors, components of complement, plasma proteins, lipids, and enzymes. A proteomics approach identified a unique protein structurally similar to haptoglobin in the peritoneal fluid in patients with endometriosis [30]. This protein was subsequently found to bind to macrophages, reduce their phagocytic activity, and increase their production of IL-6. Other cytokines or chemokines found to be increased in the peritoneal fluid of patients with endometriosis include macrophage migration inhibitory factor, TNF-α, IL-1β, IL-6, and IL-8, regulated on activation normal T expressed and secreted, and monocyte.

2.7 Conclusions

The pathogenesis of endometriosis has been studied among major theories; however, no single theory is sufficient to explain the development of the disease. It has been suggested that peritoneal endometriosis, chocolate cysts of the ovary, and adenomyotic nodules of the rectovaginal septum or deeply infiltrating endometriosis are three different disease entities, each with a different pathogenesis. This concept leads that diverse pathological conditions underlie endometriosis and leads to the proposal of endometriosis as a series of syndromes that develop through different mechanisms depending on the host tissue or organ. Recently, a combination of the metastatic and metaplastic theories has been favored to explain that endometriosis represents a polygenetic disorder, with alterations in multiple biological pathways leading to a metaplastic process under the irritating effect of endometrial tissue shed during retrograde menstrual flow. Thus, endometriosis has a long medical and historical background and is appropriately referred to as an enigmatic disease. Clinical treatment in line with individual pathology is required because of the diverse symptoms and findings. Further assessment of the pathology of endometriosis may open the way for development of new drugs for this disease.

Co-workers in our Department

Okamura H, Matsuura K, Ohba T, Tashiro H, Fukumatsu Y, Nakamura M, Ohtake H, Motohara K, Miyamura S.



von Rokitansky C. Ueber Uterusdrusen-Neubilding in Uterus- und Ovarial – Sarcomen. Ztschr KK Gesellsch Der Aerzte zu Wien. 1860;37:577–81.


Cullen TS. Adeno-myoma uteri diffusum benignum. Johns Hopkins Hosp Bull. 1896;6:133–7.


Sampson JA. Perforating hemorrhagic cysts of the ovary. Their importance and especially their relation to adenomas of the endometrial type. Arch Surg. 1921;3:245–323.CrossRef


Sampson JA. Inguinal endometriosis. Am J Obstet Gynecol. 1925;10:462–503.


Sampson JA. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14:422–69.


Olive DL, Pritts EA. Treatment of endometriosis. N Engl J Med. 2001;345:266–75.PubMedCrossRef


Suginami H. A reappraisal of the coelomic metaplasia theory by reviewing endometriosis occurring in unusual sites and instances. Am J Obstet Gynecol. 1991;165:214–8.PubMedCrossRef


Lauchlan SC. The secondary müllerian system. Obstet Gynecol Surv. 1972;27:133–46.PubMedCrossRef


Clement PB. Reactive tumor-like lesions of the peritoneum. Am J Clin Pathol. 1995;103:673–6.PubMed


Lauchlan SC. The secondary Müllerian system revisited. Int J Gynecol Pathol. 1994;13:73–9.PubMedCrossRef


Kitawaki 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;83:149–55.PubMedCrossRef


Okamura H, Katabuchi H. Pathophysiological dynamics of human ovarian surface epithelial cells in epithelial ovarian carcinogenesis. Int Rev Cytol. 2005;242:1–54.PubMedCrossRef


Ridley JH. Pathogenesis of endometriosis. A review of facts and fancies. Obstet Gynecol Surv. 1968;23:1–35.CrossRef


Victory R, Diamond MP, Johns DA. Villar’s node: a case report and systematic review of endometriosis externa of the umbilicous. J Mnim Invasive Gynecol. 2007;14:23–33.CrossRef


Katabuchi H. J Japan Societ Endo. 2009.


Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol. 1984;64:151–4.PubMed


Okamura H, Katabuchi H. Detailed morphology of human ovarian surface epithelium focusing on its metaplastic and neoplastic capability. Ital J Anat Embryol. 2001;106:263–76.PubMed


Nakamura M, Katabuchi H, Ohba T, Fukumatsu Y, Okamura H. Isolation, growth and characteristics of human ovarian surface epithelium. Virchows Arch. 1994;424:59–67.PubMedCrossRef


Ohtake H, Katabuchi H, Matsuura K, Okamura H. A novel in vitro experimental model for ovarian endometriosis: the three-dimensional culture of human ovarian surface epithelial cells in collagen gels. Fertil Steril. 1999;71:50–5.PubMedCrossRef


Okamura H, Katabuchi H, Nitta M, Ohtake H. Structural changes and cell properties of human ovarian surface epithelium in ovarian pathophysiology. Microsc Res Tech. 2006;69:469–81.PubMedCrossRef


Zeitoun K, Takayama K, Sasano H, Suzuki T, Moghrabi N, Andersson S, Johns A, Meng L, Putman M, Carr B, Bulun SE. Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol. J Clin Endocrinol Metab. 1998;83:4474–80.PubMed


Bulun SE, Cheng YH, Yin P, Imir G, Utsunomiya H, Attae E, Innes J, Julie KJ. Progesterone resistance in endometriosis: link to failure to metabolize estradiol. Mol Cell Endocrinol. 2006;248:94–103.PubMedCrossRef


Attia GR, Zeitoun K, Edward D, Johns A, Carr BR, Bulun SE. Progesterone receptor isoform A but not B is expressed in endometriosis. J Clin Endocrinol Metab. 2000;85:2897–902.PubMed


Burney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M, Nezhat CR, Lessey BA, Giudice LC. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology. 2007;148:3814–26.PubMedCrossRef


Jones RK, Searle RF, Bulmer JN. Apoptosis and bcl-2 expression in normal human endometrium, endometriosis and adenomyosis. Hum Reprod. 1998;13:3496–502.PubMedCrossRef


Treloar SA, Wicks J, Nyholt DR, Montgomery GW, Bahlo M, Smith V, Dawson G, Mackay IJ, Weeks DE, Bennett ST, Carey A, Ewen-White KR, Duffy DL, O’Connor DT, Barlow DH, Martin NG, Kennedy SH. 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;77:365–76.PubMedCentralPubMedCrossRef


Painter JN, Anderson CA, Nyholt DR, Macgregor S, Lin J, Lee SH, Lambert A, Zhao ZZ, Roseman F, Guo Q, Gordon SD, Wallace L, Henders AK, Visscher PM, Kraft P, Martin NG, Morris AP, Treloar SA, Kennedy SH, Missmer SA, Montgomery GW, Zondervan KT. Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis. Nat Genet. 2011;43:51–4.PubMedCentralPubMedCrossRef


Fukumatsu Y, Katabuchi H, Miyamura S, Matsuura K, Okamura H, Naito M, Takahashi K. Activated macrophages in the peritoneal fluid of women with endometriosis: examination of the intracytoplasmic localization of endogenous peroxidase and interleukin-1. Acta Obst Gynaec Jpn. 1992;44:529–36.


Okamura H, Katabuchi H, Kanzaki H. Macrophages in reproductive biology. In: Lewis C, Burke B, editors. The Macrophages. London: Oxford University Press; 2002. p. 548–76.


Sharpe-Timms KL, Piva M, Ricke EA, Surewicz K, Zhang YL, Zimmmer RL. Endometriotic lesions synthesize and secrete a haptoglobin-like protein. Biol Reprod. 1998;58:988–94.PubMedCrossRef