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Review

Metabolomic Insight into Polycystic Ovary Syndrome—An Overview

1
Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Hallera 107, 80-416 Gdańsk, Poland
2
Department of Clinical and Experimental Endocrinology, Medical University of Gdańsk, Dębinki 7, 80-211 Gdańsk, Poland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(14), 4853; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144853
Received: 20 May 2020 / Revised: 4 July 2020 / Accepted: 7 July 2020 / Published: 9 July 2020

Abstract

Searching for the mechanisms of the polycystic ovary syndrome (PCOS) pathophysiology has become a crucial aspect of research performed in the last decades. However, the pathogenesis of this complex and heterogeneous endocrinopathy remains unknown. Thus, there is a need to investigate the metabolic pathways, which could be involved in the pathophysiology of PCOS and to find the metabolic markers of this disorder. The application of metabolomics gives a promising insight into the research on PCOS. It is a valuable and rapidly expanding tool, enabling the discovery of novel metabolites, which may be the potential biomarkers of several metabolic and endocrine disorders. The utilization of this approach could also improve the process of diagnosis and therefore, make treatment more effective. This review article aims to summarize actual and meaningful metabolomic studies in PCOS and point to the potential biomarkers detected in serum, urine, and follicular fluid of the affected women.
Keywords: metabolomics; polycystic ovary syndrome (PCOS); metabolites; biomarkers; mass spectrometry metabolomics; polycystic ovary syndrome (PCOS); metabolites; biomarkers; mass spectrometry

1. Introduction

1.1. Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a complex endocrinopathy, which affects more than 10% of women of reproductive age [1]. It is the main cause of female infertility due to oligo- or anovulation. Despite such a high incidence, the pathogenesis of PCOS is still unexplained. Some studies suggest that it is due to the genetic factors associated with ovarian steroidogenesis [2]. According to the Androgen Excess and PCOS Society (AE&PCOS), the diagnosis of PCOS should be based on the presence of clinical and/or biochemical hyperandrogenism (HA) and the ovarian dysfunction defined as menstrual abnormalities (anovulatory oligomenorrhea (AnO)) or/and the presence of the polycystic ovary morphology (PCOM) in the transvaginal ultrasound (TV-US) [3]. These criteria yield three separate PCOS phenotypes: A, B, and C. Phenotype A includes all the three features (HA, AnO, and PCOM) whereas phenotype B and C only two (HA and AnO or HA and PCOM, respectively). However, regarding Rotterdam criteria, the fourth phenotype (D) was separated to comprise AnO and PCOM presence. The clinical symptoms of hyperandrogenism include hirsutism (present in 60% of women), androgenic alopecia, and acne, which negatively affect women’s psyche, their femininity and lead to low self-esteem and depression [4]. In addition to the reproductive and endocrine dysfunction, PCOS is characterized by intrinsic insulin resistance (IR), which lead to the development of the metabolic syndrome (MetS) and its consequences such as disturbed carbohydrate metabolism and type 2 diabetes mellitus (T2DM). Most common clinical manifestation in PCOS is abdominal obesity, which is involved in the development of dyslipidemia, arterial hypertension (AH), as well as non-alcoholic fatty liver disease (NAFLD) [5,6,7,8]. These in turn lead to the development of cardiovascular disease (CVD), which still remains the main cause of death among women [9]. The clinical picture of this complex endocrinopathy was presented in Figure 1. Therefore, the treatment of PCOS focuses not only on the symptoms of hyperandrogenism and infertility, but also on improving IR and its metabolic consequences [10]. Thus, there is a need for a better understanding of the pathomechanisms of this complex disorder through the identification of potential biomarkers with the use of new, non-invasive and specific methods. In recent years, one of the developing scientific approaches is metabolomics [11].

1.2. Metabolomic Approach in Studying the Pathogenesis of Polycystic Ovary Syndrome

Among “omics” techniques, metabolomics plays an important role in studying the potential mechanisms responsible for the development of PCOS. Metabolomics allows to identify and quantify small molecules, which occur in all living organisms [12]. The set of all human metabolites that have been identified so far is stored in the Human Metabolome Database (HMDB). Each year, the number of identified metabolites grows. Few years ago, about 41,000 metabolites were found, but now this database contains over 114,190 compounds. Among them, the following groups can be found: amino acids, lipids, peptides, vitamins, organic acids and both endo- and exogenous carbohydrates. Therefore, metabolomics serves as a valuable source of information. The metabolome indicates not only a genetically determined phenotype, but also points to the differences determined by other factors, such as age, diet, or physical activity. The application of metabolomics enables monitoring of the state of an organism and provides information on the compounds formed as a result of many biochemical processes. Any disturbances occurring in a living organism cause changes to the qualitative and quantitative profile of the metabolites. The metabolome describes both the physiological and pathological state of the organism. For this reason, it is known to be an attractive approach, compared to genomics and proteomics, which only suggest the presence of metabolic derangements that occur in the organism [13,14,15,16]. Due to this fact, the use of metabolomics in studying the pathophysiology of PCOS allows to monitor even the smallest biochemical changes in this endocrinopathy and therefore, may help in its diagnosis [17].
Among the many analytical techniques, chromatography coupled with mass spectrometry (MS) seems to be the “gold technique”. While chromatography allows for the separation of metabolites present in complex, biological samples, mass spectrometry provides specific information about the chemical structure of the compounds, such as characteristic fragmentation ions, accurate mass, and isotope distribution pattern utilized for the identification of metabolites. MS characterizes very high selectivity and sensitivity that allows to detect and measure trace amounts of metabolites [18]. The combination of MS with gas chromatography (GC-MS) and liquid chromatography (LC-MS) enables to analyse complex biological samples broadly used in metabolomics. GC-MS is suitable for volatile and non-volatile compounds, which require a derivatization step, but first of all thermally stable analytes. The LC-MS technique is widely used for targeted and non-targeted metabolomic analysis and allows to qualify and identify more polar compounds [19]. Nuclear magnetic resonance (NMR), despite its lower sensitivity than MS, allows to analyse metabolites that are difficult to ionize or require derivative reaction for MS and identify compounds with the same masses [20]. A combination of these complementary techniques enables to analyse a broader array of metabolites and offers more certain results than their separate use.

1.3. Matrices for Metabolomic Studies

The application of metabolomics allows the use of several matrices such as tissue and body fluids (i.e., plasma, serum, saliva, follicular fluid, semen). The choice of the matrices is associated with the aim of the conducted study as well as the characteristics of the studied disorder. Ovarian tissue can also be used; however, sampling is invasive and problematic. It is usually obtained during laparoscopic wedge resection surgery. For this reason, the use of ovarian tissue in studying the pathophysiology of PCOS is not very common. The matrices widely used in metabolomic studies associated with PCOS are plasma and urine. Serum and urine samples are more common, because they are easily collectible and simple to prepare. On comparing the significantly altered metabolites, it can be observed that the results obtained for both matrices do not completely overlap. The new alternative matrix is follicular fluid, which is innovative in case of PCOS research, especially in terms of oocytes maturation and their quality [21,22,23].

2. Metabolic Alterations in PCOS

PCOS includes a number of abnormalities, which influence several metabolic pathways. It is especially characterized by disturbed metabolism of the steroid hormones, amino acids, carbohydrates, lipids, purines, and the citric acid cycle. Searching for these pathological changes is possible through the metabolomic analyses of biological samples such as serum or plasma, urine, and follicular fluid. Most studies focus on serum and plasma analysis; however, other biological samples also provide substantial information on the existing biochemical derangements. In this review paper, we concentrated on metabolomic studies that were performed in the period of 2014 to 2020 and analysed different biological samples. The PubMed database was searched using the terms “polycystic ovary syndrome” or “PCOS” and “metabolomics”. The most important and actual studies using plasma, serum, urine, or FF samples were then analysed.

