Time to Redefine Endometriosis Including Its Pro-fibrotic Nature

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


Hum Reprod. 2018;33(3):347-352. 

In This Article

Why Changing the Definition

There are essentially three reasons for including the term 'fibrosis' in the definition of endometriosis:

  1. Myofibroblasts and fibrosis may receive more attention as potential targets of medical treatments for endometriosis. Shifting the focus on fibrosis with a new definition may re-orient current research efforts towards more effective therapies. When considering the challenges of treating a fibrotic disease such as endometriosis, there is a pressing need to identify effective pharmacological agents to block fibrosis, in addition to seek for agents acting on ectopic endometrium (Somigliana et al., 2012). Moreover, the scientific community should pay utmost attention to the progress on the management of fibrosis in other areas of medicine. If in the future some effective and safe antifibrotic drugs will be developed for other disorders, endometriosis might benefit as well.

  2. Given the consistent presence of myofibroblasts and fibrosis in all disease forms, animal models of endometriosis should also present this feature. The current definition could lead researchers astray in this regard, as they tend to consider an animal model reliable merely because endometrium is placed at ectopic sites. However, endometriosis is much more than that and fibrosis represents a crucial histological aspect. Mouse, hamster or rat models have been developed so far by intraperitoneal or subcutaneous transplantation of autologous endometrial tissue from the same or syngeneic donors, or from humans in nude mice. 'Endometriosis' is often induced surgically by suturing fragments of uterine tissue onto the peritoneum or, in mice, an alternative procedure is to simply inject fragments of minced uterine horns from donor mice into the peritoneum of recipient animals (Mariani et al., 2012; Greaves et al., 2017). A great variety of compounds with different functional activities have been used in these models, and many of them have shown various degrees of inhibition of lesion growth (Bedaiwy et al., 2017). Unfortunately, to date, translation of these findings to the clinic has been limited, with some paradoxical but enlightening results. Raloxifene, for instance, was repeatedly demonstrated to be effective in rodent models (Altintas et al., 2010) but, when tested in women in a RCT, it even accelerated pelvic pain recurrence after surgery when compared to placebo (Stratton et al., 2008). A possible explanation could be the poor alignment of the outcome measures evaluated in the current animal models to the real nature of the disease. Disease features in an animal model should also include the evaluation of fibrosis presence that can be done in several ways (Kushiyama et al., 2011; Dong et al., 2017; Rittié, 2017) (Figure 2).

  3. A modification in the definition of endometriosis would not only aim at driving research towards more successful therapies, but may also have some immediate clinical implications. Indeed, from a diagnostic standpoint, based on histologic findings, endometriotic lesions can sometimes be misjudged. Some cases of endometriosis-related extensive pelvic adhesions may paradoxically remain without a definite diagnosis or erroneously considered long-term consequence of pelvic inflammatory disease (PID). This may be particularly true in the absence of endometriomas or deep peritoneal lesions and/or when surgical access to pelvic organs at surgery is impeded by the severity of the adhesions. In fact, extending the definition of endometriosis beyond the mere presence of ectopic endometrial tissue would allow clinicians to classify women with extensive pelvic adhesions and without evidence of past pelvic insults (such as for instance a damage of the tubal mucosa) as affected even in the absence of the two classic components of the histologic diagnosis, i.e. endometrial stroma and glands. It is noteworthy that even when available, surgical specimens are rarely serially sectioned in standard practice, and lesions with no or only small areas with endometrial lining can be missed by pathologists (Nisenblat et al., 2016). False negative diagnoses can occur if pathologists stick stringently to the current definition of endometriosis requiring the concurrent demonstration of both endometrial stroma and glands. With a cautious approach in order not to increase false positive cases, the definitive recognition of fibrosis as an essential component of endometriosis may overcome these uncertainties. Of note, the debate on the reliability of non-invasive diagnosis of endometriosis may also be influenced by a change in the definition of endometriosis. For instance, one cannot exclude that the current high accuracy of transvaginal ultrasound for the diagnosis of endometriomas (sensitivity of 93% and specificity of 94%) (Nisenblat et al., 2016) may improve further if the definition of endometriosis was modified. Sensitivity in particular may increase and transvaginal ultrasound could reach the requirements to become a replacement test (sensitivity ≥94% and specificity ≥79%) and thus definitively replace laparoscopy for the diagnosis of these lesions. It is noteworthy that for some fibrosis-based conditions such as retroperitoneal fibrosis, the diagnosis relies more upon the typical imaging features on CT or MRI, than on percutaneous biopsy (Cohan et al., 2017).

Figure 2.

Sirius red staining of an ectopic endometrial tissue in the mouse to visualize the area occupied by fibrous collagen. This stain is often used to assess a fibrotic phenomenon (Kushiyama et al., 2011; Rittié, 2017). Left panels, magnification 2.5×; right panels, magnification 16×.