title: Molecular Mechanisms of Androstenediol in the Regulation of the Proliferative Process of Human Endometrial Cells.
abstract: Proliferation in endometria of women with polycystic ovarian syndrome (PCOS) is increased, similar to the biosynthesis of androstenediol (estrogenic metabolite). As previously shown, in human endometrial cells, androstenediol increases CYCLIN D1 levels and KI67 and decreases P27 content. The objective of the present investigation was to determine the mechanisms by which androstenediol promotes endometrial cell-cycle progression. Estrogen receptor α (ERα) activation and changes in CYCLIN D1 and P27 levels were evaluated by Western blot in T-HESC and St-T1b endometrial cell lines, using receptor antagonists; activation of PI3K-protein kinase B (AKT) and mitogen-activated protein kinases-extracellular signal-regulated kinases (MAPK-ERK)1/2 pathways was evaluated using PI3K, MAPK/ERK kinase (MEK)1/2, and RNA-polymerase II inhibitors. The data showed that androstenediol treatment significantly increases CYCLIN D1 and decreases P27 levels through ERα activation ( P < .05). In addition, an increase in AKT/ERK1/2 phosphorylations was determined ( P < .05). In the presence of RNA-polymerase II inhibitor, phosphorylation of AKT/ERK1/2 decreased ( P < .05), meaning that endometrial cells need transcriptional activity to activate the kinases involved. It was also observed that PI3K action is required for P27 and CYCLIN D1 changes. Therefore, the action of androstenediol in endometria depends on PI3K-AKT and MAPK-ERK1/2 pathways activation, together with cell transcriptional machinery. This could be of clinical significance, as in pathologies such as PCOS, increased endometrial levels of androstenediol together with a high prevalence of endometrial hyperplasia and adenocarcinoma have been reported.
authors.affiliation: 1 Department of Obstetrics and Gynecology, School of Medicine, University of Chile Clinical Hospital, Santiago, Chile.
authors.forename: Francisca
authors.initials: F
authors.lastname: Plaza-Parrochia
authors.affiliation: 1 Department of Obstetrics and Gynecology, School of Medicine, University of Chile Clinical Hospital, Santiago, Chile.
authors.forename: Lorena
authors.initials: L
authors.lastname: Oróstica
authors.affiliation: 1 Department of Obstetrics and Gynecology, School of Medicine, University of Chile Clinical Hospital, Santiago, Chile.
authors.forename: Paula
authors.initials: P
authors.lastname: García
authors.affiliation: 1 Department of Obstetrics and Gynecology, School of Medicine, University of Chile Clinical Hospital, Santiago, Chile.
authors.forename: Carolina
authors.initials: C
authors.lastname: Vera
authors.affiliation: 1 Department of Obstetrics and Gynecology, School of Medicine, University of Chile Clinical Hospital, Santiago, Chile.
authors.forename: Carmen
authors.initials: C
authors.lastname: Romero
authors.affiliation: 2 Institute of Nutrition and Food Technology, University of Chile, Macul, Chile.
authors.forename: Luis
authors.initials: L
authors.lastname: Valladares
authors.affiliation: 1 Department of Obstetrics and Gynecology, School of Medicine, University of Chile Clinical Hospital, Santiago, Chile.
authors.forename: Margarita
authors.initials: M
authors.lastname: Vega
mesh_terms: D015114:Androstenediol / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D004717:Endometrium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology
chemical_list: D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D009570:Nitriles; D000081082:Phosphoinositide-3 Kinase Inhibitors; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D013739:Testosterone; D004958:Estradiol; D015114:Androstenediol; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: MAPK; PCOS; PI3 K; androstenediol; endometria