Downregulation of autophagy gene expression in endometria from women with polycystic ovary syndrome

Mirjana Sumarac-Dumanovic; Milica Apostolovic; Kristina Janjetovic; Danka Jeremic; Dusan Popadic; Aleksandar Ljubic; Jelena Micic; Jelena Dukanac-Stamenkovic; Aleksandra Tubic; Darko Stevanovic; Dragan Micic; Vladimir Trajkovic

doi:10.1016/j.mce.2016.11.009

Downregulation of autophagy gene expression in endometria from women with polycystic ovary syndrome

Mol Cell Endocrinol. 2017 Jan 15:440:116-124. doi: 10.1016/j.mce.2016.11.009. Epub 2016 Nov 11.

Affiliations

¹ Clinic for Endocrinology, Diabetes, and Diseases of Metabolism, Clinical Center of Serbia, Belgrade, Serbia; School of Medicine, University of Belgrade, Belgrade, Serbia.
² School of Medicine, University of Belgrade, Belgrade, Serbia.
³ Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
⁴ Clinic for Endocrinology, Diabetes, and Diseases of Metabolism, Clinical Center of Serbia, Belgrade, Serbia.
⁵ Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia.
⁶ MediGroup General Hospital, Belgrade, Serbia.
⁷ School of Medicine, University of Belgrade, Belgrade, Serbia; Clinic for Gynecology and Obstetrics, Clinical Center of Serbia, Belgrade, Serbia.
⁸ Clinic for Gynecology and Obstetrics, Clinical Center of Nis, Nis, Serbia.
⁹ Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
¹⁰ School of Medicine, University of Belgrade, Belgrade, Serbia. Electronic address: dragan.micic@med.bg.ac.rs.
¹¹ Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia. Electronic address: vtrajkovic@med.bg.ac.rs.

PMID: 27845161
DOI: 10.1016/j.mce.2016.11.009

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.

Keywords: Autophagy; Autophagy-related genes; Endometrium; Free androgen index; Polycystic ovary syndrome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Autophagy / drug effects
Autophagy / genetics*
Case-Control Studies
Down-Regulation / drug effects
Down-Regulation / genetics*
Endometrium / drug effects
Endometrium / metabolism*
Endometrium / pathology
Female
Gene Expression Profiling
Humans
Metformin / pharmacology
Metformin / therapeutic use
Polycystic Ovary Syndrome / drug therapy
Polycystic Ovary Syndrome / genetics*

Substances

Metformin