Retinoic Acid Biosynthesis Is Impaired in Human and Murine Endometriosis1

Abstract

Endometriosis is characterized by the presence of endometrial glands and stroma in extrauterine sites. Our objective was to determine whether endometriotic lesions (ELs) from women with endometriosis have altered retinoid levels compared with their eutopic endometrium, and to test the hypothesis that defects in all-trans retinoic acid (ATRA) biosynthesis in EL is related to reduced expression of cellular retinol-binding protein type 1 (RBP1). Retinoids were evaluated by liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography in eutopic endometrial biopsies (EBs) and ELs from 42 patients with pathologically confirmed endometriosis. The ATRA levels were reduced, whereas the retinol and retinyl ester concentrations were elevated in EL compared with EB tissue. Similar results were found in a mouse model of endometriosis that used green fluorescent protein-positive endometrial tissue injected into the peritoneum of syngeneic hosts to mimic retrograde menses. The ATRA biosynthesis in vitro in retinol-treated primary human endometrial stromal cell (ESC) cultures derived from ELs was reduced compared with that of ESCs derived from patient-matched EBs. Correspondingly, RBP1 expression was reduced in tissue and ESCs derived from EL versus EB. Rbp1(-/-) mice showed reduced endometrial ATRA concentrations compared with wild type, associated with loss of tissue organization and hypercellularity. These findings provide the first quantitative measurements of ATRA in human endometrium and endometriosis, demonstrating reduced ATRA in ectopic tissue and corresponding ESC cultures. Quantitation of retinoids in murine endometriosis and in Rbp1(-/-) mice supports the contention that impaired ATRA synthesis caused by reduced RBP1 promotes an "endometriosis phenotype" that enables cells to implant and grow at ectopic sites.

Physiological and pathological implications of retinoid action in the endometrium

“…Although the theories of endometriosis histogenesis remain controversial, recent findings suggest that defective epigenetic landscape possibly associated with deficient differentiation of endometrial tissue stem cells is a central mechanism responsible for the cellular origins of endometriosis (Bulun et al 2015). Meanwhile, retinoid pathway is fundamentally flawed in endometriotic tissues and even systemically in women with endometriosis (Pavone et al 2010, Pierzchalski et al 2014, Taylor et al 2015.…”

“…ALDH1A2 expression levels were significantly reduced in endometriotic tissue and stromal cells (Table 4), resulting in reduced RA levels. Pierzchalski et al (2014) directly quantified RA levels and biosynthesis from retinol in endometrial stromal cells, which were derived from corresponding eutopic and ectopic biopsies; retinol uptake and RA production predominantly occur in these stromal cells (Vermot et al 2000, Pavone et al 2011, Yamagata et al 2014 (Fig. 1).…”

“…As previously mentioned, excess RA concentration is harmful to decidualization and implantation. Thus, actual retinoid concentrations in the endometrium, as have been performed in some limited studies (Pierzchalski et al 2014), should be measured in future studies.…”

“…In addition, accumulating evidence shows that an aberrant RA metabolism can be a critical factor in the development of endometriosis (Pavone et al 2011, Wieser et al 2012, Pierzchalski et al 2014, Yamagata et al 2015, a common gynecological disease that affects up to 10% of reproductive-age women. This disease is characterized by the ectopic localization of endometrial-like tissues in the pelvic cavity, and its pathogenesis involves uncontrollable cell proliferation and is associated with local invasion and distant metastasis.…”

“…RA plays fundamental roles in the normal maintenance of endometrial physiology (Zheng et al 2000, Sidell et al 2002, Ding et al 2003, Kuroda et al 2013, and aberrant RA metabolism might be a predisposing factor for the development of endometriosis (Pavone et al 2011, Wieser et al 2012, Pierzchalski et al 2014, Yamagata et al 2015. However, a comprehensive and systematic analysis and understanding of RA pathway in endometrial physiology and pathology remain lacking.…”