scholarly journals How to Screen and Prevent Metabolic Syndrome in Patients of PCOS Early: Implications From Metabolomics

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoxuan Zhao ◽  
Xiaoling Feng ◽  
Xinjie Zhao ◽  
Yuepeng Jiang ◽  
Xianna Li ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Clinical Diagnosis ◽  
Operating Characteristic ◽  
Polycystic Ovary ◽  
Healthy Controls ◽  
Ovary Syndrome ◽  
Metabolic Characteristics ◽  
Pcos Group ◽  
Reproductive Endocrine ◽  
Metabolic Biomarkers

BackgroundPolycystic ovary syndrome (PCOS) is a complex reproductive endocrine disorder. And metabolic syndrome (MS) is an important bridge for PCOS patients to develop other diseases, such as diabetes and coronary heart disease. Our aim was to study the potential metabolic characteristics of PCOS-MS and identify sensitive biomarkers so as to provide targets for clinical screening, diagnosis, and treatment.MethodsIn this study, 44 PCOS patients with MS, 34 PCOS patients without MS, and 32 healthy controls were studied. Plasma samples of subjects were tested by ultraperformance liquid chromatography (UPLC) system combined with LTQ-orbi-trap mass spectrometry. The changes of metabolic characteristics from PCOS to PCOS-MS were systematically analyzed. Correlations between differential metabolites and clinical characteristics of PCOS-MS were assessed. Differential metabolites with high correlation were further evaluated by the receiver operating characteristic (ROC) curve to identify their sensitivity as screening indicators.ResultsThere were significant differences in general characteristics, reproductive hormone, and metabolic parameters in the PCOS-MS group when compared with the PCOS group and healthy controls. We found 40 differential metabolites which were involved in 23 pathways when compared with the PCOS group. The metabolic network further reflected the metabolic environment, including the interaction between metabolic pathways, modules, enzymes, reactions, and metabolites. In the correlation analysis, there were 11 differential metabolites whose correlation coefficient with clinical parameters was greater than 0.4, which were expected to be taken as biomarkers for clinical diagnosis. Besides, these 11 differential metabolites were assessed by ROC, and the areas under curve (AUCs) were all greater than 0.7, with a good sensitivity. Furthermore, combinational metabolic biomarkers, such as glutamic acid + leucine + phenylalanine and carnitine C 4: 0 + carnitine C18:1 + carnitine C5:0 were expected to be sensitive combinational biomarkers in clinical practice.ConclusionOur study provides a new insight to understand the pathogenesis mechanism, and the discriminating metabolites may help screen high-risk of MS in patients with PCOS and provide sensitive biomarkers for clinical diagnosis.

scholarly journals How to Screen and Prevent Metabolic Syndrome in Patients of PCOS Early: Implications From Metabolomics

2021 ◽  
Author(s):  
Xiaoxuan Zhao ◽  
Xiaoling Feng ◽  
Xinjie Zhao ◽  
Yuepeng Jiang ◽  
Xianna Li ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Clinical Diagnosis ◽  
Polycystic Ovary ◽  
Ultra Performance Liquid Chromatography ◽  
Healthy Controls ◽  
Metabolic Characteristics ◽  
Increased Risk ◽  
Significant Difference ◽  
Pcos Group ◽  
Reproductive Endocrine

