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.
Highlights
Hyperandrogenemia, insulin resistance, a state of low-grade inflammation, body adiposity and a pro-atherogenic lipid profile are usually present in adolescents and young women with polycystic ovary syndrome (PCOS) [1,2,3]
It has been reported that the addition of low-dose pioglitazone (Pio, a PPARc agonist) to the aforementioned polytherapy confers further reductions of visceral fat and carotid intima-media thickness (IMT), and increases further circulating high molecular-weight (HMW) adiponectin [10,11,12,13]
Our results suggest that the Pio/Flu/Met polytherapy has a dramatic effect on the lipoprotein profile of PCOS patients
Summary
Hyperandrogenemia, insulin resistance, a state of low-grade inflammation, body adiposity and a pro-atherogenic lipid profile are usually present in adolescents and young women with polycystic ovary syndrome (PCOS) [1,2,3]. PCOS may accelerate the development of a cardiovascular-risk profile even in the absence of clinical signs of atherosclerosis. Whether this adverse pro-atherogenic profile and the enhanced oxidant status may increase the risk for cardiovascular disease remains unclear [7,8,9]. The phenotypic evidences demonstrate endocrine-metabolic improvements in a wide spectrum of long-term health markers, the molecular mechanisms underlying such polytherapy remain to be elucidated
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