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![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.](profile/Yue-Zhao-175/publication/233825257/figure/fig3/AS:214206499561474@1428082217273/Metabolic-pathways-associated-with-polycystic-ovary-syndrome-PCOS-development-The.png)
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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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 PC...
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Citations
... Mechanistically, studies in rodent models have shown that feeding an excess of BCAA lead to insulin resistance, associated to inhibitory serine/threonine phosphorylation in several players of insulin signaling, including mTOR (mammalian target of rapamycin), and IRS1 (insulin receptor substrate 1) [4]. An increase in aromatic amino acids (AAA) [5] and decreased glycine also occurs in obesity [6] and obesity-associated conditions such as nonalcoholic fatty liver disease [7], type 2 diabetes [8] and polycystic ovary syndrome [9]. These observations have also been expanded to the adolescent diabetic population [10], in which the pattern of decreased glycine and elevated BCAA and AAA was associated with impairment in insulin sensitivity and adiponectin secretion. ...
(1) Background: Dysregulated serum amino acids (AA) are known to be associated with obesity and risk of Type 2 Diabetes (T2D) in adults, and recent studies support the same notion in the pubertal age. It is, however, unknown whether childhood overweight may already display alterations of circulating AA. (2) Methods: We used liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS)—targeted metabolomics to determine plasma concentrations of AA and AA-related molecules in 36 children aged 7–12 years with normal weight or overweight. Clinical and anthropometric parameters were measured. (3) Results: Overweight in children is associated with an altered AA profile, with increased branched-chain amino acids (BCAA) and decreased glycine levels, with no clinically manifested metabolic conditions. Moreover, z-BMI was positively and negatively correlated with BCAA and glycine levels, respectively, even after adjustment for age and gender. We also found a correlation between the AA profile and clinical parameters such as lipids profile and glycemia. (4) Conclusions: A pattern of low glycine, and increased BCAA is correlated to z-BMI, total cholesterol, and triglycerides in overweight but otherwise healthy children. Our data suggest that, in childhood overweight, AA disturbances may precede other clinical parameters, thus providing an early indicator for the later development of metabolic disease.
... However, a study using targeted metabolomics revealed the opposite results: a lower level of lactate and a higher level of pyruvate in the follicular fluid of classic PCOS patients [82] . This result suggests that the shift toward metabolic glycolysis in the CCs of classic PCOS is consistent with the results of other studies [83] . The TCA cycle was also found to be inhibited in patients with PCOS. ...
The female ovaries are critical for follicle growth and development in the process known as "folliculogenesis". This complex process is regulated by various factors, among which the microenvironment around follicles appears to be crucial. According to previous studies, folliculogenesis is an energy-demanding process. In fact, well-balanced follicular energy metabolism is associated with ovarian function and female fertility. Consequently, glucose metabolism has been widely described as the main source of energy during folliculogenesis. Generally, the follicular glucose metabolism profiles change dynamically during follicular development. Metabolic abnormalities during folliculogenesis are associated with aging, primary ovarian insufficiency, and polycystic ovary syndrome, thereby leading to subfertility and infertility in females. The signaling pathways in follicles appear to form a link between glucose metabolism and folliculogenesis. Therefore, a better understanding of glucose metabolism dynamics at different stages of folliculogenesis and the associated signaling pathways will provide potential implications for follicle developmental competence. This review aimed to describe variations in glucose metabolism at different stages of folliculogenesis, provide new insights into glucose metabolic disorder-related diseases, and specifically discuss two major signaling pathways that regulate glucose metabolism during folliculogenesis: phosphatidylinositol 3-kinase, protein kinase B (PI3K-PKB/AKT), and AMP-activated protein kinase (AMPK) signaling pathways.
... Increased lactate in non-obese PCOS-IR following insulinstimulated uptake and breakdown of glucose in muscle could indicate a central (not peripheral) type of IR in them. [20,21] Besides surge in low-density lipoprotein-cholesterol (LDL-C), very LDL-C, and fall in high-density lipoproteincholesterol (HDL-C), increased hormone-sensitive lipase activity in white adipose tissue (as described in adipose tissue expandability hypothesis) was found to yield raised titers of free fatty acids, like palmitic, stearic, linoleic acids in patients with PCOS. [22,23] Linoleic acid being proinflammatory [24] could halt the maturation of developing oocytes. ...
