Time to Redefine Endometriosis Including Its Pro-fibrotic Nature

P. Vigano; M. Candiani; A. Monno; E. Giacomini; P. Vercellini; E. Somigliana

Disclosures

Hum Reprod. 2018;33(3):347-352. 

In This Article

Abstract and Introduction

Abstract

Endometriosis is currently defined as presence of endometrial epithelial and stromal cells at ectopic sites. This simple and straightforward definition has served us well since its original introduction. However, with advances in disease knowledge, endometrial stromal and glands have been shown to represent only a minor component of endometriotic lesions and they are often absent in some disease forms. In rectovaginal nodules, the glandular epithelium is often not surrounded by stroma and frequently no epithelium can be identified in the wall of ovarian endometriomas. On the other hand, a smooth muscle component and fibrosis represent consistent features of all disease forms. Based on these observations, we believe that the definition of endometriosis should be reconsidered and reworded as 'A fibrotic condition in which endometrial stroma and epithelium can be identified'. The main reasons for this change are: (1) to foster the evaluation of fibrosis in studies on endometriosis pathogenesis using animal models; (2) to limit potential false negative diagnoses if pathologists stick stringently to the current definition of endometriosis requiring the demonstration of endometrial stromal and glands; (3) to consider fibrosis as a potential target for treatment in endometriosis. This opinion article is aimed at boosting the attention paid to a largely neglected aspect of the disease. We hope that targeting the fibrotic process might increase success in developing new therapeutic approaches.

Introduction

With advances in knowledge, borders of diseases may change. Occasionally, these changes are large enough to require a redefinition of the disease. In endometriosis, since the original description by Sampson (1927), there have been radical changes in our vision of the disease, starting with a better description of the various manifestations and more specific pathologic findings. Moreover, our understanding continues to expand with increasing knowledge of genetics and risk factors and progresses in biological mechanisms and animal models of the disease. With these advances, clinicians and specialists in genetics, epidemiology, pathology and basic science have developed their own conceptualizations of endometriosis which are much more than the current simplistic definition that is based on the mere presence of endometrial epithelial and stromal cells in ectopic sites.

Several important issues challenge this obsolete definition. Although the presence of endometrial stromal and glands in ectopic sites may be the starting point in the pathogenesis of endometriosis, it is unquestionable that endometrial stromal and glands represent only a minor component of endometriotic lesions. Indeed, this classic pathologic evidence may even be lacking. In rectovaginal nodules, the glandular epithelium can often be observed deeply in the fibromuscolar tissue without any surrounding stroma (Donnez et al., 1996), and in 40% of ovarian endometriomas, no endometrial epithelium can be identified and the inner surface of the cyst is covered only by fibrotic tissue (Muzii et al., 2007). Finally, pelvic adhesions are typically free of endometrial components despite being an essential pathologic characteristic of the disease (Somigliana et al., 2012). It is noteworthy that pelvic adhesions may contribute to the origin of some classical endometriosis-related symptoms, such as deep dyspareunia, chronic pelvic pain and infertility, and may play a role in the formation of endometriomas or deep nodules (Somigliana et al., 2012). This opinion paper is intended as an introductory discussion article, an opening of dialog in order to consider some changes in the general definition of endometriosis. The need for a modification is also supported by previous attempts in this context (Holt and Weiss, 2000). We will emphasize the consistent presence of fibrosis and myofibroblasts in endometriotic lesions and their crucial role in the pathogenesis of the disease (Anaf et al., 2000; Barcena de Arellano et al., 2011; Zhang et al., 2016). Highlighting these features is aimed at boosting up the attention of the scientific community to a largely neglected but essential disease aspect. Ultimately, an enhanced sensitivity to fibrosis may orient the focus of researchers towards a more modern and realistic vision of endometriosis, direct animal models to the real nature of the disease, open new and more fruitful avenues of pharmacological research and increase the success of new therapeutic approaches to endometriosis, which have shown a high attrition rate during the last decades (Vercellini et al., 2011).

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