2.1. Metabolomic Profile Plasma and Serum Samples

Murri et al. (2014) published a valuable review where they compared few studies based on the analyses of plasma obtained from PCOS women and healthy controls [11,24,25,26,27]. In this paper, we quoted this publication and also presented the results of new studies in this field published since 2014 [28,29,30,31,32,33,34,35,36,37]. A set of metabolites found as the most characteristic for PCOS is presented in Table 1. Additionally, information about the applied technique as well as the trend of regulation is included. As can be observed, three metabolic pathways seem to characterise PCOS. Among them, metabolites connected with lipid, amino acid, as well as energy metabolism such as citric acid cycle seem to be the most common. In the case of PCOS, down-regulation of glycerophospholipid metabolism and up-regulation of glucose metabolism was observed. The results published by Zhao et al. (2012) show that all of the determined fatty acids are up-regulated in PCOS compared to the control subjects [25]. A contrary phenomenon occurs in the case of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and its derivatives lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE). Metabolites including PC, PE, LPE, and LPC are decreased. In turn, Fan et al. (2019) observed a decreased level of compounds involved in the metabolism of lecithin [36]. In several studies, androgen metabolism was also taken into account. Three major metabolites connected with elevated androgen metabolism were found, namely dehydroepiandrosterone sulphate (DHEAS), dihydrotestosterone sulphate (DHTS), and androsterone sulphate (ANDS) (Table 1). Amino acids (AAs) are the next group of endogenous compounds determined in samples collected from women with PCOS. According to the presented database, there is no homogenous pattern in AAs’ regulation. For instance, the levels of arginine, choline, citrulline, glutamate, glycine, and histidine were found to be decreased. In turn, Zhao et al. (2012) reported increased levels of endogenous AAs and glucogenic AAs [25].

2.2. Metabolomic Profile of the Urine Samples

There are relatively few metabolomic studies on PCOS where urine is used as the biological matrix. Urine samples are a convenient study material due to non-invasive sampling as well as easy sample preparation because of the lower content of protein compared to serum and plasma [38]. This matrix is also rich in metabolites of the metabolic pathways, which may be deranged in PCOS. Metabolites, which were down- and up-regulated in women with PCOS compared to healthy controls, are presented in Table 2 [39,40,41]. Zou et al. (2018) reported that some carbohydrates and fatty acids metabolites are up-regulated in PCOS in comparison with the control subjects [40]. A contrary phenomenon occurs in the case of glycerolipids, where levels of 5 out of 7 compounds are decreased, while up-regulation of triglyceride (TG) and DG (16:1(9Z)/14:0/0:0) was reported. Dhayat et al. (2018) focused on the determination of androgens in PCOS, which were all elevated [41]. A similar trend is reported for AAs, glucocorticoids, and peptides.

2.3. Metabolomic Profile of Follicular Fluid Samples

Follicular fluid (FF) is an alternative and a useful biological matrix to study the potential mechanism of PCOS pathophysiology. FF is the product of plasma modified by the secretory activity of the granulosa and theca cells [42]. This matrix is collected from women with PCOS undergoing in vitro fertilization. FF contains metabolites essential for oocyte growth and maturation. The analysis of the metabolic derangements in FF samples from women with PCOS allows to understand pathological changes and also disclose the metabolites that could potentially disturb normal oocyte growth [43].
We reviewed a few metabolomic studies that analysed FF from women with PCOS and compared them with healthy controls [44,45,46,47,48]. They were performed with the use of different metabolomic techniques. As can be observed, the concentration of metabolites involved in the TCA cycle, as well as α-keto acids, are relatively higher in samples obtained from women with PCOS in comparison with the control subjects. The contrary trend was shown for acylcarnitines. For all of the determined metabolites belonging to acylcarnitines, the decreased level was determined for samples obtained from PCOS patients. However, there are a few metabolic pathways where the trend is not similar among the pathway, but is specific for individual subgroups of compounds. For example, as was reported by Liu et al. (2018), the decreased level of PC was observed in PCOS patients, while the contrary trend (up-regulation) was shown for Lyso PC [46]. In the case of fatty acyls, the general direction demonstrates down-regulation. However, Liu et al. (2018) reported an increased level of 1-Hydroxy-2,12,15-heneicosatrien-4-one in PCOS patients in comparison with the control subjects. The diversity was also observed in the case of AAs metabolism. For example, increased level of phenylalanine, valine, and isoleucine was observed, while a decreased amount of alanine, glutamine, and tyrosine was reported. The results are presented in Table 3.

