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.

The pathogenesis and treatment of polycystic ovary syndrome: What’s new?

“…An interesting alternative was proposed recently by Vinaixa et al, who subjected non-obese women with PCOS to 3-month flutamide-metformin-pioglitazone polytherapy combined with ester-progestogen treatment, pointing to the benefit of such treatment with respect to the lipid profile (reduced LDL, increased HDL) higher androgen levels as well as increased carotid intima media (CIM) thickness, which in turn prevents the occurrence of atherosclerosis and related complications. 29 Another alternative is the use of thiazolidinedione derivatives, which stimulate peroxisome proliferator-activated receptor type γ (PPAR-γ), enhance insulin sensitivity, reduce the level of glucose. However, these drugs do not reduce androgen levels and can contribute to patients' weight gain; in addition, they are contraindicated for women wishing to become pregnant.…”

Mechanism by which Metformin Influence Metabolic Changes in Human: A Systematic-Review

“…The studies by Henk den Ouden et al [23] and Irving et al [24] examining treatment with metformin alone for 5 years and in combination with pioglitazone for 3 months showed a decrease in the plasma glucose concentration. The results of studies by Henk den Ouden et al [23] Irving et al [24] and Vinaixa et al [26] showed a significant decrease in blood glutamate levels compared to those before treatment. Treatment with metformin 850 mg/d, pioglitazone 7.5 mg/d, and flutamide 62.5 mg/d in PCOS showed an approximately 54.0% decrease in glutamate levels [26] and another study indicated a 17.0% decrease [24] in these levels at 3 months follow-up after combination therapy.…”

“…The results of studies by Henk den Ouden et al [23] Irving et al [24] and Vinaixa et al [26] showed a significant decrease in blood glutamate levels compared to those before treatment. Treatment with metformin 850 mg/d, pioglitazone 7.5 mg/d, and flutamide 62.5 mg/d in PCOS showed an approximately 54.0% decrease in glutamate levels [26] and another study indicated a 17.0% decrease [24] in these levels at 3 months follow-up after combination therapy. Moreover, the results of the study by Vinaixa et al showed that the serum levels of lysine, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol varied considerably; the levels of lysine and LDL cholesterol decreased by approximately 45.0% and 5.28%, respectively; however, the HDL cholesterol levels increased by 34.0%.…”

“…We identified many metabolites according to (1) various disease types (e.g., healthy [22] T2DM [9,[22][23][24][25] [26] (2) diverse number of patients (n=9 to 151); (3) different doses of metformin and its treatment period in the included trials (the shortest treatment period, 12 h and the longest follow-up period, 7 years); and (4) various analytical techniques used to identify metabolites from biological fluids (e.g., gas chromatography mass spectrometry [GC/MS], liquid chromatography mass spectrometry [LC/MS] and nuclear magnetic resonance [NMR]). We evaluated further details in the full-text article and included literature on the "metformin medication" regardless of above all conditions.…”

“…Preiss et al [25] showed that metformin monotherapy in 86 patients with coronary disease for 18 months induced a decrease in the levels of aromatic amino acid metabolites such as tyrosine by 10% and phenylalanine by 4% and an increase in the levels of alanine by approximately 16%. Henk den Ouden et al [26] showed that the levels of HbA1c as an indicator of T2DM decreased after metformin administration at 5 years follow up in 132 patients with T2DM and 82 controls. Samino et al [8] and Irving et al [27] showed a decrease in insulin levels in the clinical blood specimen.…”