Metabolomic Biomarkers in Polycystic Ovary Syndrome: A Review of the Evidence

Simon Alesi; Drishti Ghelani; Aya Mousa

doi:10.1055/s-0041-1729841

Seminars in Reproductive Medicine, Table of Contents

Semin Reprod Med 2021; 39(03/04): 102-110
DOI: 10.1055/s-0041-1729841

Review Article

Metabolomic Biomarkers in Polycystic Ovary Syndrome: A Review of the Evidence

Simon Alesi‡^*

¹Monash Centre for Health Research and Implementation (MCHRI), School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia

,

Drishti Ghelani‡^*

¹Monash Centre for Health Research and Implementation (MCHRI), School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia

,

Aya Mousa

¹Monash Centre for Health Research and Implementation (MCHRI), School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia

› Author Affiliations

Abstract

Polycystic ovary syndrome (PCOS) is an endocrinologic condition affecting one in five women of reproductive age. PCOS is often characterized by disruptions to the menstrual cycle, development of male-pattern hair growth (hirsutism), and polycystic ovary morphology. Recently, PCOS has been linked to metabolic dysfunction, with 40 to 80% of women characterized as overweight or obese. Despite these well-known negative health effects of PCOS, 75% of sufferers remain undiagnosed. This is most likely due to the variability in symptom presentation and the lack of a definitive test for the condition. Metabolomics, which is a platform used to analyze and characterize a large number of metabolites, has recently been proposed as a potential tool for investigating the metabolic pathways that could be involved in the pathophysiology of PCOS. In doing so, novel biomarkers could be identified to improve diagnosis and treatment of PCOS. This review aims to summarize the findings of recent metabolomic studies that highlight metabolic-specific molecules which are deranged in PCOS, to identify potential biomarkers for the condition. Current limitations for metabolomic studies are discussed, as well as future directions to progress the field toward further validation and integration into clinical practice.