... [25] In other studies, low levels of linoleic acid were also noted. [21] Lower level of palmitoleic acid and other long-chain fatty acids (LCFAs), glycerol, and high level of lactate were found among PCOS cases than control -both being non-obese. This could be metabolically explained by insulin-mediated suppression of lipolysis, and increased glucose uptake and conversion in muscles. ...
... [33] A study [20] reported an inverse relationship between LCFA levels and androgen levels in PCOS patients; contradicting the findings of some other similar studies. [34][35][36] Less activation of the mTOR pathway and thereby less restoration of insulin signaling due to decreased leucine level could lead to IR. [27] However, Sun et al. [20] and Zhao et al. [21] reported conflicting results of decreased and increased level of leucine, respectively, in PCOS. ...
Polycystic ovary syndrome (PCOS) is a complex and multifaceted disorder that has been extensively studied from various angles, including genomics, metabolomics, and other multiomics approaches. This narrative review seeks to provide an updated understanding of PCOS, with a particular focus on metabolomics. PCOS encompasses four primary phenotypes: Classic PCOS with or without polycystic ovary morphology, ovulatory PCOS, and non-hyperandrogenic PCOS. Each phenotype exhibits distinct clinical and biochemical characteristics. Classic PCOS, characterized by hyperinsulinemia, insulin resistance (IR), and metabolic complications, has garnered significant attention in recent studies. In the pursuit of unraveling PCOS’s pathophysiology, researchers have embraced a multiomics approach, exploring the genome, epigenome, transcriptome, exosomes, proteome, and metabolome. The genomic landscape of PCOS includes genes related to androgen synthesis, regulation, insulin receptors, and growth factors, among others. Epigenetic mechanisms have also been investigated, revealing the roles of non-coding RNA, histone acetylation, and deacetylation. Transcriptomic biomarkers and mitochondrial RNAs targets, such as miR-9 and miR-32, have been explored in granulosa cells of PCOS patients. Metabolomics studies have identified various biomarkers and metabolic pathways that differentiate PCOS from healthy individuals. A diverse range of alterations in carbohydrate and lipid metabolism has been observed, shedding light on the underpinnings of PCOS-related metabolic dysfunction. These studies have uncovered numerous biomolecules with potential relevance to PCOS, including kininogen 1, cytoketatin 9, and many others. In addition, the intricate relationships between IR, inflammation, and metabolic factors have been elucidated. Recent research extends beyond high-end research centers, even using urine samples to identify metabolomic markers for PCOS. This approach has led to the discovery of distinct biomarker panels related to metabolic pathways that differentiate PCOS from healthy subjects. In summary, PCOS is a complex and heterogeneous condition, with multiomics studies offering promising avenues for a deeper understanding of its pathophysiology. These studies may ultimately provide valuable insights that can revolutionize the diagnosis and treatment of PCOS, ending a centurylong scientific expedition with a crescendo of discoveries.
... The propensity for ovarian hyperstimulation significantly escalates in PCOS patients following COS stimulation [15,29]. Several metabolomic studies on PCOS patients have consistently documented significantly reduced glycine levels compared to controls [30][31][32], which aligns with our results of lower glycine levels in the PCOS group compared to the CON-NOR group. Furthermore, research has indicated heightened glycine expression in women with diminished ovarian reserve (DOR) [33], which is correlated with a poor response to ovarian stimulation [34]. ...
Background
In the realm of assisted reproduction, a subset of infertile patients demonstrates high ovarian response following controlled ovarian stimulation (COS), with approximately 29.7% facing the risk of Ovarian Hyperstimulation Syndrome (OHSS). Management of OHSS risk often necessitates embryo transfer cancellation, leading to delayed prospects of successful pregnancy and significant psychological distress. Regrettably, these patients have received limited research attention, particularly regarding their metabolic profile. In this study, we aim to utilize gas chromatography-mass spectrometry (GC-MS) to reveal these patients’ unique serum metabolic profiles and provide insights into the disease’s pathogenesis.
