Serum metabolomic profiling reveals potential biomarkers in assessing the management of women with polycystic ovary syndrome: a randomized controlled trial

Xuesong Ding, Yan Deng, Yanfang Wang, Wei Xue, Shiyang Zhu, Xiao Ma, Ruilin Ma, Aijun Sun, Xuesong Ding, Yan Deng, Yanfang Wang, Wei Xue, Shiyang Zhu, Xiao Ma, Ruilin Ma, Aijun Sun

Abstract

Background: As one of the most common endocrinal disorders for women at childbearing age, the diagnostic criteria of polycystic ovary syndrome (PCOS) have been defined differently among different international health organizations. Phenotypic heterogeneity of PCOS also brings about difficulties for its diagnosis and management assessment. Therefore, more efficient biomarkers representing the progression of PCOS are expected to be integrated into the monitoring of management process using metabolomic approaches.

Methods: In this prospective randomized controlled trial, 117 PCOS patients were enrolled from December 2016 to September 2017. Classical diagnostic parameters, blood glucose, and metabolome were measured in these patients before and at 2 months and 3 months of different medical interventions. The receiver operating characteristic (ROC) curves were built based on multivariate statistical analysis using data at baseline and 3 months' management, and combinational biomarkers with appreciable sensitivity and specificity were selected, which then validated with data collected at 2 months.

Results: A set of metabolites including glutamic acid, aspartic acid, 1-methylnicotinamide, acetylcarnitine, glycerophosphocholine, and oleamide were filtered out with high performance in representing the improvement through 3-month management of PCOS with high sensitivity and specificity in ROC analysis and validation with other two groups showed an appreciable area under the curve over 0.96.

Conclusions: The six metabolites were representative of the remission of PCOS through medical intervention, making them a set of potential biomarkers for assessing the outcome of PCOS management.

Trial registration: ClinicalTrials.gov, NCT03264638.

Conflict of interest statement

None.

Copyright © 2021 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.

Figures

Figure 1
Figure 1
The fold enrichment of metabolites.
Figure 2
Figure 2
Abundance of the set of six metabolites after various medications. (A) Methylnicotinamide, (B) acetylcarnitine, (C) glutamic acid, (D) aspartic acid, (E) glycerophosphocholine, and (F) oleamide. Groups A1, B1, and C1 are from serums before drug treatment. Groups A2, B2, and C2 as well as Groups A3, B3, and C3 are the ones after taking 2-month and 3-month medicine, respectively.
Figure 3
Figure 3
ROC curves of the set of six metabolites. Methylnicotinamide, acetylcarnitine, glutamic acid, aspartic acid, glycerophosphocholine, and oleamide were used to evaluate drug efficacy in the group of (A) herbal medicine, (B) western drug. ROC: Receiver operating characteristic.
Figure 4
Figure 4
The predicted class probabilities for (A) herbal medicine, (B) western drug, (C) combo drugs after 2-month treatment using the set of six metabolites.

