Redefining endometriosis: Is deep endometriosis a progressive disease?

I.A. Brosens1,3 and J.J. Brosens2

1 Leuven Institute for Fertility and Embryology, Leuven, Belgium, and 2 Department of Reproductive Sciences and Medicine, Division of Paediatrics, Obstetrics and Gynaecology, ICSM at Hammersmith Hospital, London, UK


    Introduction
 Top
 Introduction
 The microenvironment determines...
 Peritoneal and ovarian...
 Deep endometriosis is...
 Endometriotic adenomyotic...
 Clinical implications
 References
 
Current literature on endometriosis distinguishes between superficial and deep lesions. Deep lesions are assumed to reflect invasive and progressive disease. The American Fertility Society classification system for endometriosis (American Fertility Society, 1985Go) distinguishes lesions, which extend below the surface of the peritoneum and the ovaries by <1, 1–3 and >3 cm and scores them 2–8 times higher than superficial lesions. More recently, some authors have recommended to make a distinction at 6 mm, suggesting that lesions deeper than 5 mm represent progressive disease (Cornillie et al., 1990Go).

The concept of deep, and therefore progressive disease is based on Sampson's hypothesis that endometriosis is due to the menstrual dissemination into the peritoneal cavity (Sampson, 1927Go). Although this view may appear logical, there is little evidence that superficial endometriosis progresses to deep endometriosis. Before Sampson the localizations of ectopic endometrial-like tissue were described (Cullen, 1920Go) to occur principally along the Müllerian tract, including the inner third of the myometrium (adenomyosis), the posterior fornix and the uterine ligaments. All these lesions were described as adenomyotic nodules. On the other hand, Sampson (1921) discovered endometriosis by observing menstrual shedding in endometrial-like tissue lining the wall of chocolate cysts of the ovary (Sampson, 1921Go). When Sampson's reflux concept became generally accepted, all ectopic, endometrial-like tissue outside the uterus became endometriosis and as a consequence the confusing terminology of deep endometriosis was introduced. In this debate we will try to demonstrate that the classification of endometriosis should not be based on depth, but on the expression of a specific endometrial activity: sex steroid hormone-dependent bleeding or smooth muscle metaplasia.


    The microenvironment determines the phenotype of endometrial tissue
 Top
 Introduction
 The microenvironment determines...
 Peritoneal and ovarian...
 Deep endometriosis is...
 Endometriotic adenomyotic...
 Clinical implications
 References
 
Tabibzadeh et al. performed elegant in-vitro studies to address the mechanisms underlying the spatial polarization of the eutopic endometrium into the basal and superficial layers (Tabibzadeh et al., 1993Go). They demonstrated that the `classical' sex steroid hormone (SSH)-dependent differentiation of endometrial cells can be abrogated by factors, e.g. interferon-{gamma} which are released in the eutopic endometrium by resident CD3-positive T-lymphocyte aggregates in the endometrio–myometrial junction. The absence of a `classical' SSH-dependent differentiation process in the basal layer does not imply cellular refractoriness to ovarian hormones. The basal endometrial layer is the site of active cyclic metaplasia of the basal endometrial stromal cells into myofibroblasts and vice versa (Fujii et al., 1989Go) and a source of factors, e.g. endothelins and prostaglandins, that modulate the response of underlying junctional zone myometrium to ovarian hormones (Bacon et al., 1995Go). Evidence for metaplasia can be found in the endometrium, e.g. decidual stromal cells express {alpha}-smooth muscle actin and show ultrastructural similarities with myofibroblasts (Oliver et al., 1999Go). In summary, the morphological endometrial activity is manifested in the superficial layer by predecidualization and menstrual bleeding and in the basal layer/junctional zone compartment by cyclic smooth muscle metaplasia and differentiation. Active ectopic endometrial-like tissue is also morphologically characterized by either cyclic bleeding and endometrioma formation or smooth mucle metaplasia and fibromuscular nodule formation.


    Peritoneal and ovarian endometriosis are characterized by hormone-dependent bleeding
 Top
 Introduction
 The microenvironment determines...
 Peritoneal and ovarian...
 Deep endometriosis is...
 Endometriotic adenomyotic...
 Clinical implications
 References
 
In peritoneal and ovarian endometriosis the endometrial activity is characterized by menstrual shedding or SSH-dependent bleeding, as originally observed and described (Sampson, 1921Go). Peritoneal lesions are most active when they are superficial and haemorrhagic and become less active when they heal by fibrosis to become deeper and form fibrotic nodules (Nisolle and Donnez, 1997Go).