Methods
We categorized 145 infertile women into two main groups: the CON infertility group from tubal infertility patients and the Polycystic Ovary Syndrome (PCOS) infertility group. Within these groups, we further subdivided them into four categories: patients with normal ovarian response (CON-NOR group), patients with high ovarian response and at risk for OHSS (CON-HOR group) within the CON group, as well as patients with normal ovarian response (PCOS-NOR group) and patients with high ovarian response and at risk for OHSS (PCOS-HOR group) within the PCOS group. Serum metabolic profiles were analyzed using GC-MS. The risk criteria for OHSS were: the number of developing follicles > 20, peak Estradiol (E2) > 4000pg/mL, and Anti-Müllerian Hormone (AMH) levels > 4.5ng/mL.
Results
The serum metabolomics analysis revealed four different metabolites within the CON group and 14 within the PCOS group. Remarkably, 10-pentadecenoic acid emerged as a discernible risk metabolite for the CON-HOR, also found to be a differential metabolite between CON-NOR and PCOS groups. cysteine and 5-methoxytryptamine were also identified as risk metabolites for the PCOS-HOR. Furthermore, KEGG analysis unveiled significant enrichment of the aminoacyl-tRNA biosynthesis pathway among the metabolites differing between PCOS-NOR and PCOS-HOR.
Conclusion
Our study highlights significant metabolite differences between patients with normal ovarian response and those with high ovarian response and at risk for OHSS within both the tubal infertility control group and PCOS infertility group. Importantly, we observe metabolic similarities between patients with PCOS and those with a high ovarian response but without PCOS, suggesting potential parallels in their underlying causes.
... GDF9 plays an important role in the process of follicular development, such as the recruitment of primordial follicles, ovulation, and even in corpus luteum formation [31][32][33]. They may have a synergistic effect on folliculogenesis and embryonic development by coordinating fluid physiology, specifically in subgroups of obese women with HA [34]. Likewise, the impact of HA on oocyte quality is subject to debate. ...
... Interestingly, individuals with PCOS often exhibit disturbances of the TCA cycle. This is manifested by reduced citrate levels and elevated plasma levels of threonine, valine, phenylalanine, and tyrosine which in turn leads to a decrease in succinyl-CoA and fumarate 67 . The elevated levels of these amino acids could serve as a compensatory mechanism to provide cellular energy and counteract deficiencies in the TCA cycle activity. ...
Long non-coding RNA (lncRNA) regulates many physiological processes by acting as competitive endogenous RNA (ceRNA). The dysregulation of lncRNA X-inactive specific transcript (XIST) has been shown in various human disorders. However, its role in the pathogenesis of polycystic ovary syndrome (PCOS) is yet to be explored. This study aimed to explore the underlying mechanism of XIST in the pathogenesis of PCOS, specifically through dataset functional analysis. GEO PCOS datasets including RNA-seq, microarray, and miRNA-seq in granulosa cells (GCs) and blood, were examined and comprehensively analyzed. Enrichment analysis, ROC curve constructions, lncRNA-miRNA-mRNA interaction network analyses, and qRT-PCR validation were performed followed by a series of drug signature screenings. Our results revealed significant dysregulation in the expression of 1131 mRNAs, 30 miRNAs, and XIST in GCs of PCOS patients compared to healthy individuals. Of the120 XIST-correlated upregulated genes, 25 were enriched in inflammation-related pathways. Additionally, 5 miRNAs were identified as negative regulators of XIST-correlated genes. Accordingly, a ceRNA network containing XIST-miRNAs-mRNAs interactions was constructed. Furthermore, 6 genes, including AQP9, ETS2, PLAU, PLEK, SOCS3, and TNFRSF1B served as both GCs and blood-based biomarkers. By analyzing the number of interactions among XIST, miRNAs, and mRNAs, we pinpointed ETS2 as the pivotal gene within the ceRNA network. Our findings reveal a novel XIST- hsa-miR-146a-5p, hsa-miR-144-3p, and hsa-miR-1271-5p-ETS2 axis that comprehensively elucidates the XIST-associated mechanism underlying PCOS onset. qRT-PCR analysis further confirmed the, overexpression of both XIST and ETS2 . Furthermore, our results demonstrated that XIST and ETS2 were correlated with some assisted reproductive technologies outcomes. Finally, we identified two novel compounds including, methotrexate/folate and threonine using drug–gene interaction databases for PCOS management. These findings provide novel insights into the molecular etiology, diagnosis, and potential therapeutic interventions for PCOS.
