title: Retinoic acid biosynthesis is impaired in human and murine endometriosis.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland.
authors.forename: Keely
authors.initials: K
authors.lastname: Pierzchalski
authors.affiliation: Department of Obstetrics & Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Taylor
authors.affiliation: Nezhat Medical Center, Atlanta, Georgia.
authors.forename: Ceana
authors.initials: C
authors.lastname: Nezhat
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland.
authors.forename: Jace W
authors.initials: JW
authors.lastname: Jones
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, California.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Napoli
authors.affiliation: Department of Gynecology & Obstetrics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Guixiang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland mkane@rx.umaryland.edu.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Kane
authors.affiliation: Department of Gynecology & Obstetrics, Emory University School of Medicine, Atlanta, Georgia nsidell@emory.edu.
authors.forename: Neil
authors.initials: N
authors.lastname: Sidell
mesh_terms: D000818:Animals; D004715:Endometriosis / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D018345:Mice, Knockout; D054840:Retinol-Binding Proteins, Cellular / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D014212:Tretinoin / Q000378:metabolism*
chemical_list: C518456:RBP1 protein, human; C518457:Rbp1 protein, mouse; D054840:Retinol-Binding Proteins, Cellular; D014212:Tretinoin
keywords: RBP1; endometriosis; retinoic acid