3. Discussion

The summary of all the metabolites detected in three different biological matrices gives us a complementary overview of the metabolomic profile of women with PCOS and allows us to look for a correlation between altered levels of metabolites from different biochemical pathways.
Lipids are the largest group of molecules whose metabolism is deranged in women with PCOS. They are involved in various metabolic pathways, such as steroid hormone biosynthesis, sphingolipid, and fatty acids metabolisms like oxidation or amide metabolism. Phospholipids, which take part in multiple biological pathways, are down-regulated in PCOS. There are few studies confirming the decreased levels of sphinganine, LPE, especially LPE (22:5) and LPC, mainly LPC (18:2) in women with PCOS [27,28,34]. LPCs are involved in glucose metabolism, and low levels of LPC (18:2) correlate with IR and increased risk of T2DM. Thus, this would be in accordance with the observation that women with PCOS are more prone to these metabolic alterations [34]. Hauola et al. (2015) noticed that the differences in the lipid profiles between PCOS and healthy women correlate with the phase of the menstrual cycle. The most significant changes were detected between samples collected from healthy women during the luteal phase of the menstrual cycle and women with PCOS [35]. Among sphingolipids, phytosphingosine (PHS), which stimulates the transcriptional activity of the peroxisome proliferator-activated receptor γ (PPARγ), is downregulated in women with PCOS. According to the literature, PPARs are ligand-dependent transcription factors that regulate the expression of numerous genes associated with the metabolism of carbohydrates, lipids, and proteins [30]. Dysfunction of these receptors may also contribute to the increased risk of MetS and T2DM. The latest lipidomic studies indicate that elevated levels of DG and cholesterol ester, and lower levels of LysoPC correlate with IR, irrespective of a person being overweight or obese [49].
Szczuko et al. (2017) analysed plasma fatty acids in women with PCOS. Their results showed that the levels of all free fatty acids were lower in women with PCOS; however, the concentration of nervonic acid was several times (almost 330 times) higher than in the control subjects. This level of nervonic acid was observed in two analysed groups of women, namely women with PCOS with a biochemical indication of hyperandrogenism and women with normal androgen levels. Poly-unsaturated fatty acids (PUFAs), the precursors of eicosanoids, were significantly increased in women with PCOS compared with the control subjects, which may be due to the presence of low-grade systemic inflammation. In recent years, some studies reported that this process could be stimulated by the pro-inflammatory interleukin-1 (IL-1), which is overexpressed in women with PCOS [50].
One of the detected metabolites, which may be considered as a potential biomarker of PCOS, is DHEA. Excess levels of DHEA are mostly detected in the metabolome of women with PCOS [29,30,33,34]. Serum concentrations of DHEA-S are also evaluated in clinical practice for the evaluation of biochemical hyperandrogenism in women. Besides, 19-oxotestosterone levels are also elevated in women with POCS. This could be due to the higher activity of aromatase, which catalyses the formation of C18 estrogens from C19 androgens [30]. Zhao et al. (2014) showed that, apart from elevated DHEA levels in women with PCOS, there is a significant increase of DHTS and ANDS, which points to the exaggerated androgen synthesis [29]. Dhayat et al. (2018) reported that in women with PCOS, there is an alternative pathway of 11-oxygenated androgen production. They also reported that four steroids such as androstanediol, estriol, 20-β-dihydrocortisone, and cortisol are found as potential markers of PCOS [41].
Lipidomic analysis was also the main goal of the study conducted by Vonica et al. (2019). The authors reported that alterations in acylglycerols, PGs and LTs, phosphocholines, and carnitine metabolites occur in women with PCOS. As a result, cholestane-5α (18:1/0:0), triacylglycerol (18:2/18:2/0-18:0), cholestane-3β, 5α, 6β-triol (18:0/0:0) were found as the crucial metabolites to identify women with PCOS from the controls. Serum levels of these metabolites were decreased. Moreover, elevated acylcarnitine: 2-hydroxylauroylcarnitine with decreased phosphocholines metabolites (18:1/18:4, 18:3/18:2) were also observed. The authors assumed that this alteration might be linked to the lipid peroxidation. Levels of some of the TG (18:2/18:2/0-18:0) and DG species (18:1/20:0/0:0, 18:0/0:0/20:1, 22:4n6/0:0/18:4n3, 18:3/0:0/22:5, 20:0/0:0/20:0, 18:1/24:0/0:0, 18:0/0:0/24:1) were also elevated in women with PCOS in comparison with the control subjects [37]. This can be explained by a higher BMI and increased intra-abdominal fat deposition, which is also a hallmark of PCOS. Dyslipidemia, which occurs in PCOS is characterized by the increased concentrations of total cholesterol (TCh), low density lipoproteins (LDL), very-low density lipoproteins (VLDL), and TGs coupled with decreased high-density lipoproteins (HDL) and HDL-cholesterol. During intestinal absorption, TGs are degraded to fatty acids. After that, they are again resynthesized and transported by the chylomicrons through the bloodstream to the adipose and muscle tissue, where their degradation into free fatty acids and monoacylglycerol takes place. Elevated levels of TGs in PCOS women may be caused by a high fat intake or reduced fat energy consumption at night. It was confirmed that in women with PCOS, the reduced ability to switch to lipid oxidation during fasting also occurs at night [37].
7β-Hydroxycholesterol is another lipid metabolite that could also be a potential biomarker of PCOS. It highly correlates with a PCOS diagnosis. This oxysterol is found as a metabolic intermediate or the end-product of cholesterol metabolism. Due to its bioactivity, it could induce oxidative stress and disturb the metabolism of fatty acids. Chen et al. (2020) showed that elevated levels of 7β-hydroxycholesterol measured in the FF by the induction of the oxidative stress may disturb the growth of oocytes in PCOS [48].
There also are some specific alterations of the bile acid metabolism. These abnormalities and dysfunction of fat absorption in women with PCOS is due to the decreased level of glycocholic acid, which was reported by Zhao et al. (2014) [29] and confirmed by Jia et al. (2019) [34].
The metabolism of prostaglandins and carnitine also seems to be deranged in women with PCOS. Vonica et al. (2019) reported an increased level of the prostaglandin (PG) E2 pathway and oxo-leukotrienes (LT) known to play a pivotal role in inflammation [37]. Dong et al. (2015) showed an increase of prostaglandin F2a (FPG-2a) and a decrease of l-carnitine in women with PCOS [30]. Elevated levels of FPG-2a may also be related to the presence of a low-grade systemic inflammation in PCOS. In turn, l-carnitine plays an essential role in fatty acid metabolism as well as their transport across the mitochondrial membrane to the mitochondrial matrix where β-oxidation of fatty acids (FAs) occurs. Decreased levels of l-carnitine may point to the impairment of these processes in PCOS. It could result in an accumulation of the FAs in the cytosol. It is noticed that l-carnitine supplementation may improve oocyte quality and therefore, may have a positive effect on fertility [30]. Carnitine is also involved in stabilizing acetylCoA and coenzyme A levels and plays an essential role during fetal maturation [34]. Elevated levels of acetate found by Whigham et al. (2014) and RoyChodhury et al. (2016) also indicate reduced FAs oxidation in women with PCOS [28].
Impaired carbohydrate metabolism is a hallmark of PCOS. Elevated serum lactate and reduced level of glucose determined in plasma samples suggest alterations in glucose metabolism accompanied with elevated glycolytic activity associated with the TCA cycle impairment. Whigham et al. (2014) suggested that in women with PCOS, some AAs are utilized as a source of alternative energy metabolism [24]. Alanine is an important amino acid in the process of gluconeogenesis. Serum alanine-amino transaminase (ALT) activity is elevated in women with PCOS, which usually is the result of NAFLD and lead to increased alanine transformation [27]. According to the literature, ALT is involved in urea cycle and AAs metabolism, where alanine may be converted to pyruvate by donating an amine group and enter the TCA cycle as well as be formed from pyruvate by accepting an amine group, respectively. Serum levels of glucogenic AAs acids such as valine, leucine, and threonine, which may also enter the TCA cycle or be involved in the process of gluconeogenesis were also significantly elevated in women with PCOS. The higher number of growing antral follicles in PCOS utilizes more energy. For this purpose, carbohydrate metabolism may not be sufficient and may thus lead to the utilization of other energy substrates like glutamine, glutamate, or 3-hydroxybutyric acid. Whigham et al. (2014) pointed out that the TCA cycle and glucose metabolism are the major pathways deranged in PCOS [28]. As reported, glucose metabolism can be carried out via alternative pathways such as glycolysis or pentose phosphate pathways and lead to an increased FAs synthesis, which may explain the observed increased FAs accumulation in the adipocytes (Figure 2).
In women with PCOS elevated levels of phenylalanine and glycated phenylalanine were also detected. The accumulation of the glycated AAs was also reported in T2DM [25]. The lower level of other AAs such as proline and histidine may be due to the increased utilization of these AAs as antioxidants during the oxidative stress present in PCOS.
Vitamin B6 metabolism may also be deranged in women with PCOS. One of its metabolic pathways is the synthesis and degradation of the AAs. The results of Chen et al. (2020) showed a significant increase of pyridoxal 5′-phosphate (PLP) and d-glutamic acid in the FF of women with PCOS. The authors claimed that both compounds are linked with the vitamin B6 metabolism. On the other hand, it is known that PLP is a coenzyme in the metabolism of homocysteine. Moreover, increased levels of homocysteine were observed in women with PCOS. Taking this into the account, disruption of the homocysteine metabolism in PCOS may impair the oocyte microenvironment. The second metabolite detected by the authors was glutamic acid. Its levels are strictly associated with efficiency of the glutamate decarboxylase, while the activity of this enzyme is regulated by the presence of vitamin B6. Glutamic acid is essential for the growth of oocytes, because it can be utilized as an alternative source of energy. These authors also suggested that the increased level of this metabolite is due to its accumulation in the FF [48].
Tang et al. (2019) pointed out that amino acid metabolic abnormalities are also characteristic of PCOS [51]. Among the branched-chain AAs, three were pointed out: valine, leucine, and isoleucine. All of them were up-regulated in women with PCOS. It is assumed that increased levels of valine, leucine, and isoleucine may affect the progression of the IR and obesity. From a biological point of view, branched-chain AAs can serve as substrates for the synthesis of glucose. It occurs in the case of IR, where abnormal glucose metabolism is carried out and alanine is obtained by the transamination of pyruvic acid. Second subgroup of AAs, which are associated with IR are lysine, phenylalanine, and 2-aminoadipic acid. Studies conducted by Tang et al. (2019) pointed to significantly higher concentrations of these metabolites in women with PCOS, which can also be associated with the IR [51]. Chen et al. (2020) reported that phenylalanine may be important for the growth and development of oocytes and could therefore be associated with ovulatory dysfunction [48].
IR plays a key role in the pathophysiology of PCOS and is associated with ovulatory dysfunction and hyperandrogenism. Some mechanisms of IR in women with PCOS are connected to an excessive activity of 17 α-hydroxylase, which regulates the conversion of 17-hydroxyprogesterone into androstenedione, excessive stimulation of IGF-I receptors, and diminished synthesis of insulin-like growth factor binding protein 1 (IGF-BP1) [52].
The Rotterdam diagnostic criteria yield four separate PCOS phenotypes (A, B, C, and D). Phenotype A includes all the three features (HA, AnO, and PCOM), whereas phenotype B, C, and D include only two (HA and AnO or HA and PCOM or AnO and PCOM, respectively). Among the mentioned PCOS studies, only one analyzed the metabolites among four different PCOS phenotypes (A, B, C, and D). Zhao et al. (2012) reported elevated levels of leucine and decreased levels of serine and threonine in women with the C (HA + PCOM) phenotype in comparison to the other phenotypes [25].

Limitations of Metabolomic Studies

The range of described metabolites identified during metabolomic studies is enormous and gives an overview of the metabolic profile of women with PCOS. Several different compounds and many biochemical pathways seem to be involved in the pathogenesis of PCOS, which indicates the complexity of this common endocrinopathy. These alterations may be caused by an increased or reduced efficiency of different biochemical reactions, up- or down-regulation of genes, increased or decreased activity of enzymes, as well the formation of alternative metabolic pathways. Metabolomics enables us to study these biochemical pathways, which might be involved in the pathogenesis of PCOS. However, it is important to remember that there are some limitations of metabolomic studies. An enormous challenge in research, which is performed with the use of human matrices is inter-individual variability, especially in women, in whom the range of the detected metabolites could be correlated to different hormone levels during the menstrual cycle. Some metabolomic studies were performed relatively in a small group of women, with only tentatively identified metabolites. There could also be some difficulties with the efficiency of the analysers, which sometimes yield false positive results. Furthermore, differences in sample preparation also have a significant impact on the final results.
Therefore, in metabolomics research, every step of the study is significant—from appropriate patient requirements through analytical accuracy to the identification and statistical analysis of the obtained results. That is why there is the need to confirm if the detected compounds could become reliable biomarkers, which would selectively distinguish PCOS from other endocrinopathies.