... Interestingly, the correlations between PCOS and amino acid metabolism have been reported in several clinical investigations. Perturbations in the tryptophan metabolism pathway, enriched in ovarian metabolomes of HFHS mice, have also been identified in metabolomics analyses of follicular fluid [39], urine [40], and plasma [41,42] of PCOS patients. In addition, the differential metabolites such as citrulline and cystine identified in HFHS ovaries were also enriched in the plasma metabolomics of PCOS patients [43,44]. ...
Background
Excessive energy intake in modern society has led to an epidemic surge in metabolic diseases, such as obesity and type 2 diabetes, posing profound threats to women’s reproductive health. However, the precise impact and underlying pathogenesis of energy excess on female reproduction remain unclear.
Methods
We established an obese and hyperglycemic female mouse model induced by a high-fat and high-sucrose (HFHS) diet, then reproductive phenotypes of these mice were evaluated by examing sexual hormones, estrous cycles, and ovarian morphologies. Transcriptomic and precise metabolomic analyses of the ovaries were performed to compare the molecular and metabolic changes in HFHS mice. Finally, orthogonal partial least squares discriminant analysis was performed to compare the similarities of traits between HFHS mice and women with polycystic ovary syndrome (PCOS).
Results
The HFHS mice displayed marked reproductive dysfunctions, including elevated serum testosterone and luteinizing hormone levels, irregular estrous cycles, and impaired folliculogenesis, mimicking the clinical manifestations of women with PCOS. Precise metabolomic overview suggested that HFHS diet disrupted amino acid metabolism in the ovaries of female mice. Additionally, transcriptional profiling revealed pronounced disturbances in ovarian steroid hormone biosynthesis and glucolipid metabolism in HFHS mice. Further multi-omics analyses unveiled prominent aberration in ovarian arginine biosynthesis pathway. Notably, comparisons between HFHS mice and a cohort of PCOS patients identified analogous reproductive and metabolic signatures.
Conclusions
Our results provide direct in vivo evidence for the detrimental effects of overnutrition on female reproduction and offer insights into the metabolic underpinnings of PCOS.
... Only individuals with hyperandrogenemia, anovulation, and polycystic ovaries exhibited higher levels of UA compared to the control group, suggesting a correlation between UA alterations and the severity of clinical symptoms. 63 The elevation of UA in patients with PCOS is attributed to multiple factors; nevertheless, several clinical studies have endeavored to investigate these factors. A comprehensive single-center study involving 1183 patients with PCOS and 10,772 control subjects without PCOS demonstrated a robust correlation between elevated levels of T and increased UA as well as the prevalence of hyperuricemia. ...
Uric acid (UA) is the end product of purine metabolism in the human, and the imbalance between production and excretion results in the disturbance of serum uric acid (SUA). There is evidence suggesting that pituitary-target gland hormones can affect UA metabolism through regulating the activity of xanthine oxidase and UA transporters. Related endocrine diseases including thyroid dysfunction, polycystic ovary syndrome, acromegaly and Cushing’s syndrome are often accompanied by elevated UA levels. In addition to the direct influence of abnormal hormones, obesity and insulin resistant play a pivotal role. Diabetes insipidus and the syndrome of inappropriate antidiuretic hormone secretion also present with abnormal SUA levels due to the action of antidiuretic hormone. However, certain evidence within the population is disputed. This review summarized the effects of pituitary-target gland hormones on UA metabolism, and preliminarily described the related mechanisms, offering a theoretical foundation for assessing SUA in endocrine disorders as well as guiding its management.
... Glycolysis also involves in PCOS. For example, Zhao et al. have demonstrated that elevated glycolysis and decreased tricarboxylic acid cycle were presented in women with PCOS [17]. Dysregulation of glycolysis has also been associated with PCOS patients with hyperplasia [18]. ...
... More importantly, it has been reported that perturbation of the expression of glycolytic enzymes was associated with infertility [16]. Zhao et al. have reported that enhanced glycolysis and inhibited tricarboxylic acid cycle were found in women with PCOS [17]. Here, we found that DHT administration resulted in significant damage of KGN cells through regulating PHLPP1 expression. ...
