Deep nodular endometriosis : from observational studies to experimental model

Endometriosis is one of the most frequent benign gynecological diseases and is known to occur in 7-10% of women of reproductive age. It is now well established that three different forms of endometriosis must be considered in the pelvis: peritoneal endometriosis, ovarian endometriosis and deep endometriotic nodules of the rectovaginal septum. Most of these lesions originate from the posterior part of the cervix (types II & III) and secondarily infiltrate the anterior wall of the rectum (type III).\nThis study focuses on the characterization of deep endometriotic nodules, and more specifically type III nodules, which are one the most painful and least characterized forms of endometriosis. Our main objective was to gain further insights into invasion processes leading to infiltration of the rectal wall and surrounding organs by endometriotic lesions (proliferation of glands and stroma). The project was divided into 5 parts:\n1. In the first part, we reported the largest clinical series of surgical removal of type III deep endometriotic nodules. Our data confirm that a conservative surgical approach offers good results in terms of quality of life, recurrence and pregnancy. When compared to the existing literature, the shaving technique has a lower complication rate than more radical surgery. The shaving technique should be offered as a first-line surgical approach in case of type III nodules. Bowel resection should be reserved for cases with complete stenosis, whose prevalence is relatively low (less than 2%).\n2. In the second part, we described iatrogenic adenomyotic lesions. Radiological, laparoscopic, and histological findings in iatrogenic nodules were similar to those in type III nodular endometriosis. Indeed, iatrogenic lesions were found to resemble adenomyomas, circumscribed nodular aggregates of smooth muscle, endometrial glands and stroma. From analysis of these lesions, the role of the junctional zone (JZ) was highlighted. Indeed, we proved that a fragment of tissue containing both endometrium and subendometrial myometrium (the so-called JZ) was able to induce adenomyotic tumor development.\n3. In the third part, we induced endometriotic nodules in an experimental baboon model, mimicking human deep nodular endometriotic lesions. It was demonstrated that induced nodular endometriotic lesions were significantly larger and showed a stronger invasion process when tissue specimens containing the JZ were grafted. In this experimental model, the JZ was also found to be a key element in the process of proliferation and invasion of induced nodular lesions.\n4. In the fourth part, we analyzed nerve densities in type III nodules and induced experimental nodules. As NFD was confirmed to be high in human endometriotic nodules, and most of these nerve fibers were found to be unmyelinated, they could well be implicated in pain. Moreover, we demonstrated that deep nodular lesions may be neuroattractive through the action of NGF. In the experimental model, nerve fiber density was investigated and the kinetics of neurogenesis was considered. Increased expression of NGF, together with the low NFD observed in experimental lesions, suggest that these lesions actually recruit nerve fibers.\n5. Our clinical results (type III nodules and iatrogenic adenomyotic lesions) and data from baboons show morphological similarities, confirming that multicellular coordination between the leading (invasive) edge and the training (cohesive) edge is mandatory. This explains the good results of the surgical technique used in our department, which removes the cohesive part of the nodule.\nIn conclusion, this study evidences clear similarities between the baboon model and spontaneous disease observed in humans. This model could therefore be used in the future to explore the invasion process of the disease, validate medical or surgical strategies in terms of pain, fertility and disease recurrence, and finally explain the pathophysiology of deep nodular endometriosis.