4. Conclusions

Metabolomics has proven to be a potential tool in studying the pathophysiology of PCOS. The application of metabolomics allows us to discover metabolic pathways that have been shown to be deranged. These abnormalities are associated mainly with the metabolism of lipids, fatty acids, sphingolipids and glycerophospholipids, steroids as well as carbohydrates and amino acids (Figure 3). Additionally, some alternative biochemical processes have been shown to be up-regulated in women with PCOS; however, their clinical significance should be confirmed and evaluated. Determination of disturbed pathways allows identification of the specific compounds characteristic of PCOS, which might be considered as biomarkers and became potential targets for future metabolomic research. Finding appropriate biochemical markers could be a milestone in early diagnosis of this endocrinopathy and a starting point for targeted future pharmacological interventions.

Author Contributions

Conceptualization, A.R.; resources, A.R.; data curation, A.R.; writing—original draft preparation, A.R. and M.B.-F.; writing—review and editing, M.B.-F., D.R.; visualization, A.R.; supervision, M.B.-F., D.R. and M.J.M.; funding acquisition, A.R. All authors have read and agreed to the published version of the manuscript.

Funding

This review article was financed by the Polish National Science Centre (grant number 2018/31/N/NZ7/03781).

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

HAHyperandrogenism
AnOAnovulatory oligomenorrhea
TV-USTransvaginal ultrasound
PCOSPolycystic ovary syndrome
PCOMPolycystic ovary morphology
T2DMType 2 diabetes mellitus
AHArterial hypertension
MetSMetabolic syndrome
NAFLDNon-alcoholic fatty liver disease
CVDCardiovascular disease
IRInsulin resistance
HMDBHuman Metabolome Database
MSMass spectrometry
GC-MSGas chromatography–mass spectrometry
LC-MSLiquid chromatography–mass spectrometry
NMRNuclear magnetic resonance
FFFollicular fluid
PPARγPeroxisome proliferator-activated receptor γ
PUFAsPoly-unsaturated fatty acids
IGF-BP1Insulin-like growth factor binding protein 1

