title: Metabolomics reveals reduction of metabolic oxidation in women with polycystic ovary syndrome after pioglitazone-flutamide-metformin polytherapy.
abstract: Polycystic ovary syndrome (PCOS) is a variable disorder characterized by a broad spectrum of anomalies, including hyperandrogenemia, insulin resistance, dyslipidemia, body adiposity, low-grade inflammation and increased cardiovascular disease risks. Recently, a new polytherapy consisting of low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen resulted in the regulation of endocrine clinical markers in young and non-obese PCOS women. However, the metabolic processes involved in this phenotypic amelioration remain unidentified. In this work, we used NMR and MS-based untargeted metabolomics to study serum samples of young non-obese PCOS women prior to and at the end of a 30 months polytherapy receiving low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen. Our results reveal that the treatment decreased the levels of oxidized LDL particles in serum, as well as downstream metabolic oxidation products of LDL particles such as 9- and 13-HODE, azelaic acid and glutaric acid. In contrast, the radiuses of small dense LDL and large HDL particles were substantially increased after the treatment. Clinical and endocrine-metabolic markers were also monitored, showing that the level of HDL cholesterol was increased after the treatment, whereas the level of androgens and the carotid intima-media thickness were reduced. Significantly, the abundance of azelaic acid and the carotid intima-media thickness resulted in a high degree of correlation. Altogether, our results reveal that this new polytherapy markedly reverts the oxidant status of untreated PCOS women, and potentially improves the pro-atherosclerosis condition in these patients.
authors.affiliation: Metabolomics Platform of the Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders, Rovira i Virgili University, Tarragona, Spain. maria.vinaixa@urv.cat
authors.forename: Maria
authors.initials: M
authors.lastname: Vinaixa
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Rodriguez
authors.forename: Sara
authors.initials: S
authors.lastname: Samino
authors.forename: Marta
authors.initials: M
authors.lastname: Díaz
authors.forename: Antoni
authors.initials: A
authors.lastname: Beltran
authors.forename: Roger
authors.initials: R
authors.lastname: Mallol
authors.forename: Cinta
authors.initials: C
authors.lastname: Bladé
authors.forename: Lourdes
authors.initials: L
authors.lastname: Ibañez
authors.forename: Xavier
authors.initials: X
authors.lastname: Correig
authors.forename: Oscar
authors.initials: O
authors.lastname: Yanes
mesh_terms: D050153:Abdominal Fat / Q000187:drug effects / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D059168:Carotid Intima-Media Thickness; D002849:Chromatography, Gas; D002853:Chromatography, Liquid; D003998:Dicarboxylic Acids / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005485:Flutamide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006262:Health; D006801:Humans; D019787:Linoleic Acid / Q000737:chemistry / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D055432:Metabolomics / Q000379:methods*; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015999:Multivariate Analysis; D010084:Oxidation-Reduction / Q000187:drug effects; D000077205:Pioglitazone; D011085:Polycystic Ovary Syndrome / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D003998:Dicarboxylic Acids; D008074:Lipoproteins; D045162:Thiazolidinediones; D005485:Flutamide; D008687:Metformin; D019787:Linoleic Acid; C010038:azelaic acid; D000077205:Pioglitazone