Background
Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphologic features, and PCOS is associated with infertility. PH domain Leucine-rich repeat Protein Phosphatase 1 (PHLPP1) has been shown to regulate AKT. The aim of present study is to investigate the role of PHLPP1 in PCOS.
Methods
The expression levels of PHLPP1 in dihydrotestosterone (DHT)-treated human ovarian granular KGN cells were determined by qRT-PCR and Western blot. PHLPP1 was silenced or overexpressed using lentivirus. Cell proliferation was detected by CCK-8. Apoptosis and ROS generation were analyzed by flow cytometry. Glycolysis was analyzed by measuring extracellular acidification rate (ECAR).
Results
DHT treatment suppressed proliferation, promoted apoptosis, enhanced ROS, and inhibited glycolysis in KGN cells. PHLPP1 silencing alleviated the DHT-induced suppression of proliferation and glycolysis, and promotion of apoptosis and ROS in KGN cells. PHLPP1 regulated cell proliferation and glycolysis in human KGN cells via the AKT signaling pathway.
Conclusions
Our results showed that PHLPP1 mediates the proliferation and aerobic glycolysis activity of human ovarian granular cells through regulating AKT signaling.
... Under conditions in which ADMA activity is increased as with PCOS, the competitive inhibition through the L-Arg binding site may decrease the competition between NOS and arginase allowing arginase to consume the free L-Arg. This pathway may explain the enhancement of arginase levels and alteration in arginine metabolism seen in PCOS leading to the commonly observed increased ornithine levels [132,133]. Kyselova and collaborators [133] found that the ratio of ornithine to arginine was significantly increased in plasma from PCOS patients and was associated with a significant increase in plasma arginase levels and activity compared to control. Further, this theory is in agreements with the work done by Krishna et al., [51] who in a retrospective cohort study analyzed NO 2 − /NO 3 − and H 2 O 2 concentrations, transcript levels of endothelial NOS (eNOS)/ iNOS, arginine modulators, and H 2 O 2 regulators in PCOS women (N = 29) and non PCOS controls (N = 20). ...
Polycystic ovary syndrome (PCOS) is a heterogeneous functional endocrine disorder associated with a low-grade, chronic inflammatory state. Patients with PCOS present an increased risk of metabolic comorbidities and often menstrual dysregulation and infertility due to anovulation and/or poor oocyte quality. Multiple mechanisms including oxidative stress and low-grade inflammation are believed to be responsible for oocyte deterioration; however, the influence of nitric oxide (NO) insufficiency in oocyte quality and ovulatory dysfunction in PCOS is still a matter for debate. Higher production of superoxide (O2•−) mediated DNA damage and impaired antioxidant defense have been implicated as contributory factors for the development of PCOS, with reported alteration in superoxide dismutase (SOD) function, an imbalanced zinc/copper ratio, and increased catalase activity. These events may result in decreased hydrogen peroxide (H2O2) accumulation with increased lipid peroxidation events. A decrease in NO, potentially due to increased activity of NO synthase (NOS) inhibitors such as asymmetric dimethylarginine (ADMA), and imbalance in the distribution of reactive oxygen species (ROS), such as decreased H2O2 and increased O2•−, may offset the physiological processes surrounding follicular development, oocyte maturation, and ovulation contributing to the reproductive dysfunction in patients with PCOS. Thus, this proposal aims to evaluate the specific roles of NO, oxidative stress, ROS, and enzymatic and nonenzymatic elements in the pathogenesis of PCOS ovarian dysfunction, including oligo- anovulation and oocyte quality, with the intent to inspire better application of therapeutic options. The authors believe more consideration into the specific roles of oxidative stress, ROS, and enzymatic and nonenzymatic elements may allow for a more thorough understanding of PCOS. Future efforts elaborating on the role of NO in the preoptic nucleus to determine its influence on GnRH firing and follicle-stimulating hormone/Luteinizing hormone (FSH/LH) production with ovulation would be of benefit in PCOS. Consequently, treatment with an ADMA inhibitor or NO donor may prove beneficial to PCOS patients experiencing reproductive dysfunction and infertility.