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Figure 1. Clinical picture of Polycystic Ovary Syndrome.
Figure 1. Clinical picture of Polycystic Ovary Syndrome.
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Figure 2. Alteration of glucose metabolism in PCOS.
Figure 2. Alteration of glucose metabolism in PCOS.
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Figure 3. The main biochemical pathways disturbed in PCOS.
Figure 3. The main biochemical pathways disturbed in PCOS.
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Table 1. The most significant changes in metabolites measured in plasma and serum samples in women with PCOS in comparison with control subjects.
Table 1. The most significant changes in metabolites measured in plasma and serum samples in women with PCOS in comparison with control subjects.
MetabolitesPCOS vs. ControlMetabolic PathwaysStudiesTechniques
CholesterolLipid metabolismZhao et al., 2012GC-MS
GC-MS
Escobar-Morreale et al., 2012
Buszewska-Forajta et al., 2019
Alpha-TocopherolLipid metabolismEscobar-Morreale et al., 2012GC-MS
HDLLipid metabolismZhao et al., 2012NMR
PhosphatidylcholineLipid metabolismZhao et al., 2012NMR
Sun et al., 2012NMR
Linoleic acidLipid metabolismZhao et al., 2012GC-MS
Dong et al., 2015LC-MS
LipoproteinLipid metabolismZhao et al., 2012NMR
Palmitic acidLipid metabolismZhao et al., 2012GC-MS
C18:0 stearic acidLipid metabolismZhao et al., 2012GC-MS
Szczuko et al., 2017GC-MS
Unsaturated fatty acidLipid metabolismZhao et al., 2012NMR
VLDL/LDLLipid metabolismZhao et al., 2012NMR
Lipid-CH2CH2COLipid metabolismAtiomo et al., 2012NMR
Zhao et al., 2012NMR
FFA 16:1Lipid metabolismZhao et al., 2014LC-MS
FFA 16:2Lipid metabolismZhao et al., 2014LC-MS
FFA 18:1Lipid metabolismZhao et al., 2014LC-MS
FFA 18:3Lipid metabolismZhao et al., 2014LC-MS
FFA 20:1Lipid metabolismZhao et al., 2014LC-MS
FFA 20:2Lipid metabolismZhao et al., 2014LC-MS
FFA 20:3Lipid metabolismZhao et al., 2014LC-MS
FFA 20:4Lipid metabolismZhao et al., 2014LC-MS
FFA 20:5Lipid metabolismZhao et al., 2014LC-MS
FFA 20:6Lipid metabolismZhao et al., 2014LC-MS
FFA 22:5Lipid metabolismZhao et al., 2014LC-MS
FFA 22:6Lipid metabolismZhao et al., 2014LC-MS
FFA 24:2Lipid metabolismZhao et al., 2014LC-MS
MG 18:1Lipid metabolismZhao et al., 2014LC-MS
MG 20:3Lipid metabolismZhao et al., 2014LC-MS
LPC (16:1)Lipid metabolismZhao et al., 2014LC-MS
LPC (16:0)Lipid metabolismHaoula et al., 2015LC-MS
LPC (18:0)Lipid metabolismHaoula et al., 2015LC-MS
LPC (18:1)Lipid metabolismZhao et al., 2014LC-MS
Haoula et al., 2015LC-MS
LPC (18:2)Lipid metabolismZhao et al., 2014LC-MS
Dong et al., 2015LC-MS
Jia et al., 2019LC-MS
Buszewska-Forajta et al., 2019LC-MS
Haoula et al., 2015LC-MS
LPC 18:3Lipid metabolismZhao et al., 2014LC-MS
Dong et al., 2015LC-MS
LPC 20:5Lipid metabolismZhao et al., 2014LC-MS
LPC 22:5Lipid metabolismZhao et al., 2014LC-MS
LPE 16:0Lipid metabolismZhao et al., 2014LC-MS
LPE 18:1Lipid metabolismZhao et al., 2014LC-MS
LPE 18:2Lipid metabolismZhao et al., 2014LC-MS
LPE 20:4Lipid metabolismZhao et al., 2014LC-MS
LPE 22:5Lipid metabolismZhao et al., 2014LC-MS
Dong et al., 2015LC-MS
Jia et al., 2019LC-MS
PC (18:1/18:4)Lipid metabolismVonica et al., 2019LC-MS
PC (18:3/18:2)Lipid metabolismVonica et al., 2019LC-MS
PC (32:4)Lipid metabolismHaoula et al., 2015LC-MS
PC (30:0)Lipid metabolismHaoula et al., 2015LC-MS
PE (42:1)Lipid metabolismHaoula et al., 2015LC-MS
PE (34:0)Lipid metabolismHaoula et al., 2015LC-MS
SM (d18:0/20:2)Lipid metabolismHaoula et al., 2015LC-MS
SM (d18:0/18:0)Lipid metabolismHaoula et al., 2015LC-MS
TriglyceridesLipid metabolismHaoula et al., 2015LC-MS
DG (36:2)Lipid metabolismHaoula et al., 2015LC-MS
DG (36:3)Lipid metabolismHaoula et al., 2015LC-MS
Plasmalogen (30:0)Lipid metabolismHaoula et al., 2015LC-MS
Plasmalogen (40:7)Lipid metabolismHaoula et al., 2015LC-MS
Azelaic acidLipid metabolismDong et al., 2015LC-MS
N-undecanoylglycineLipid metabolismDong et al., 2015LC-MS
Chenodeoxycholic acidLipid metabolismFan et al., 2019LC-MS
Cholic acidLipid metabolismFan et al., 2019LC-MS
ClupanodonylcarnitineLipid metabolismFan et al., 2019LC-MS
2-HydroxylauroylcarnitineLipid metabolismVonica et al., 2019LC-MS
Trans-2-dodecenoylcarnitineLipid metabolismVonica et al., 2019LC-MS
Cholestane-3βSterol lipid metabolismVonica et al., 2019LC-MS
Cholestane-5α (18:0/0:0)Sterol lipid metabolismVonica et al., 2019LC-MS
Cholestane-6β-triolSterol lipid metabolismVonica et al., 2019LC-MS
Cholestane (18:1/0:0)Sterol lipid metabolismVonica et al., 2019LC-MS
Androsterone sulphateLipid transport and metabolismFan et al., 2019LC-MS
11′-Carboxy-α-chromanolLipid transport and metabolismFan et al., 2019LC-MS
(9-cis,9′-cis)-7,7′,8,8′-Tetrahydro-y,y-CaroteneLipid transport and metabolismFan et al., 2019LC-MS
SphinganineSphingolipid metabolismDong et al., 2015LC-MS
Jia et al., 2019LC-MS
Buszewska-Forajta et al., 2019LC-MS
PhytosphingosineSphingolipid metabolismDong et al., 2015LC-MS
PalmitoylsphingomyelinSphingomyelin metabolismFan et al., 2019LC-MS
SM (d18:1/16:0)Sphingomyelin metabolismFan et al., 2019LC-MS
LysoPC (O-18:0)Lecithin metabolismFan et al., 2019LC-MS
LysoPC (16:0)Lecithin metabolismFan et al., 2019LC-MS
LysoPC [20:2(11Z,14Z)]Lecithin metabolismFan et al., 2019LC-MS
Glyceric acidGlycerolipid metabolismDong et al., 2015LC-MS
LPC (20:2)Glycerophospholipid metabolismDong et al., 2015LC-MS
2-ArachidonoylGlycerophospholipid metabolismFan et al., 2019LC-MS
glycerophosphocholine
PG [18:1(9Z)/16:0]Glycerophospholipid metabolismFan et al., 2019LC-MS
PE [O-18:1(1Z)/20:4
(5Z,8Z,11Z,14Z)]
Glycerophospholipid metabolismFan et al., 2019LC-MS
LysoPE [0:0/22:1(13Z)]Glycerophospholipid metabolismFan et al., 2019LC-MS
PE [O-16:1(1Z)/22:6
(4Z,7Z,10Z,13Z,16Z,19Z)]
Glycerophospholipid metabolismFan et al., 2019LC-MS
PE [22:4(7Z,10Z,13Z,16Z)/16:0]Glycerophospholipid metabolismFan et al., 2019LC-MS
PC [16:1(9Z)/22:2(13Z,16Z)]Glycerophospholipid metabolismFan et al., 2019LC-MS
PG (18:0/16:0)Glycerophospholipid metabolismFan et al., 2019LC-MS
PG (18:1(9Z)/18:0)Glycerophospholipid metabolismFan et al., 2019LC-MS
DG (18:1n9/0:0/20:4n3)Diacyloglycerol metabolismFan et al., 2019LC-MS
TG (18:2/18:2/0-18:0)Diacyloglycerol metabolismVonica et al., 2019LC-MS
DG (22:2/0:0/22:4)Diacyloglycerol metabolismVonica et al., 2019LC-MS
ArginineAmino acids metabolismAtiomo et al., 2012NMR
Sun et al., 2012NMR
CholineAmino acids metabolismSun et al., 2012NMR
CitrulineAmino acids metabolismAtiomo et al., 2012NMR
GlutamateAmino acids metabolismAtiomo et al., 2012NMR
Glycerophosphocholine/phosphocholineAmino acids metabolismSun et al., 2012NMR
GlycineAmino acids metabolismZhao et al., 2012GC-MS
HistidineAmino acids metabolismAtiomo et al., 2012NMR
RoyChoudhury et al., 2016
AAAAmino acids metabolismZhao et al., 2012GC-MS
BCAAAmino acids metabolismZhao et al., 2012GC-MS
BCAA/AAAAmino acids metabolismZhao et al., 2012GC-MS
AspartateAmino acids metabolismZhao et al., 2012GC-MS
Endogenous AAsAmino acids metabolismZhao et al., 2012GC-MS
Gluconeogenic AAsAmino acids metabolismZhao et al., 2012GC-MS
