title: Ovarian-like differentiation in eutopic and ectopic endometrioses with aberrant FSH receptor, INSL3 and GATA4/6 expression.
abstract: Endometriosis, the hormone-dependent extrauterine dissemination of endometrial tissue outside the uterus, affects 5-15% of women of reproductive age. Pathogenesis remains poorly understood as well as the estrogen production by endometriotic tissue yielding autocrine growth. Estrogens (E2) are normally produced by the ovaries. We investigated whether aberrant "ovarian-like" differentiation occurred in endometriosis. 69 women, with (n= 38) and without (n= 31) histologically proven endometriosis were recruited. Comparative RT-qPCR was performed on 20 genes in paired eutopic and ectopic lesions, together with immunohistochemistry. Functional studies were performed in primary cultures of epithelial endometriotic cells (EEC). A broaden ovarian-like differentiation was found in half eutopic and all ectopic endometriosis with aberrant expression of transcripts and protein for the transcription factors GATA4 and GATA6 triggering ovarian differentiation, for the FSH receptor (FSHR) and the ovarian hormone INSL3. Like in ovaries the FSHR induced aromatase, the key enzyme in E2 production, and vascular factors in EEC. The LH receptor (LHR) was also aberrantly expressed in a subset of ectopic endometriosis (21%) and induced strongly androgen-synthesizing enzymes and INSL3 in EEC, as in ovaries, as well as endometriotic cell growth. The ERK pathway mediates signaling by both hormones. A positive feedback loop occurred through FSHR and LHR-dependent induction of GATA4/6 in EEC, as in ovaries, enhancing the production of the steroidogenic cascade. This work highlights a novel pathophysiological mechanism with a broadly ovarian pattern of differentiation in half eutopic and all ectopic endometriosis. This study provides new tools that might improve the diagnosis of endometriosis in the future.
authors.affiliation: Faculté de Médecine Paris Sud, Univ Paris Sud, Université Paris Saclay, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Fouquet
authors.affiliation: Faculté de Médecine Paris Sud, Univ Paris Sud, Université Paris Saclay, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
authors.forename: Pietro
authors.initials: P
authors.lastname: Santulli
authors.affiliation: Erasme University Hospital, Department of Pathology, Université Libre de Bruxelles, Belgium.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Noel
authors.affiliation: Faculté de Médecine Paris Sud, Univ Paris Sud, Université Paris Saclay, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
authors.forename: Micheline
authors.initials: M
authors.lastname: Misrahi
keywords: CYP11A1, Cytochrome P450 Family 11 Subfamily A Member 1; CYP17, Cytochrome P450 Family 17 Subfamily A Member 1; CYP19A1, Cytochrome P450 Family 19 Subfamily A Member 1; EEC, Epithelial Endometriotic Cells; EGVEGF, Endocrine Gland-derived vascular endothelial growth factor; Endometriosis; FSHR; FSHR, Follicle Stimulating Hormone Receptor; GATA4/6; GATA4/6, GATA binding protein 4/6; INSL3; INSL3, Insulin Like 3; LHR; LHR, Luteinizing Hormone Receptor; Ovarian- like differentiation; PTGER, Prostaglandin E Receptor; PTGS2, Prostaglandin-Endoperoxide Synthase 2; RT-qPCR, Reverse Transcription quantitative Polymerase Chain Reaction; SF1, Steroidogenic Factor-1; VEGF, Vascular Endothelial Growth Factor