Abstract Background: Polycystic ovary syndrome (PCOS) is a complex reproductive endocrine disorder，with an increased risk of type 2 diabetes mellitus and cardiovascular disease, of which metabolic syndrome (MS) is an indispensable springboard to communicate PCOS and various comlications. Our aim was to study the potential metabolic characteristics of PCOS-MS, and identify sensitive biomarkers so as to provide targets for clinical screening, diagnosis and treatment.Methods: 44 PCOS patients with MS, 34 PCOS patients without MS and 32 healthy controls were studied. Plasma samples of subjects were tested by ultra performance liquid chromatography (UPLC) system combined with LTQ-orbi-trap mass spectrometry. The changes of metabolic characteristics from PCOS to PCOS-MS were systematically analyzed. Correlations between differential metabolites and clinical characteristics of PCOS-MS were assessed. Differential metabolites with high correlation were further evaluated by the receiver operating characteristic (ROC) curve to identify their sensitivity as screening indicators.Results: There were significant difference in general characteristics, reproductive hormone and metabolic parameters in PCOS-MS group when compared with PCOS group and healthy controls. We found 30 differential metabolites which were involved in 23 pathways when compared with PCOS group. The metabolic network further reflects the metabolic environment, including the interaction between metabolic pathways, modules, enzymes, reactions and metabolites.In the correlation analysis, 17 pairs of correlation coefficient between differential metabolites and clincal parameters were greater than 0.4, involving 11 metabolites that has the potential to be a marker for clinical diagnosis. They were assessed by ROC whose area under curve (AUC) were all greater than 0.7, with a good sensitivity. Furthermore, combinational metabolic biomarkers, such as glutamic acid+leucine+phenylalanine and carnitine C 4: 0+carnitine C18:1+carnitine C5:0 are expected to be sensitive combinational biomarkers in clinical practice.Conclusion: Our study provides a new insight to understand the pathogenesis mechanism, and the discriminating metabolites may help screen high-risk of MS in patients with PCOS and provide sensitive biomarkers for clinical diagnosis.

scholarly journals PREVALENCE OF NON-ALCOHOLIC FATTY LIVER DISEASE IN WOMEN WITH POLYCYSTIC OVARY SYNDROME AND ITS CORRELATION WITH METABOLIC SYNDROME

2015 ◽  
Vol 52 (2) ◽  
pp. 117-123 ◽  
Author(s):  
Mariana Drechmer ROMANOWSKI ◽  
Monica Beatriz PAROLIN ◽  
Alexandre C T FREITAS ◽  
Mauri J PIAZZA ◽  
Jorgete BASSO ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Liver Disease ◽  
Fatty Liver Disease ◽  
Polycystic Ovary ◽  
International Diabetes Federation ◽  
Control Group ◽  
Ovary Syndrome ◽  
Alcoholic Fatty Liver ◽  
Pcos Group ◽  
Alcoholic Fatty Liver Disease

Background The polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women at childbearing age. Metabolic syndrome is present from 28% to 46% of patients with PCOS. Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic expression of metabolic syndrome. There are few published studies that correlate PCOS and NAFLD. Objective To determine the prevalence of NAFLD and metabolic syndrome in patients with PCOS, and to verify if there is a correlation between NAFLD and metabolic syndrome in this population. Methods Study developed at Gynecology Department of Clinical Hospital of Federal University of Parana (UFPR). The sessions were conducted from April 2008 to January 2009. One hundred and thirty-one patients joined the analysis; 101 were diagnosed with PCOS and 30 formed the control group. We subdivided the PCOS patients into two subgroups: PCOS+NAFLD and PCOS. All the patients were submitted to hepatic sonography. For hepatoestheatosis screening, hepatic ecotexture was compared do spleen’s. For diagnosis of metabolic syndrome, we adopted the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) criteria, as well as the criteria proposed by International Diabetes Federation. Statistical analysis were performed with t of student and U of Mann-Whitney test for means and chi square for proportions. Results At PCOS group, NAFLD was present in 23.8% of the population. At control group, it represented 3.3%, with statistical significance (P=0.01). Metabolic syndrome, by NCEP/ATP III criteria, was diagnosed in 32.7% of the women with PCOS and in 26.6% of the women at control group (no statistical difference, P=0.5). At PCOS+DHGNA subgroup, age, weight, BMI, abdominal circumference and glucose tolerance test results were higher when compared to PCOS group (P<0.01). Metabolic syndrome by NCEP/ATPIII criteria was present in 75% and by International Diabetes Federation criteria in 95.8% of women with PCOS+NAFLD with P<0.01. Insulin levels at SOP+DHGNA were higher than at PCOS group with P<0.01. Conclusion Almost 25% of the patients with PCOS were diagnosed for NAFLD. Metabolic syndrome was present between 32.7% and 44.6% of patients with PCOS. At subgroup PCOS+NAFLD, metabolic syndrome is highly prevalent. These patients are more obese, with higher BMI and higher glucose levels.