SerineAmino acids metabolismZhao et al., 2012GC-MS
2-AminobutyrateAmino acid metabolismWhigham et al., 2014NMR
2-HydroxybutyrateAmino acid metabolismWhigham et al., 2014NMR
2-HyroxyisovalerateAmino acid metabolismWhigham et al., 2014NMR
2-OxocaproateAmino acid metabolismWhigham et al., 2014NMR
2-OxoisocaproateAmino acid metabolismWhigham et al., 2014NMR
3-HydroxybutyrateAmino acid metabolismWhigham et al., 2014NMR
3-Methyl-2-oxovalerateAmino acid metabolismWhigham et al., 2014NMR
BetadineAmino acid metabolismWhigham et al., 2014NMR
CreatinineAmino acid metabolismWhigham et al., 2014NMR
Sun et al., 2012NMR
DimethylamineAmino acid metabolismWhigham et al., 2014NMR
LysineAmino acid metabolismWhigham et al., 2014NMR
Zhao et al., 2012GC-MS
Atiomo et al., 2012NMR
MethionineAmino acid metabolismWhigham et al., 2014NMR
Sun et al., 2012NMR
OrnithineAmino acid metabolismWhigham et al., 2014NMR
Zhao et al., 2012GC-MS
Atiomo et al., 2012NMR
SarcosineAmino acid metabolismWhigham et al., 2014NMR
TaurineAmino acid metabolismWhigham et al., 2014NMR
TryptophanAmino acid metabolismWhigham et al., 2014NMR
Zhao et al., 2012GC-MS
Buszewska-Forajta et al., 2019GC/LC-MS
TyrosineAmino acid metabolismWhigham et al., 2014NMR
Zhao et al., 2012GC-MS
Buszewska-Forajta et al., 2019GC-MS
GlutamateAmino acids metabolismRoyChoudhury et al., 2016NMR
Whigham et al., 2014NMR
GlutamineAmino acids metabolismRoyChoudhury et al., 2016NMR
Whigham et al., 2014NMR
Sun et al., 2012NMR
ProlineAmino acids metabolismAtiomo et al., 2012NMR
Zhao et al., 2012GC-MS
RoyChoudhury et al., 2016NMR
Whigham et al., 2014NMR
AlanineAmino acids metabolismRoyChoudhury et al., 2016NMR
Whigham et al., 2014NMR
Zhao et al., 2012NMR
Escobar-Morreale et al., 2012GC-MS
LeucineAmino acids metabolismRoyChoudhury et al., 2016NMR
Whigham et al., 2014NMR
Sun et al., 2012NMR
Zhao et al., 2012GC-MS
IsoleucineAmino acids metabolismWhigham et al., 2014NMR
Zhao et al., 2012GC-MS
ValineAmino acids metabolismRoyChoudhury et al., 2016NMR
Whigham et al., 2014NMR
Zhao et al., 2012GC-MS
ThreonineAmino acids metabolismRoyChoudhury et al., 2016NMR
Whigham et al., 2014NMR
Zhao et al., 2012GC-MS
Buszewska-Forajta et al., 2019GC-MS
Cysteine-S-sulphateAmino acid metabolismFan et al., 2019LC-MS
Glu-GluAmino acid metabolismDong et al., 2015LC-MS
AsparagineAmino acid metabolismWhigham et al., 2014NMR
KetoleucineValine, leucine, and isoleucine degradationDong et al., 2015LC-MS
Glutamic acidcGlutamate metabolism, amino sugar metabolismDong et al., 2015LC-MS
Phenylpyruvic acidPhenylalanine and tyrosine metabolismDong et al., 2015LC-MS
Gly.PhePhenylalanine and tyrosine metabolismZhao et al., 2014LC-MS
PhenylalaninePhenylalanine and tyrosine metabolismZhao et al., 2014LC-MS
Whigham et al., 2014NMR
Zhao et al., 2012GC-MS
Buszewska-Forajta et al., 2019GC-MS
Phe−PhePhenylalanine and tyrosine metabolismZhao et al., 2014LC-MS
KynurenineTryptophan metabolismZhao et al., 2014LC-MS
5-Hydroxyindoleacetic acidTryptophan metabolismDong et al., 2015LC-MS
HomoserineMethionine metabolismZhao et al., 2014LC-MS
Whigham et al., 2014NMR
S-AdenosylmethionineThiol amino acid metabolic cycleFan et al., 2019LC-MS
Pyroglutamic acidGlutathione metabolismDong et al., 2015LC-MS
Lysyl-albuminProtein metabolismZhao et al., 2012NMR
Trimethylamine N-oxideProtein metabolismSun et al., 2012NMR
2-Ketoisocaproic acidProtein metabolismEscobar-Morreale et al., 2012GC-MS
DimethylamineProtein metabolismSun et al., 2012NMR
N-acetylglycoproteinProtein metabolismZhao et al., 2012NMR
Sun et al., 2012NMR
HypoxanthinePurine metabolismZhao et al., 2014LC-MS
InosinePurine metabolismZhao et al., 2014LC-MS
Allantoic acidPurine metabolismDong et al., 2015LC-MS
Uric acidPurine metabolismZhao et al., 2012GC-MS
Buszewska-Forajta et al., 2019GC/LC-MS
Cyclic GMPPurine metabolismFan et al., 2019LC-MS
UridinePyrimidine metabolismZhao et al., 2014LC-MS
Dong et al., 2015LC-MS
5,6-DihydrouridinePyrimidine metabolic cycleFan et al., 2019LC-MS
DHEASAndrogen metabolismZhao et al., 2014LC-MS
Dong et al., 2015LC-MS
Buszewska-Forajta et al., 2019LC-MS
Jia et al., 2019LC-MS
Fan et al., 2019LC-MS
ANDSAndrogen metabolismZhao et al., 2014LC-MS
DHTSAndrogen metabolismZhao et al., 2014LC-MS
Pregnenolone sulphateSteroid hormone biosynthesisDong et al., 2015LC-MS
19-OxotestosteroneSteroid hormone biosynthesisDong et al., 2015LC-MS
C10:0 lauric acidFatty acid metabolismSzczuko et al., 2017GC-MS
C15:0 pentadecanoic acidFatty acid metabolismSzczuko et al., 2017GC-MS
C15:1 cis-10-pentadecanoic acidFatty acid metabolismSzczuko et al., 2017GC-MS
C17:0 heptadecanoic acidFatty acid metabolismSzczuko et al., 2017GC-MS
C20:0 arachidic acidFatty acid metabolismSzczuko et al., 2017GC-MS
C20:1 cis-11-eicosanoic acidFatty acid metabolismSzczuko et al., 2017GC-MS
C22:5 EPAFatty acid metabolismSzczuko et al., 2017GC-MS
C22:0 behenic acidFatty acid metabolismSzczuko et al., 2017GC-MS
C23:0 tricosanoic acidFatty acid metabolismSzczuko et al., 2017GC-MS
C22:4n6 docosatetraenic acidFatty acid metabolismSzczuko et al., 2017GC-MS
C24:0 lignoceric acidFatty acid metabolismSzczuko et al., 2017GC-MS
C24:1 nervonic acidFatty acid metabolismSzczuko et al., 2017GC-MS
9-HODE/13-HODEFatty acid metabolismDong et al., 2015LC-MS
α-Linolenic acidFatty acid metabolismDong et al., 2015LC-MS
C18:2n6c linoleic acidFatty acid metabolismSzczuko et al., 2017GC-MS
Vaccenic acidFatty acid metabolismDong et al., 2015LC-MS
Docosatrienoic acidFatty acid metabolismDong et al., 2015LC-MS
Eicosapentaenoic acidFatty acid metabolismDong et al., 2015LC-MS
Galbanic acidFatty acid metabolismFan et al., 2019LC-MS
C14:0 myristic acidFatty acid biosynthesisDong et al., 2015LC-MS
Szczuko et al., 2017GC-MS
Palmitoleic acidFatty acid biosynthesisDong et al., 2015LC-MS
PalmitoleoylethanolamideFatty acid amide metabolismDong et al., 2015LC-MS
OleamideFatty acid amide metabolismZhao et al., 2014LC-MS
Dong et al., 2015LC-MS
Palmitic amideFatty acid amide metabolismZhao et al., 2014LC-MS
Dong et al., 2015LC-MS
PEAFatty acid amide metabolismZhao et al., 2014LC-MS
AEAFatty acid amide metabolismZhao et al., 2014LC-MS
Carnitine C2:0Beta oxidation of fatty acidsZhao et al., 2014LC-MS
Carnitine C6:0Beta oxidation of fatty acidsZhao et al., 2014LC-MS
Carnitine C18Beta oxidation of fatty acidsZhao et al., 2014LC-MS
CarnitineOxidation of fatty acidsDong et al., 2015LC-MS
Jia et al., 2019LC-MS
Glycocholic acidBile acid metabolismZhao et al., 2014LC-MS
Jia et al., 2019LC-MS
3,7-Dihydroxy-5-cholestenoic acidBile acid metabolismFan et al., 2019LC-MS
3-β-Hydroxy-4-β-methyl-5-α-cholest-7-ene-4-α-carboxylateBile acid metabolismFan et al., 2019LC-MS
FormatePyruvate metabolismWhigham et al., 2014NMR
FructosePyruvate metabolismWhigham et al., 2014NMR
MannosePyruvate metabolismWhigham et al., 2014NMR
CitrateTCA cycle metabolismWhigham et al., 2014NMR
Atiomo et al., 2012NMR
Sun et al., 2012NMR
AcetateTCA cycle metabolismRoyChoudhury et al., 2016NMR
Whigham et al., 2014NMR
4a-Methylzymosterol-4-carboxylic acidTCA cycle metabolismFan et al., 2019LC-MS