Keywords

polycystic ovary syndrome - metabolomics - biomarkers - metabolites

Full Text

References

References
1 Apridonidze T, Essah PA, Iuorno MJ, Nestler JE. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90 (04) 1929-1935
2 Wolf WM, Wattick RA, Kinkade ON, Olfert MD. Geographical prevalence of polycystic ovary syndrome as determined by region and race/ethnicity. Int J Environ Res Public Health 2018; 15 (11) 15
3 Boyle J, Teede HJ. Polycystic ovary syndrome: an update. Reprod Health 2011
4 Rosenfield RL, Ehrmann DA. The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev 2016; 37 (05) 467-520
5 Sam S. Obesity and polycystic ovary syndrome. Obes Manag 2007; 3 (02) 69-73
6 Kamangar F, Okhovat JP, Schmidt T. et al. Polycystic ovary syndrome: special diagnostic and therapeutic considerations for children. Pediatr Dermatol 2015; 32 (05) 571-578
7 Johnson CH, Gonzalez FJ. Challenges and opportunities of metabolomics. J Cell Physiol 2012; 227 (08) 2975-2981
8 Omabe M, Elom S, Omabe KN. Emerging metabolomics biomarkers of polycystic ovarian syndrome; targeting the master metabolic disrupters for diagnosis and treatment. Endocr Metab Immune Disord Drug Targets 2018; 18 (03) 221-229
9 Wilroy Jr RS, Givens JR, Wiser WL, Coleman SA, Andersen RN, Summitt RL. Hyperthecosis: an inheritable form of polycystic ovarian disease. Birth Defects Orig Artic Ser 1975; 11 (04) 81-85
10 Govind A, Obhrai MS, Clayton RN. Polycystic ovaries are inherited as an autosomal dominant trait: analysis of 29 polycystic ovary syndrome and 10 control families. J Clin Endocrinol Metab 1999; 84 (01) 38-43
11 Rutkowska AZ, Diamanti-Kandarakis E. Polycystic ovary syndrome and environmental toxins. Fertil Steril 2016; 106 (04) 948-958
12 Teede HJ, Joham AE, Paul E. et al. Longitudinal weight gain in women identified with polycystic ovary syndrome: results of an observational study in young women. Obesity (Silver Spring) 2013; 21 (08) 1526-1532
13 Mikhael S, Punjala-Patel A, Gavrilova-Jordan L. Hypothalamic-pituitary-ovarian axis disorders impacting female fertility. Biomedicines 2019; 7 (01) 7
14 Tanguturi SC, Nagarakanti S. Polycystic ovary syndrome and periodontal disease: underlying links—a review. Indian J Endocrinol Metab 2018; 22 (02) 267-273
15 Pasquali R, Zanotti L, Fanelli F. et al. Defining hyperandrogenism in women with polycystic ovary syndrome: a challenging perspective. J Clin Endocrinol Metab 2016; 101 (05) 2013-2022
16 Lakkakula BV, Thangavelu M, Godla UR. Genetic variants associated with insulin signaling and glucose homeostasis in the pathogenesis of insulin resistance in polycystic ovary syndrome: a systematic review. J Assist Reprod Genet 2013; 30 (07) 883-895
17 Rodriguez Paris V, Bertoldo MJ. The mechanism of androgen actions in PCOS etiology. Med Sci (Basel) 2019; 7 (09) 7
18 Franks S. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: in defense of the Rotterdam criteria. J Clin Endocrinol Metab 2006; 91 (03) 786-789
19 Lujan ME, Chizen DR, Pierson RA. Diagnostic criteria for polycystic ovary syndrome: pitfalls and controversies. J Obstet Gynaecol Can 2008; 30 (08) 671-679
20 Sanchez-Garrido MA, Tena-Sempere M. Metabolic dysfunction in polycystic ovary syndrome: pathogenic role of androgen excess and potential therapeutic strategies. Mol Metab 2020; 35: 100937
21 Rosenfield RL. Clinical review: identifying children at risk for polycystic ovary syndrome. J Clin Endocrinol Metab 2007; 92 (03) 787-796
22 Bremer AA. Polycystic ovary syndrome in the pediatric population. Metab Syndr Relat Disord 2010; 8 (05) 375-394
23 Hasin Y, Seldin M, Lusis A. Multi-omics approaches to disease. Genome Biol 2017; 18 (01) 83
24 Pinu FR, Goldansaz SA, Jaine J. Translational metabolomics: current challenges and future opportunities. Metabolites 2019; 9 (06) 9
25 Ni C-M, Huang W-L, Jiang Y-M. et al. Improving the accuracy and efficacy of diagnosing polycystic ovary syndrome by integrating metabolomics with clinical characteristics: study protocol for a randomized controlled trial. Trials 2020; 21 (01) 169
26 Goodacre R, Vaidyanathan S, Dunn WB, Harrigan GG, Kell DB. Metabolomics by numbers: acquiring and understanding global metabolite data. Trends Biotechnol 2004; 22 (05) 245-252
27 Rajska A, Buszewska-Forajta M, Rachoń D, Markuszewski MJ. Metabolomic insight into polycystic ovary syndrome-an overview. Int J Mol Sci 2020; 21 (14) 21
28 Segers K, Declerck S, Mangelings D, Heyden YV, Eeckhaut AV. Analytical techniques for metabolomic studies: a review. Bioanalysis 2019; 11 (24) 2297-2318
29 Wishart DS, Feunang YD, Marcu A. et al. HMDB 4.0: the human metabolome database for 2018. Nucleic Acids Res 2018; 46 (D1): D608-D617
30 Griffin JL, Nicholls AW, Daykin CA. et al. Standard reporting requirements for biological samples in metabolomics experiments: mammalian/in vivo experiments. Metabolomics 2007; 3: 179-188
31 Legro RS, Kunselman AR, Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am J Med 2001; 111 (08) 607-613
