Metabolic profiles characterizing different phenotypes of polycystic ovary syndrome: plasma metabolomics analysis

Yue Zhao, Li Fu, Rong Li, Li-Na Wang, Yan Yang, Na-Na Liu, Chun-Mei Zhang, Ying Wang, Ping Liu, Bin-Bin Tu, Xue Zhang, Jie Qiao, Yue Zhao, Li Fu, Rong Li, Li-Na Wang, Yan Yang, Na-Na Liu, Chun-Mei Zhang, Ying Wang, Ping Liu, Bin-Bin Tu, Xue Zhang, Jie Qiao

Abstract

Background: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder accompanied with an increased risk of developing type 2 diabetes mellitus and cardiovascular disease; despite being a common condition, the pathogenesis of PCOS remains unclear. Our aim was to investigate the potential metabolic profiles for different phenotypes of PCOS, as well as for the early prognosis of complications.

Methods: A total of 217 women with PCOS and 48 healthy women as normal controls were studied. Plasma samples of subjects were tested using two different analytical platforms of metabolomics: 1H nuclear magnetic resonance (NMR) and gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS).

Results: Our results showed that carbohydrate, lipid and amino acid metabolisms were influenced in PCOS. The levels of lactate, long-chain fatty acids, triglyceride and very low-density lipoprotein were elevated, while glucose, phosphatidylcholine and high-density lipoprotein (HDL) concentrations were reduced in PCOS patients as compared with controls. Additionally, the levels of alanine, valine, serine, threonine, ornithine, phenylalanine, tyrosine and tryptophan were generally increased, whereas the levels of glycine and proline were significantly reduced in PCOS samples compared to controls. Furthermore, the ratio of branched-chain amino acid to aromatic amino acid concentrations (BCAA/AAA) in PCOS plasma was significantly reduced in PCOS patients and was insusceptible to obesity and insulin sensitivity.

Conclusions: Our results suggested that the enhanced glycolysis and inhibited tricarboxylic acid cycle (TAC) in women with PCOS. Decrease of BCAA/AAA ratio was directly correlated with the development of PCOS. Ovulatory dysfunction of PCOS patients was associated with raised production of serine, threonine, phenylalanine, tyrosine and ornithine. Elevated levels of valine and leucine, and decreased concentrations of glycine in PCOS plasma could contribute to insulin sensitivity and could be considered as the potential biomarkers for long-term risk assessment of diabetes mellitus.

Figures

Figure 1
Figure 1
1H nuclear magnetic resonance (NMR) analysis. Orthogonal signal correction/principal component analysis (OSC-PCA) scores plot (left column) and loadings plots (right column) for Carr-Purcell-Meiboom-Gill (CPMG) 1H-NMR spectra of plasma from the four phenotypes of polycystic ovary syndrome (PCOS) patients (red squares) and controls (black triangles). (A) PCOS patients with hyperandrogenism (HA), anovulation (AO) and polycystic ovaries (PCO) (HA+AO+PCO) vs controls; (B) PCOS patients with anovulation and polycystic ovaries (AO+PCO) vs controls; (C) PCOS patients with hyperandrogenism and anovulation (HA+AO) vs controls; (D) PCOS patients with hyperandrogenism and polycystic ovaries (HA+PCO) vs controls.
Figure 2
Figure 2
Gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS) analysis. Orthogonal signal correction/partial least squares (OSC-PLS) scores plot of GC/TOF-MS data of plasma from the four phenotypes of polycystic ovary syndrome (PCOS) patients (red squares) and the controls (black triangles). (A) PCOS patients with hyperandrogenism (HA), anovulation (AO) and polycystic ovaries (PCO) (HA+AO+PCO) vs controls; (B) PCOS patients (AO+PCO) vs controls; (C) PCOS patients (HA+AO) vs controls; (D) PCOS patients (HA+PCO) vs controls.
Figure 3
Figure 3
Metabolic pathways associated with polycystic ovary syndrome (PCOS) development. The schematic map was modified from [17], with permission from the American Chemical Society (copyright (2007)). Amino acid metabolic pathways are grouped according to their points of entry into the tricarboxylic acid (TCA) cycle, glycolysis, ketogenesis, lipolysis, proteolysis and urea cycles. Glucogenic amino acids can be broken down into one of the following metabolites: pyruvate (Ala, Ser, Thr, Try, Gly, Cys), α-ketoglutarate (KGA) (Pro, Arg, His, Glu, Orn, Cit), succinyl CoA (Val, Thr, Ile, Met), fumarate (Phe, Tyr) or oxaloacetate (OAA) (Asp); while ketogenic amino acids can be broken down into acetoacetyl-CoA (Phe, Tyr, Trp, Lys, Leu) or acetyl-CoA (Ile, Leu, Try). The increase (red) and decrease (blue) of metabolites concentrations in the PCOS plasma were on the basis of both our data and previous report (reduction of arginine and citrate in PCOS patients [19]). The glycolysis, lipolysis and proteolysis pathways were induced in women with PCOS, whereas the TCA cycle and ketogenesis were inhibited in PCOS. Fatty acids included linoleic acid, palmic acid and stearic acid. Amino acids are abbreviated using the standard three-letter convention. AA = amino acids; ACAC-CoA = acetoacetyl-CoA; ASA = argininosuccinate.

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