The typical ovarian endometrioma is an even more striking example of superficial endometrial activity. Detailed histopathological studies have been based on ovaries with the chocolate cyst in situ. Sampson (1921) showed on such specimens that foci of endometrial-like tissue are lining the wall and manifesting menstrual shedding.

Hughesdon (1957) found no evidence that `ectopic endometrium ate its way into the ovary like insects eating into an apple'. On resected specimens the endometrial tissue can appear deep due to tangential section, dislocation or, as documented in detail on an in-situ specimen by Sampson (1921), by early colonization of a lutein cyst at the site of communication with a small endometrioma. Our endoscopic investigations of large in-situ endometriomata, complemented by selective biopsies, have shown that in young women where fibrosis is absent, the endometrial lining is patchily distributed and loosely attached to the white ovarian cortex (Brosens et al., 1994Go). These observations have led to the hypothesis that the chocolate cyst is secondary to an endometriotic bleeding involving adhesions and retraction and giving rise to invagination of the ovarian cortex as previously suggested (Hughesdon, 1957Go) and to colonization of the wall by superficial endometrial tissue.

Whatever the exact origin, there is now ample evidence from histological and histochemical studies that the endometrial lining of the endometrioma has, at least focally, the specific features of superficial endometrium by the type of vascularization (Nisolle and Donnez, 1997Go), the expression of matrix metalloproteinase-1 (MMP-1) mRNA (Kokerine et al., 1997Go) and the occurrence of menstrual shedding (Nieminen, 1962Go), indicating that tissues responses to oestrogen and progesterone mimic that of superficial endometrium.

Deep ovarian endometriosis is a misnomer: first, a typical endometrioma is not on the inside, but on the outside of the ovary and secondly, the endometriotic tissue on the inside is morphologically and functionally similar to superficial endometrium.


    Deep endometriosis is adenomyosis
 Top
 Introduction
 The microenvironment determines...
 Peritoneal and ovarian...
 Deep endometriosis is...
 Endometriotic adenomyotic...
 Clinical implications
 References
 
When Sampson's concept of endometriosis became generally accepted, the disease was defined histologically by the presence of glands and stroma and indirectly by visual or histological signs of SSH bleeding. This conceptual definition disregarded the other phenotype, which was originally described as adenomyoma and characterized by features of basal endometrium/junctional zone myometrium. Recently, magnetic resonance imaging has allowed to visualize the principal locations of this phenotype almost exactly as previously described (Cullen, 1920Go).

In a series of 39 excisional specimens of deep peritoneal endometriosis we found specimens with purely fibrotic tissue, sclerotic tissue with glands and adenomyosis (Brosens, 1994Go). Clearly, `deep endometriosis' can represent as well inactive, fibrotic tissue as active, haemorrhagic or adenomyotic disease.

At the posterior fornix or rectovaginal space, the lesions are morphologically similar to uterine adenomyosis and have rarely a plane of cleavage with the surrounding fibromuscular tissues of the cervix or ligaments. The surgical consequences can be illustrated by a recent case report, in which a pregnancy following laparoscopic resection of `deep rectovaginal endometriosis' resulted in rupture of the posterior lower uterine segment (Van de Putte et al., 1999Go).


    Endometriotic adenomyotic disease is characterized by pleiotropic reproductive abnormalities
 Top
 Introduction
 The microenvironment determines...
 Peritoneal and ovarian...
 Deep endometriosis is...
 Endometriotic adenomyotic...
 Clinical implications
 References
 
Endometriosis is characterized by a low-grade sterile inflammation of the pelvic peritoneum, which is manifested by an increase in peritoneal fluid volume, macrophages number, degree of activation of macrophages and concentration of macrophages secretory product, i.e. prostaglandins, proteolytic enzymes, cytokines and growth factors, although the concentration of these factors usually shows a wide variation between patients (Haney et al., 1991Go). The disease is further characterized by impaired T-cell mediated cytotoxicity (Dmowski et al., 1981Go), natural killer (NK) cell activity (Oosterlynck et al., 1991Go) and B-cell function (Badawy et al., 1984Go). Downstream signalling intermediates of these growth factors and cytokines may bind to the nuclear SSH receptor and modulate expression of SSH-dependent genes in eutopic endometrium (Kalkhoven et al., 1996Go).