LactateGluconeogenesis/GlycolysisRoyChoudhury et al., 2016NMR
Whigham et al., 2014NMR
Zhao et al., 2012GC-MS/
NMR
Lactic acidGluconeogenesis/GlycolysisBuszewska-Forajta et al., 2019GC-MS
GluconolactonePentose phosphate pathwayDong et al., 2015LC-MS
3-Hydroxybutyric acidEnergy metabolismRoyChoudhury et al., 2016NMR
GlucoseEnergy metabolismRoyChoudhury et al., 2016NMR
Zhao et al., 2012GC-MS
Whigham et al., 2014/NMR
NMR
Glyceraldehyde 3-phosphateATP metabolismFan et al., 2019LC-MS
GlycerolGlucose metabolismWhigham et al., 2014NMR
AcetoacetateGlucose metabolismWhigham et al., 2014NMR
PyruvateGlucose metabolismWhigham et al., 2014NMR
AcetoneGlucose metabolismWhigham et al., 2014NMR
Atiomo et al., 2012NMR
Fructose 6-phosphateAmino sugar metabolismDong et al., 2015LC-MS
Aspartic acidAspartate metabolismZhao et al., 2014LC-MS
Thyroxine sulphateATP metabolismFan et al., 2019LC-MS
Pantothenic acidPantothenate and CoA biosynthesisDong et al., 2015LC-MS
Prostaglandin F2aArachidonic acid metabolismDong et al., 2015LC-MS
Vonica et al., 2019LC-MS
25-Methyl-1-hexacosanolFatty alcoholsFan et al., 2019LC-MS
S-(PGJ2)—glutathioneImmune modulationFan et al., 2019LC-MS
Oryzanol AEndocrine modulationFan et al., 2019LC-MS
HDL = high-density lipoproteins, VLDL/LDL = very-low density lipoproteins/ low density lipoproteins, FFA = free fatty acid, PC = phosphatidylcholine, PE = phosphatidylethanolamine, LPC (LysoPC) = lysophosphatidylcholine, LPE = lysophospha-tidylethanolamine, SM = sphingomyelin, DG = diglyceride, TG = trigliceride, PG = phosphatidylglycerol, AAA = aromatic amino acids, BCAA = branched-chain amino acid, AAs = amino acid, GMP = guanosine monophosphate, DHEAS = dehydro-epiandrosterone sulphate, ANDS = androsterone sulphate, DHTS = dihydrotestosterone sulphate, EPA = eicosapentaenoic acid, HODE = hydroxyoctadecadienoic acid, PEA = palmitoylethanolamide, AEA = N-arachidonoylethanolamine; ↑ up-regulation; ↓ down-regulation.
Table 2. The most significant changes in urinary metabolites in women with PCOS in comparison with the control subjects.
Table 2. The most significant changes in urinary metabolites in women with PCOS in comparison with the control subjects.
MetabolitesPCOS vs. ControlMetabolic PathwaysStudiesTechniques
LactoseCarbohydrate metabolismZou et al., 2018GC-MS
Gluconic acidCarbohydrate metabolismZou et al., 2018GC-MS
3-hydroxypropionic acidCarbohydrate metabolismZou et al., 2018GC-MS
ArabinitolCarbohydrate metabolismZou et al., 2018GC-MS
FucoseCarbohydrate metabolismZou et al., 2018GC-MS
Oxalic acidCarbohydrate metabolismZou et al., 2018GC-MS
Arabic candyLipid metabolismZou et al., 2018GC-MS
Stearic acidLipid metabolismZou et al., 2018GC-MS
Palmitic acidLipid metabolismZou et al., 2018GC-MS
PhosphoethanolamineLipid metabolismZou et al., 2018GC-MS
2-(14,15-Epoxyeicosatrienoyl)GlycerolipidsWang et al., 2015LC-MS
TG (14:1(9Z)/14:0/22:2(13Z,16Z))GlycerolipidsWang et al., 2015LC-MS
TG (14:0/24:1(15Z)/14:1(9Z))GlycerolipidsWang et al., 2015LC-MS
TG(16:0/14:0/18:0)GlycerolipidsWang et al., 2015LC-MS
TG (16:0/14:1(9Z)/20:1(11Z))GlycerolipidsWang et al., 2015LC-MS
TGGlycerolipidsWang et al., 2015LC-MS
DG (16:1(9Z)/14:0/0:0)GlycerolipidsWang et al., 2015LC-MS
PC (22:2(13Z,16Z)/18:1(9Z))GlycerophospholipidsWang et al., 2015LC-MS
PC (14:1(9Z)/14:1(9Z))GlycerophospholipidsWang et al., 2015LC-MS
LPA (16:0/0:0)GlycerophospholipidsWang et al., 2015LC-MS
PE (14:1(9Z)/14:1(9Z))GlycerophospholipidsWang et al., 2015LC-MS
LysoPC (18:1(9Z))GlycerophospholipidsWang et al., 2015LC-MS
Cer (d18:0/20:0)SphingolipidsWang et al., 2015LC-MS
PhytosphingosineSphingolipidsWang et al., 2015LC-MS
Glycocholic acidSteroidsWang et al., 2015LC-MS
Chenodeoxycholic acid 3-sulphateSteroidsWang et al., 2015LC-MS
3-Oxo-4,6-choladienoic acidSteroidsWang et al., 2015LC-MS
Cortolone-3-glucuronideSteroidsWang et al., 2015LC-MS
11α-HydroxyprogesteroneSteroidsWang et al., 2015LC-MS
Testosterone glucuronideSteroidsWang et al., 2015LC-MS
Tetrahydroaldosterone-3-glucuronideSteroidsWang et al., 2015LC-MS
DehydroepiandrosteroneAndrogen metabolismDhayat et al., 2018GC-MS
16α-OH-dehydroepiandrosteroneAndrogen metabolismDhayat et al., 2018GC-MS
AndrostenediolAndrogen metabolismDhayat et al., 2018GC-MS
TestosteroneAndrogen metabolismDhayat et al., 2018GC-MS
5α-DH-testosteroneAndrogen metabolismDhayat et al., 2018GC-MS
AndrostanediolAndrogen metabolismDhayat et al., 2018GC-MS
AndrosteroneAndrogen metabolismDhayat et al., 2018GC-MS
11β-OH-androsteroneAndrogen metabolismDhayat et al., 2018GC-MS
EtiocholanoloneAndrogen metabolismDhayat et al., 2018GC-MS
EstriolEstrogen metabolismDhayat et al., 2018GC-MS
Suberic acidFatty acid metabolismZou et al., 2018GC-MS
3,4,5-hydroxyvaleric acidFatty acid metabolismZou et al., 2018GC-MS
(R)-3-Hydroxy-hexadecanoic acidFatty acid metabolismWang et al., 2015LC-MS
6-Keto-decanoylcarnitineFatty acid estersWang et al., 2015LC-MS
TiglylcarnitineFatty acid estersWang et al., 2015LC-MS
ButyrylcarnitineFatty acid estersWang et al., 2015LC-MS
4-hydroxyphenylacetic acidTyrosine metabolismZou et al., 2018GC-MS
CapryloylglycineAmino acid metabolismWang et al., 2015LC-MS
N-(7-Isocucurbinoyl)isoleucineAmino acid metabolismWang et al., 2015LC-MS
AspartylglycosamineAmino acid metabolismWang et al., 2015LC-MS
α-ketoglutarateAmino acid metabolismZou et al., 2018GC-MS
ThreonineAmino acid metabolismZou et al., 2018GC-MS
SerineAmino acid metabolismZou et al., 2018GC-MS
GlycineAmino acid metabolismZou et al., 2018GC-MS
5-OxoprolineAmino acid metabolismZou et al., 2018GC-MS
BenzoylglycineAmino acid metabolism Zou et al., 2018GC-MS
Indoleacetyl glutamineAromatic Amino acidsWang et al., 2015LC-MS
Flazine methyl etherAromatic Amino acidsWang et al., 2015LC-MS
SuccinyladenosineAromatic Amino acidsWang et al., 2015LC-MS
ThyronineAromatic Amino acidsWang et al., 2015LC-MS
Gamma-glutamyl-leucinePeptidesWang et al., 2015LC-MS
Tryptophyl-prolinePeptidesWang et al., 2015LC-MS
Methionyl-phenylalaninePeptidesWang et al., 2015LC-MS
Phenylalanyl-histidinePeptidesWang et al., 2015LC-MS
Arginyl-valineyPeptidesWang et al., 2015LC-MS
Threoninyl-lysinePeptidesWang et al., 2015LC-MS
Tryptophyl-argininePeptidesWang et al., 2015LC-MS
Tyrosyl-leucinePeptidesWang et al., 2015LC-MS
Tryptophyl-valinePeptidesWang et al., 2015LC-MS
Cis-aconitic acidCTA metabolismZou et al., 2018GC-MS
3-Hydroxy-3-Methylglutaric acidEnergy metabolismZou et al., 2018GC-MS
2-Hydroxyglutaric acidEnergy metabolismZou et al., 2018GC-MS
Threonic acidSugar acids metabolismZou et al., 2018GC-MS
InosinePurine metabolismZou et al., 2018GC-MS
2,3,4-Hydroxybutyric acidEnergy metabolismZou et al., 2018GC-MS
3,4-Hydroxybutyric acidEnergy metabolismZou et al., 2018GC-MS
4-Hydroxybutyric acidEnergy metabolismZou et al., 2018GC-MS
2-Hydroxyisobutyric acidEnergy metabolismZou et al., 2018GC-MS
UracilPyrimidine metabolismZou et al., 2018GC-MS
Glyceryl acidHydroxy acid metabolismZou et al., 2018GC-MS
Glycolic acidHydroxy acid metabolismZou et al., 2018GC-MS
2-Hydroxyisobutyric acidEnergy metabolismZou et al., 2018GC-MS
Succinic acid Glucose metabolismZou et al., 2018GC-MS