32 Yilmaz M, Biri A, Bukan N. et al. Levels of lipoprotein and homocysteine in non-obese and obese patients with polycystic ovary syndrome. Gynecol Endocrinol 2005; 20 (05) 258-263
33 Wild RA, Painter PC, Coulson PB, Carruth KB, Ranney GB. Lipoprotein lipid concentrations and cardiovascular risk in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1985; 61 (05) 946-951
34 Pirwany IR, Fleming R, Greer IA, Packard CJ, Sattar N. Lipids and lipoprotein subfractions in women with PCOS: relationship to metabolic and endocrine parameters. Clin Endocrinol (Oxf) 2001; 54 (04) 447-453
35 Daghestani MH, Daghestani M, Daghistani M. et al. A study of ghrelin and leptin levels and their relationship to metabolic profiles in obese and lean Saudi women with polycystic ovary syndrome (PCOS). Lipids Health Dis 2018; 17 (01) 195
36 Schiffer L, Barnard L, Baranowski ES. et al. Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review. J Steroid Biochem Mol Biol 2019; 194: 105439
37 Askarpour M, Hadi A, Symonds ME. et al. Efficacy of l-carnitine supplementation for management of blood lipids: a systematic review and dose-response meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis 2019; 29 (11) 1151-1167
38 Chang AY, Lalia AZ, Jenkins GD. et al. Combining a nontargeted and targeted metabolomics approach to identify metabolic pathways significantly altered in polycystic ovary syndrome. Metabolism 2017; 71: 52-63
39 Samimi M, Jamilian M, Ebrahimi FA, Rahimi M, Tajbakhsh B, Asemi Z. Oral carnitine supplementation reduces body weight and insulin resistance in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Clin Endocrinol (Oxf) 2016; 84 (06) 851-857
40 Jamilian H, Jamilian M, Samimi M. et al. Oral carnitine supplementation influences mental health parameters and biomarkers of oxidative stress in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Gynecol Endocrinol 2017; 33 (06) 442-447
41 Escobar-Morreale HF, Samino S, Insenser M. et al. Metabolic heterogeneity in polycystic ovary syndrome is determined by obesity: plasma metabolomic approach using GC-MS. Clin Chem 2012; 58 (06) 999-1009
42 Niu Z, Lin N, Gu R, Sun Y, Feng Y. Associations between insulin resistance, free fatty acids, and oocyte quality in polycystic ovary syndrome during in vitro fertilization. J Clin Endocrinol Metab 2014; 99 (11) E2269-E2276
43 Zhang ZH, Vaziri ND, Wei F, Cheng XL, Bai X, Zhao YY. An integrated lipidomics and metabolomics reveal nephroprotective effect and biochemical mechanism of Rheum officinale in chronic renal failure. Sci Rep 2016; 6: 22151
44 Vonica CL, Ilie IR, Socaciu C. et al. Lipidomics biomarkers in women with polycystic ovary syndrome (PCOS) using ultra-high performance liquid chromatography-quadrupole time of flight electrospray in a positive ionization mode mass spectrometry. Scand J Clin Lab Invest 2019; 79 (06) 437-442
45 Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev 2014; 2014: 360438
46 Li J, Xie LM, Song JL. et al. Alterations of sphingolipid metabolism in different types of polycystic ovary syndrome. Sci Rep 2019; 9 (01) 3204
47 Moran LJ, Mundra PA, Teede HJ, Meikle PJ. The association of the lipidomic profile with features of polycystic ovary syndrome. J Mol Endocrinol 2017; 59 (01) 93-104
48 Haoula Z, Ravipati S, Stekel DJ. et al. Lipidomic analysis of plasma samples from women with polycystic ovary syndrome. Metabolomics 2015; 11 (03) 657-666
49 Ezeh U, Yildiz BO, Azziz R. Referral bias in defining the phenotype and prevalence of obesity in polycystic ovary syndrome. J Clin Endocrinol Metab 2013; 98 (06) E1088-E1096
50 Wild RA, Rizzo M, Clifton S, Carmina E. Lipid levels in polycystic ovary syndrome: systematic review and meta-analysis. Fertil Steril 2011; 95 (03) 1073-9.e1 , 11
51 Chen YX, Zhang XJ, Huang J. et al. UHPLC/Q-TOFMS-based plasma metabolomics of polycystic ovary syndrome patients with and without insulin resistance. J Pharm Biomed Anal 2016; 121: 141-150
52 Jia C, Xu H, Xu Y, Xu Y, Shi Q. Serum metabolomics analysis of patients with polycystic ovary syndrome by mass spectrometry. Mol Reprod Dev 2019; 86 (03) 292-297
53 Zhao Y, Fu L, Li R. et al. Metabolic profiles characterizing different phenotypes of polycystic ovary syndrome: plasma metabolomics analysis. BMC Med 2012; 10: 153-153
54 Iwase M, Sonoki K, Sasaki N. et al. Lysophosphatidylcholine contents in plasma LDL in patients with type 2 diabetes mellitus: relation with lipoprotein-associated phospholipase A2 and effects of simvastatin treatment. Atherosclerosis 2008; 196 (02) 931-936
55 Pérez-Chacón G, Astudillo AM, Ruipérez V, Balboa MA, Balsinde J. Signaling role for lysophosphatidylcholine acyltransferase 3 in receptor-regulated arachidonic acid reacylation reactions in human monocytes. J Immunol 2010; 184 (02) 1071-1078
56 Yea K, Kim J, Yoon JH. et al. Lysophosphatidylcholine activates adipocyte glucose uptake and lowers blood glucose levels in murine models of diabetes. J Biol Chem 2009; 284 (49) 33833-33840
57 Barber MN, Risis S, Yang C. et al. Plasma lysophosphatidylcholine levels are reduced in obesity and type 2 diabetes. PLoS One 2012; 7 (07) e41456
58 Zhao X, Fritsche J, Wang J. et al. Metabonomic fingerprints of fasting plasma and spot urine reveal human pre-diabetic metabolic traits. Metabolomics 2010; 6 (03) 362-374
59 Flanagan JL, Simmons PA, Vehige J, Willcox MD, Garrett Q. Role of carnitine in disease. Nutr Metab (Lond) 2010; 7: 30
60 Salehpour S, Nazari L, Hoseini S, Moghaddam PB, Gachkar L. Effects of l–carnitine on polycystic ovary syndrome. JBRA Assist Reprod 2019; 23 (04) 392-395
61 Unni SN, Lakshman LR, Vaidyanathan K, Subhakumari KN, Menon NL. Alterations in the levels of plasma amino acids in polycystic ovary syndrome--a pilot study. Indian J Med Res 2015; 142 (05) 549-554
62 RoyChoudhury S, Mishra BP, Khan T. et al. Serum metabolomics of Indian women with polycystic ovary syndrome using (1)h NMR coupled with a pattern recognition approach. Mol Biosyst 2016; 12: 3407-3416
63 Huffman KM, Shah SH, Stevens RD. et al. Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women. Diabetes Care 2009; 32 (09) 1678-1683
64 Tai ES, Tan ML, Stevens RD. et al. Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia 2010; 53 (04) 757-767
65 Wang TJ, Larson MG, Vasan RS. et al. Metabolite profiles and the risk of developing diabetes. Nat Med 2011; 17 (04) 448-453
66 Newgard CB. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab 2012; 15 (05) 606-614
67 Irving BA, Carter RE, Soop M. et al. Effect of insulin sensitizer therapy on amino acids and their metabolites. Metabolism 2015; 64 (06) 720-728
68 Hou E, Zhao Y, Hang J, Qiao J. Metabolomics and correlation network analysis of follicular fluid reveals associations between l-tryptophan, l-tyrosine and polycystic ovary syndrome. Biomed Chromatogr 2020; 35 (03) e4993
69 Whigham LD, Butz DE, Dashti H. et al. Metabolic evidence of diminished lipid oxidation in women with polycystic ovary syndrome. Curr Metabolomics 2014; 2 (04) 269-278
70 Cavalcanti JH, Esteves-Ferreira AA, Quinhones CG. et al. Evolution and functional implications of the tricarboxylic acid cycle as revealed by phylogenetic analysis. Genome Biol Evol 2014; 6 (10) 2830-2848
71 Sun L, Hu W, Liu Q. et al. Metabonomics reveals plasma metabolic changes and inflammatory marker in polycystic ovary syndrome patients. J Proteome Res 2012; 11 (05) 2937-2946
72 Webb SJ, Geoghegan TE, Prough RA, Michael Miller KK. The biological actions of dehydroepiandrosterone involves multiple receptors. Drug Metab Rev 2006; 38 (1-2): 89-116
73 Zhao X, Xu F, Qi B. et al. Serum metabolomics study of polycystic ovary syndrome based on liquid chromatography-mass spectrometry. J Proteome Res 2014; 13 (02) 1101-1111
74 Buszewska-Forajta M, Rachoń D, Stefaniak A. et al. Identification of the metabolic fingerprints in women with polycystic ovary syndrome using the multiplatform metabolomics technique. J Steroid Biochem Mol Biol 2019; 186: 176-184
75 Babińska A, Siekierska-Hellmann M, Błaut K. et al. Hormonal activity in clinically silent adrenal incidentalomas. Arch Med Sci 2012; 8 (01) 97-103
76 Fan X, Jiang J, Huang Z. et al. UPLC/Q-TOF-MS based plasma metabolomics and clinical characteristics of polycystic ovarian syndrome. Mol Med Rep 2019; 19 (01) 280-292
77 Reinehr T, Kulle A, Rothermel J. et al. Longitudinal analyses of the steroid metabolome in obese PCOS girls with weight loss. Endocr Connect 2017; 6 (04) 213-224
78 Arya BK, Haq AU, Chaudhury K. Oocyte quality reflected by follicular fluid analysis in poly cystic ovary syndrome (PCOS): a hypothesis based on intermediates of energy metabolism. Med Hypotheses 2012; 78 (04) 475-478
79 Freitas C, Neto AC, Matos L. et al. Follicular fluid redox involvement for ovarian follicle growth. J Ovarian Res 2017; 10 (01) 44
80 Rice S, Christoforidis N, Gadd C. et al. Impaired insulin-dependent glucose metabolism in granulosa-lutein cells from anovulatory women with polycystic ovaries. Hum Reprod 2005; 20 (02) 373-381
81 Sun Z, Chang HM, Wang A. et al. Identification of potential metabolic biomarkers of polycystic ovary syndrome in follicular fluid by SWATH mass spectrometry. Reprod Biol Endocrinol 2019; 17 (01) 45
82 Ma X, Fan L, Meng Y. et al. Proteomic analysis of human ovaries from normal and polycystic ovarian syndrome. Mol Hum Reprod 2007; 13 (08) 527-535
83 Matharoo-Ball B, Hughes C, Lancashire L. et al. Characterization of biomarkers in polycystic ovary syndrome (PCOS) using multiple distinct proteomic platforms. J Proteome Res 2007; 6 (08) 3321-3328
84 Azziz R, Carmina E, Dewailly D. et al; Androgen Excess Society. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91 (11) 4237-4245
85 Azziz R. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature. J Clin Endocrinol Metab 2006; 91 (03) 781-785