The effect of proinflammatory cytokines, interleukin (IL)-1 and tumour necrosis factor (TNF)-{alpha}, on steroid biosynthesis may explain the reduced granulosa cell steroidogenesis (Harlow et al., 1996Go) and the delayed rise of plasma progesterone following the luteinizing hormone (LH) peak in the presence of even mild endometriosis (Brosens et al., 1978Go). Using the new endoscopic technique of transvaginal hydrolaparoscopy, the systematic inspection of ovaries by hydroflotation shows that even mild endometriosis is associated in most cases with periovarian adhesions (Gordts et al., 1999Go; Campo et al., 1999Go).

Although histologically normal, recent biochemical examination of the endometrium and imaging studies of the junctional zone in women with endometriosis have revealed profound disturbances. The eutopic endometrium in women with adenomyosis or endometriosis is also characterized by aberrant responses to ovarian hormones, e.g. the expression of aromatase (Noble et al., 1997Go), dysregulation of IL-6 production (Tseng et al., 1996Go), and impaired temporal expression of ß3 integrin (Ota et al., 1997) and HOX genes (Taylor et al., 1999Go). Disruption of the specific micro-environment in the basal endometrium may also explain the structural and functional abnormalities of the junctional zone, such as hyperperistalsis, dysperistalsis and inordinate smooth muscle proliferation, associated with endometriosis and adenomyosis (Leyendecker et al., 1996Go). Magnetic resonance imaging (MRI) revealed a high correlation between endometriosis and adenomyosis in first degree relatives (Kennedy et al., 1998Go), suggesting that both are phenotypes of a single disorder rather than two distinct disease entities.


    Clinical implications
 Top
 Introduction
 The microenvironment determines...
 Peritoneal and ovarian...
 Deep endometriosis is...
 Endometriotic adenomyotic...
 Clinical implications
 References
 
The classification of ectopic endometrial-like lesions by their dominant endometrial activity has clinical consequences. First, the present confusion of superficial, deep, pseudo-deep, free, enclosed, invasive, metaplastic and progressive endometriosis can be clarified by the evaluation of the dominant endometrial activity of the lesion (Brosens, 1993Go). The two dominant phenotypes of ectopic endometrium largely depend on the topography: (i) along the Müllerian duct, including the uterus, the fornices (including the so-called `rectovaginal septum') and to some extent the uterine ligaments the dominant phenotype is adenomyosis; and (ii) outside the Müllerian duct on the peritoneum and the ovaries the dominant phenotype is endometriosis.

The first phenotype is characterized by a poor `classical' progesterone response of glands and stroma, but differentiation and proliferation of connective tissue and smooth muscle, which is similar to the basal endometrium response to SSH. The second phenotype is similar to superficial endometrium and is characterized by SSH-dependent bleeding as long as the lesion has not healed by fibrosis. It should, however, be noted that adenomyosis may be associated with microendometriomata, as seen in the uterus when it reaches the outer myometrium, or in posterior fornix, when it reaches the loose tissue underlying the vaginal or rectal wall. Similarly, the ovarian endometrioma can be associated with smooth muscle metaplasia of the surrounding fibromuscular structures.

Secondly, MRI is increasingly being explored for the diagnosis of endometriosis and adenomyosis (Mark et al., 1987Go; Takahashi et al., 1994Go; Rheinhold et al., 1998Go). The technique is expensive, but on the other hand, laparoscopy is invasive and responsible for almost 70% of the cost of the fertility investigation. Laparoscopy is a poor technique for the diagnosis of adenomyotic lesions, while MRI has the ability to distinguish between haemorrhagic and the adenomyotic lesions. New developments of rectal, vaginal and intrauterine coils make it likely that the MRI technique will become the gold standard for the diagnosis and differentiation between endometriosis and adenomyosis.

Thirdly, the endometriotic and adenomyotic lesions have a different SSH response. The therapeutic approach is therefore likely to differ. Recurrent ectopic bleeding is a defining feature of endometriosis and the medical suppression of recurrent ectopic bleeding can be a therapeutic target (Brosens, 1997Go; Deprest et al., 1997Go). Smooth muscle cell differentiation and proliferation is a defining feature of adenomyosis and possibly another new therapeutic target.


    Acknowledgments
 
This work was supported by a Wellcome Trust Clinician Scientist Fellowship (54043) to J.J.B.


    Notes
 
3 To whom correspondence should be addressed Back

This debate was previously published on Webtrack 89, October 6, 1999


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 Clinical implications
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