Invasion of human deep nodular endometriotic lesions is associated with collective cell migration and nerve development.

OBJECTIVE: To study the mechanisms of invasion and innervation of deep endometriosis in women. DESIGN: Morphologic and immunohistochemical analysis of human endometriotic lesions. SETTING: Academic research unit. PATIENT(S): Seventeen biopsy samples of deep endometriotic lesions were collected from patients undergoing surgery for deep endometriosis. INTERVENTION(S): The endometriotic samples were divided into two parts: the front (the most invasive area of lesions, approaching rectal infiltration) and center (the area close to the posterior part of the cervix). MAIN OUTCOME(S): To elucidate: gland morphology, proliferation, and expression of adhesion molecules (ß-catenin, E-cadherin, and N-cadherin) to determine the possible role of collective cell migration (CCM) in the invasion process; and nerve growth factor (NGF) and nerve fiber density (NFD) values to shed further light on the mechanism of innervation. RESULTS: Glands from the front showed significantly reduced thickness, but significantly higher proliferation. ß-Catenin expression was similar between the lesion center and front. E-cadherin levels were significantly lower and N-cadherin levels significantly higher in glands located at the front of the lesions. Expression of matrix metalloproteinase-9 was significantly higher in glands and stromal cells located at the invasion front. NFD and NGF expression were also significantly higher at the lesion front. CONCLUSION: Although some data in the literature point to features of epithelial to mesenchymal transition in human deep nodular endometriosis, our study suggests that gland invasion in these lesions is dominated by CCM. Innervation of deep nodular endometriotic lesions may be a consequence of nerve recruitment from surrounding organs.

Ovarian endometriosis and fertility preservation: a challenge in 2018.

Endometriosis is a benign, estrogen-dependent gynecological disorder. It is now well established that three different forms of endometriosis can occur in the pelvic cavity, namely peritoneal endometriosis, ovarian endometriosis and deep endometriotic nodules of the rectovaginal septum. Treatment of endometriosis-associated infertility has been investigated using both medical and surgical modalities. Surgery for ovarian endometriosis can lead to premature ovarian insufficiency (POI) and further infertility, so one of the most important goals of therapy should be preserving fertility. Procedures combining stripping and ablation should be considered the first-line approach for ovarian endometrioma-related infertility, in order to protect the ovarian reserve, which may already be depleted even before surgery. Autotransplantation of ovarian tissue should be considered in case of mandatory radical treatment (oophorectomy), or if conservative treatment poses a risk. For patients at risk of POI, particularly those undergoing gonadotoxic treatment, two main fertility preservation options exist: oocyte vitrification or reimplantation of fresh or frozen ovarian tissue. Both have advantages and disadvantages.

Pathogenesis of uterine adenomyosis: invagination or metaplasia?

Adenomyosis is a commonly diagnosed estrogen-dependent gynecological disorder that causes pelvic pain, abnormal uterine bleeding, and infertility. Despite its prevalence and severity of symptoms, its pathogenesis and etiology have not yet been elucidated. The aim of this manuscript is to review the different hypotheses on the origin of adenomyotic lesions and the mechanisms involved in the evolution and progression of the disease. Two main theories have been proposed to explain the origin of adenomyosis. The most common suggests involvement of tissue injury and the repair mechanism and claims that adenomyosis results from invagination of the endometrial basalis into the myometrium. An alternative theory maintains that adenomyotic lesions result from metaplasia of displaced embryonic pluripotent Müllerian remnants or differentiation of adult stem cells. Previous investigations performed in human adenomyotic lesions and corroborated by studies in mice supported the involvement of the epithelial-mesenchymal transition process in the early stages of progression and spread of adenomyosis. However, studies conducted in a recently developed baboon model indicate that collective cell migration may be implicated in the later events of invasion. This suggests that the invasiveness of this complex uterine disorder is not driven by a single mechanism of migration but by a time-dependent combination of two processes.

Important role of collective cell migration and nerve fiber density in the development of deep nodular endometriosis.

OBJECTIVE: To evaluate deep nodular endometriotic lesions induced in baboons over 12 months and analyze collective cell migration and nerve fiber density. DESIGN: Morphologic and immunohistochemical analysis of endometriotic lesions induced in baboons over the course of 1 year. SETTING: Academic research unit. ANIMAL(S): Three female baboons (Papio anubis). INTERVENTION(S): Recovery of induced deep nodular endometriotic nodules from baboons. MAIN OUTCOME MEASURE(S): Evaluation of the morphology of glands by analysis of the center of lesions and the invasion front; immunohistochemical staining with Ki67, E-cadherin, and ß-catenin for investigation of mitotic activity and cell-cell junctions, and with protein gene product 9.5 and nerve growth factor (NGF) for study of nerve fiber density (NFD). RESULT(S): All (100%) of the lesions were invasive 1 year after induction, compared with 42.29% after 6 months. Glands from the invasion front showed significantly reduced thickness but significantly higher mitotic activity. E-Cadherin and ß-catenin expression were similar between the center and front. NFD was significantly higher in lesions induced after 1 year than after 6 months, and NGF expression was significantly lower in 1-year lesions than in 6-month lesions. CONCLUSION(S): Nodular endometriotic lesions induced in the baboon model were found to be significantly more invasive and innervated after 12 months than after 6 months. The invasive phenotype was highly expressed in glands at the invasion front, and our study suggests that nerve fibers play a role in the development of lesions as observed in women.