BenzophenoneAcetophenonesWang et al., 2015LC-MS
5′-Carboxy-γ-chromanolBenzopyransWang et al., 2015LC-MS
5′-Carboxy-α-chromanolBenzopyransWang et al., 2015LC-MS
9′-Carboxy-α-chromanolBenzopyransWang et al., 2015LC-MS
11′-Carboxy-α-tocotrienolBenzopyransWang et al., 2015LC-MS
FMNH2PteridinesWang et al., 2015LC-MS
UrobilinTetrapyrrolesWang et al., 2015LC-MS
MesobilirubinogenTetrapyrrolesWang et al., 2015LC-MS
HarderoporphyrinogenTetrapyrrolesWang et al., 2015LC-MS
MG (18:4(6Z,9Z,12Z,15Z)/0:0/0:0)Lineolic acidsWang et al., 2015LC-MS
HydroxyvalerylcarnitineAlkylaminesWang et al., 2015LC-MS
LabadosideGlycosidesWang et al., 2015LC-MS
Dihydrocaffeic acid 3-O-glucuronideSugar acidsWang et al., 2015LC-MS
Dihydroferulic acid 4-O-glucuronideSugar acidsWang et al., 2015LC-MS
5-Hydroxy-6-methoxyindole glucuronideSugar acidsWang et al., 2015LC-MS
p-Cresol glucuronideSugar acidsWang et al., 2015LC-MS
6β-OH-cortisolGlucocorticoid metabolismDhayat et al., 2018GC-MS
18-OH-cortisolGlucocorticoid metabolismDhayat et al., 2018GC-MS
TH-cortisolGlucocorticoid metabolismDhayat et al., 2018GC-MS
11β-OH-etiocholanoloneGlucocorticoid metabolismDhayat et al., 2018GC-MS
TH-cortisoneGlucocorticoid metabolismDhayat et al., 2018GC-MS
TG = triglyceride, DG = diglyceride, PC = phosphatidylcholine, (LysoPC) = lysophosphatidylcholine, LPA = lysophosphatidic acid, FMNH2 = reduced flavin mononucleotide; ↑ up-regulation; ↓ down-regulation.
Table 3. The most significant changes in FF metabolites in women with PCOS in comparison with the control subjects.
Table 3. The most significant changes in FF metabolites in women with PCOS in comparison with the control subjects.
MetabolitesPCOS vs. ControlMetabolic PathwaysStudiesTechniques
Paxilline NaphthopyransLiu et al., 2018LC-MS
PC (o-22:0/20:4(8Z,11Z,14Z,17Z)) GlycerophospholipidLiu et al., 2018LC-MS
PC (o22:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)) GlycerophospholipidLiu et al., 2018LC-MS
LysoPC (16:1(9Z)) GlycerophospholipidLiu et al., 2018LC-MS
LysoPC (16:0) GlycerophospholipidLiu et al., 2018LC-MS
Sun et al., 2019LC-MS
LysoPC (14:0) GlycerophospholipidSun et al., 2019LC-MS
LysoPC (18:0) GlycerophospholipidSun et al., 2019LC-MS
LysoPC (20:4(8Z,11Z,14Z,17Z)) GlycerophospholipidLiu et al., 2018LC-MS
PGP (16:0/20:4(5Z,8Z,11Z,14Z) GlycerophospholipidLiu et al., 2018LC-MS
Glycerophosphocholine GlycerophospholipidChen et al., 2020LC-MS
Ceramide (d18:0/16:0) SphingolipidsLiu et al., 2018LC-MS
Ceramide (d18:0/24:0) SphingolipidsLiu et al., 2018LC-MS
Galabiosylceramide (d18:1/24:1(15Z)) SphingolipidsLiu et al., 2018LC-MS
Tetrahexosylceramide (d18:1/24:0) SphingolipidsLiu et al., 2018LC-MS
7β-Hydroxycholesterol Lipid metabolismChen et al., 2020LC-MS
Malyl-CoA Fatty AcylsLiu et al., 2018LC-MS
1-Hydroxy-2,12,15-heneicosatrien-4-one Fatty AcylsLiu et al., 2018LC-MS
16-hydroxypalmitic acid Fatty AcylsLiu et al., 2018LC-MS
Tridecanol Fatty AcylsLiu et al., 2018LC-MS
Carnitine Fatty acids metabolismChen et al., 2020LC-MS
4-Hydroxy-3-(16-methylheptadecyl)-2H-pyran-2-one PyransLiu et al., 2018LC-MS
Anandamide Organonitrogen compoundsLiu et al., 2018LC-MS
Indan-1-ol IndanesLiu et al., 2018LC-MS
2-p-Tolyl-1-propene, p-Mentha-1,3,5,8-tetraene PhenylpropenesLiu et al., 2018LC-MS
β -Ionol SesquiterpenoidsLiu et al., 2018LC-MS
Androstenol Androstane steroidsLiu et al., 2018LC-MS
(3R, 6′Z)-3,4-Dihydro-8-hydroxy-3-(6-pentadecenyl)-1H-2-benzopyran-1-one BenzopyransLiu et al., 2018LC-MS
6-Tridecylsalicylic acid Benzoic acids and derivativesLiu et al., 2018LC-MS
2,3-dihydroxypropyl dodecanoate Glycerol metabolismChen et al., 2020LC-MS
Methylmalonic acid Carboxylic acidsLiu et al., 2018LC-MS
Lysyl-Valine Carboxylic acids and derivativesLiu et al., 2018LC-MS
Prolyl-Methionine Carboxylic acids and derivativeLiu et al., 2018LC-MS
VPGPR Enterostatin Carboxylic acids and derivativeLiu et al., 2018LC-MS
1H-Indol-3-ylacetyl-myo-inositol Indoles and derivativesLiu et al., 2018LC-MS
1-Pentadecene Unsaturated hydrocarbonsLiu et al., 2018LC-MS
Lithocholic acid glycine conjugate Non classifiedLiu et al., 2018LC-MS
Lactate Gluconeogenesis/GlycolysisZhang et al., 2017NMR
Liu el al., 2018GC-MS
Glyceraldehyde Gluconeogenesis/GlycolysisChen et al., 2020LC-MS
Pyruvate Glucose glycolysisZhang et al., 2017NMR
Zhao et al., 2015GC-MS
Valine Amino acid metabolismZhao et al., 2015MS/MS
Isoleucine Amino acid metabolismZhao et al., 2015MS/MS
Leucine Amino acid metabolismZhao et al., 2015MS/MS
Sun et al., 2019LC-MS
Alanine Amino acid metabolismZhang et al., 2017NMR
Glutamine Amino acid metabolismZhang et al., 2017NMR
Tyrosine Amino acid metabolismZhang et al., 2017NMR
Phenylalanine Amino acid metabolismSun et al., 2019LC-MS
d-Glutamic acid Amino acid metabolismChen et al., 2020LC-MS
Ferulic acid Amino acid metabolismChen et al., 2020LC-MS
Salicylic acid Amino acid metabolismChen et al., 2020LC-MS
Lysine Amino acid metabolismChen et al., 2020LC-MS
3-Methylhistidine Amino acid metabolismChen et al., 2020LC-MS
α-Keto-β-methylvalerate Alpha-keto acidsZhao et al., 2015GC-MS
α-Ketoisovalerate Alpha-keto acidsZhao et al., 2015GC-MS
α-Ketoisocaproate Alpha-keto acidsZhao et al., 2015GC-MS
Hexanoyl (C6) AcylcarnitinesZhao et al., 2015MS/MS
Malonyl (C3DC) AcylcarnitinesZhao et al., 2015MS/MS
Hydroxyisovaleryl (C5OH) AcylcarnitinesZhao et al., 2015MS/MS
Octenoyl (C8:1) AcylcarnitinesZhao et al., 2015MS/MS
Adipyl (C6DC) AcylcarnitinesZhao et al., 2015MS/MS
β-Hydroxybutyrate KetonesZhao et al., 2015GC-MS
Succinate TCA cycle metabolitesZhao et al., 2015GC-MS
Malate TCA cycle metabolitesZhao et al., 2015GC-MS
Oxaloacetate TCA cycle metabolitesZhao et al., 2015GC-MS
Cis-aconitate TCA cycle metabolitesZhao et al., 2015GC-MS
Acetate TCA cycle metabolitesZhang et al., 2017NMR
Acetoacetate TCA cycle metabolitesZhang et al., 2017NMR
3-Hyroxybutyrate TCA cycle metabolitesZhang et al., 2017NMR
N-Methylnicotinamide Metabolites of NAD catabolismZhao et al., 2015LC-MS/MS
N1-Methyl-2-pyridone-5-carboxamide (2PY) Metabolites of NAD catabolismZhao et al., 2015LC-MS/MS
N1-Methyl-4-pyridone-3-carboxamide (4PY) Metabolites of NAD catabolismZhao et al., 2015LC-MS/MS
Deoxycorticosterone Steroid metabolismSun et al., 2019LC-MS
Pregnenolone Steroid metabolismChen et al., 2020LC-MS
17-Hydroxyprogesterone Steroid metabolismChen et al., 2020LC-MS
3-Hydroxynonanoyl carnitine Fatty acid metabolismSun et al., 2019LC-MS
Eicosapentaenoic acid Fatty acid metabolismSun et al., 2019LC-MS
Phytosphingosine Sphingolipid metabolismSun et al., 2019LC-MS
N-acetylneuraminic acid Sialic acid metabolismChen et al., 2020LC-MS
Pyridoxal 5′-phosphate Vitamin B6 metabolismChen et al., 2020LC-MS
Purine Purines metabolismChen et al., 2020LC-MS
1,3-Dimethyluracil Purines metabolismChen et al., 2020LC-MS
Oxalic acid Glyoxylic acid metabolismChen et al., 2020LC-MS
Phenylglyoxylic acid Glyoxylic acid metabolismChen et al., 2020LC-MS
PC = phosphatidylcholine, (LysoPC) = lysophosphatidylcholine, PGP = glycerol-3-phosphate, CoA = coenzyme A; ↑ up-regulation; ↓ down-regulation.
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