References

    1. Azziz R, Carmina E, Chen Z, Dunaif A, Laven JSE, Legro RS, et al. . Polycystic ovary syndrome. Nat Rev Dis Primers 2016; 2:16057.doi: 10.1038/nrdp.2016.57.
    1. Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, et al. . Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril 2018; 110:364–379. doi: 10.1016/j.fertnstert.2018.05.004.
    1. Kim JJ, Choi YM. Phenotype and genotype of polycystic ovary syndrome in Asia: ethnic differences. J Obstet Gynaecol Res 2019; 45:2330–2337. doi: 10.1111/jog.14132.
    1. Zamboni N, Saghatelian A, Patti GJ. Defining the metabolome: size, flux, and regulation. Mol Cell 2015; 58:699–706. doi: 10.1016/j.molcel.2015.04.021.
    1. Lu X, Zhao X, Bai C, Zhao C, Lu G, Xu G. LC-MS-based metabonomics analysis. J Chromatogr B Analyt Technol Biomed Life Sci 2008; 866:64–76. doi: 10.1016/j.jchromb.2007.10.022.
    1. Theodoridis G, Gika HG, Wilson ID. LC-MS-based methodology for global metabolite profiling in metabonomics/metabolomics. TrAC Trends Anal Chem 2008; 27:251–260. doi: 10.1016/j.trac.2008.01.008.
    1. Brindle JT, Antti H, Holmes E, Tranter G, Nicholson JK, Bethell HWL, et al. . Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1 H-NMR-based metabonomics. Nat Med 2002; 8:1439–1444. doi: 10.1038/nm1202-802.
    1. Zhao X, Fritsche J, Wang J, Chen J, Rittig K, Schmitt-Kopplin P, et al. . Metabonomic fingerprints of fasting plasma and spot urine reveal human pre-diabetic metabolic traits. Metabolomics 2010; 6:362–374. doi: 10.1007/s11306-010-0203-1.
    1. Barrio JR, Egbert JE, Henze E, Schelbert HR, Baumgartner FJ. L-[4-11C] aspartic acid: enzymic synthesis, myocardial uptake, and metabolism. J Med Chem 1982; 25:93–96. doi: 10.1021/jm00343a020.
    1. Digerness SB, Reddy WJ. The malate-aspartate shuttle in heart mitochondria. J Mol Cell Cardiol 1976; 8:779–785. doi: 10.1016/0022-2828(76)90084-5.
    1. Levine ES, Crozier RA, Black IB, Plummer MR. Brain-derived neurotrophic factor modulates hippocampal synaptic transmission by increasing N-methyl-D-aspartic acid receptor activity. Proc Natl Acad Sci U S A 1998; 95:10235–10239. doi: 10.1073/pnas.95.17.10235.
    1. Lima TT, Begnini J, de Bastiani J, Fialho DB, Jurach A, Ribeiro MC, et al. . Pharmacological evidence for GABAergic and glutamatergic involvement in the convulsant and behavioral effects of glutaric acid. Brain Res 1998; 802:55–60. doi: 10.1016/s0006-8993(98)00563-0.
    1. Mühlhausen C, Burckhardt BC, Hagos Y, Burckhardt G, Keyser B, Lukacs Z, et al. . Membrane translocation of glutaric acid and its derivatives. J Inherit Metab Dis 2008; 31:188–193. doi: 10.1007/s10545-008-0825-x.
    1. Jakubowski A, Sternak M, Jablonski K, Ciszek-Lenda M, Marcinkiewicz J, Chlopicki S. 1-Methylnicotinamide protects against liver injury induced by concanavalin A via a prostacyclin-dependent mechanism: a possible involvement of IL-4 and TNF-α. Int Immunopharmacol 2016; 31:98–104. doi: 10.1016/j.intimp.2015.11.032.
    1. Mateuszuk L, Jasztal A, Maslak E, Gasior-Glogowska M, Baranska M, Sitek B, et al. . Antiatherosclerotic effects of 1-Methylnicotinamide in apolipoprotein E/low-density lipoprotein receptor – deficient mice: a comparison with nicotinic acid. J Pharmacol Exp Ther 2016; 356:514–524. doi: 10.1124/jpet.115.228643.
    1. Hajra AK, Bishop JE. Glycerolipid biosynthesis in peroxisomes via the acyl dihydroxyacetone phosphate pathway. Ann N Y Acad Sci 1982; 386:170–182. doi: 10.1111/j.1749-6632.1982.tb21415.x.
    1. Sonkar K, Ayyappan V, Tressler CM, Adelaja O, Cai R, Cheng M, et al. . Focus on the glycerophosphocholine pathway in choline phospholipid metabolism of cancer. NMR Biomed 2019; 32:e4112.doi: 10.1002/nbm.4112.
    1. Hiley CR, Hoi PM. Oleamide: a fatty acid amide signaling molecule in the cardiovascular system? Cardiovasc Drug Rev 2007; 25:46–60. doi: 10.1111/j.1527-3466.2007.00004.x.
    1. Amsterdam ESHRE/ASRM-Sponsered 3rd PCOS ConsensusWorkshop Group. Consensus on women's health aspects of polycystic ovary syndrome (PCOS). Hum Reprod 2012; 27:14–24. doi: 10.1093/humrep/der396.
    1. Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS, Carmina E, et al. . American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome – part 1. Endocr Pract 2015; 21:1291–1300. doi: 10.4158/EP15748.DSC.
    1. Diamanti-Kandarakis E, Christakou CD. Farid NR, Diamanti-Kandarakis E. Insulin Resistance in PCOS. Diagnosis and Management of Polycystic Ovary Syndrome. Boston, MA: Springer; 2009. 35–61. doi:10.1007/978-0-387-09718-3_4.
    1. Huang Q, Yin P, Wang J, Chen J, Kong H, Lu X, et al. . Method for liver tissue metabolic profiling study and its application in type 2 diabetic rats based on ultra performance liquid chromatography – mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2011; 879:961–967. doi: 10.1016/j.jchromb.2011.03.009.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner