title: Downregulation of autophagy gene expression in endometria from women with polycystic ovary syndrome.
abstract: Autophagy, a process of controlled cellular self-digestion, could be involved in cyclic remodeling of the human endometrium. We investigated endometrial mRNA expression of 23 autophagy-related (ATG) genes and transcription factors in healthy controls (n = 12) and anovulatory polycystic ovary syndrome (PCOS) patients (n = 24), as well as in their subgroup (n = 12) before and after metformin treatment. The mRNA levels of transcription factor forkhead box protein O1 (FOXO1) and several molecules involved in autophagosome formation (ATG13, RB1-inducible coiled-coil 1), autophagosome nucleation (ATG14, beclin 1, SH3-domain GRB2-like endophilin B1), autophagosome elongation (ATG3, ATG5, γ-aminobutyric acid receptor-associated protein - GABARAP), and delivery of ubiquitinated proteins to autophagosomes (sequestosome 1), were significantly reduced in anovulatory PCOS compared to healthy endometrium. Free androgen index, but not free estrogen index, insulin levels, or body mass index, negatively correlated with the endometrial expression of ATG3, ATG14, and GABARAP in PCOS patients. Treatment of PCOS patients with metformin (2 g/day for 3 months) significantly increased the endometrial mRNA levels of FOXO1, ATG3, and UV radiation resistance-associated gene. These data suggest that increased androgen availability in PCOS is associated with metformin-sensitive transcriptional downregulation of endometrial autophagy.
authors.affiliation: Clinic for Endocrinology, Diabetes, and Diseases of Metabolism, Clinical Center of Serbia, Belgrade, Serbia; School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Sumarac-Dumanovic
authors.affiliation: School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Milica
authors.initials: M
authors.lastname: Apostolovic
authors.affiliation: Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
authors.forename: Kristina
authors.initials: K
authors.lastname: Janjetovic
authors.affiliation: Clinic for Endocrinology, Diabetes, and Diseases of Metabolism, Clinical Center of Serbia, Belgrade, Serbia.
authors.forename: Danka
authors.initials: D
authors.lastname: Jeremic
authors.affiliation: Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Dusan
authors.initials: D
authors.lastname: Popadic
authors.affiliation: MediGroup General Hospital, Belgrade, Serbia.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Ljubic
authors.affiliation: School of Medicine, University of Belgrade, Belgrade, Serbia; Clinic for Gynecology and Obstetrics, Clinical Center of Serbia, Belgrade, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Micic
authors.affiliation: School of Medicine, University of Belgrade, Belgrade, Serbia; Clinic for Gynecology and Obstetrics, Clinical Center of Serbia, Belgrade, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Dukanac-Stamenkovic
authors.affiliation: Clinic for Gynecology and Obstetrics, Clinical Center of Nis, Nis, Serbia.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Tubic
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Darko
authors.initials: D
authors.lastname: Stevanovic
authors.affiliation: School of Medicine, University of Belgrade, Belgrade, Serbia. Electronic address: dragan.micic@med.bg.ac.rs.
authors.forename: Dragan
authors.initials: D
authors.lastname: Micic
authors.affiliation: Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia. Electronic address: vtrajkovic@med.bg.ac.rs.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trajkovic
mesh_terms: D000328:Adult; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D016022:Case-Control Studies; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use; D011085:Polycystic Ovary Syndrome / Q000188:drug therapy / Q000235:genetics*
chemical_list: D008687:Metformin
keywords: Autophagy; Autophagy-related genes; Endometrium; Free androgen index; Polycystic ovary syndrome