scholarly journals 16S rDNA Full-Length Assembly Sequencing Technology Analysis of Intestinal Microbiome in Polycystic Ovary Syndrome

2021 ◽  
Vol 11 ◽  
Author(s):  
Sitong Dong ◽  
Jiao jiao ◽  
Shuangshuo Jia ◽  
Gaoyu Li ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Gut Microbiota ◽  
16S Rdna ◽  
Polycystic Ovary ◽  
Full Length ◽  
Healthy Controls ◽  
Sequencing Technology ◽  
Ovary Syndrome ◽  
Significant Difference ◽  
Pcos Group

ObjectiveTo study the characteristics and relationship of the gut microbiota in patients with polycystic ovary syndrome (PCOS).MethodWe recruited 45 patients with PCOS and 37 healthy women from the Reproductive Department of Shengjing Hospital. We recorded their clinical indexes, and sequenced their fecal samples by 16S rDNA full-length assembly sequencing technology (16S-FAST).ResultWe found decreased α diversity and different abundances of a series of microbial species in patients with PCOS compared to healthy controls. We found LH and AMH were significantly increased in PCOS with Prevotella enterotype when compared to control women with Prevotella enterotype, while glucose and lipid metabolism level remained no significant difference, and situations were opposite in PCOS and control women with Bacteroides enterotype. Ruminococcus gnavus, Prevotella stercorea, Dialister succinatiphilus and Bacteroides fragilis were more abundant while Christensenellaceae spp. were less abundant in the PCOS group. P. stercorea was significantly more prevalent in PCOS-not insulin resistance (NIR) compared to control-NIR and PCOS-not overweight (NOW) patient groups compared to control-NOW groups. Kyoto Encyclopedia Genes and Genomes reflecting pathways related to lipopolysaccharide biosynthesis were more abundant in the PCOS group.ConclusionOur study found gut microbiota that had different abundance in patients with PCOS compared to healthy controls. An intimate relationship was shown between the gut microbiota and pathological changes in PCOS. We suggest the gut microbiota should be taken into consideration in the treatment of symptoms of PCOS via drugs and diet.

scholarly journals Role of Single Nucleotide Variants in FSHR, GNRHR, ESR2 and LHCGR Genes in Adolescents with Polycystic Ovary Syndrome

Diagnostics ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 2327
Author(s):  
Lasma Lidaka ◽  
Laine Bekere ◽  
Adele Rota ◽  
Jekaterina Isakova ◽  
Gunta Lazdane ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Total Testosterone ◽  
Healthy Controls ◽  
Single Nucleotide Variants ◽  
Ovary Syndrome ◽  
Single Nucleotide ◽  
Pcos Group ◽  
Risk Patients ◽  
Major Allele

Background: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, affecting up to 16.6% of reproductive-age women. PCOS symptoms in adolescents comprise oligomenorrhoea/amenorrhoea and biochemical and/or clinical hyperandrogenism. Long-term health risks of PCOS patients include infertility, metabolic syndrome, type 2 diabetes and cardiovascular disease. Genetic factors have been proven to play a role in development of the syndrome and its symptoms. Objective: To investigate single nucleotide variants (SNVs) in the GNRHR, ESR2, LHCGR and FSHR genes in adolescent patients with PCOS and their association with PCOS symptoms. Methods: We conducted a cross-sectional study comprising of 152 adolescents: 63 patients with PCOS, 22 patients at risk of developing PCOS and 67 healthy controls. Participants were recruited from out-patients attending a gynaecologist at the Children’s Clinical University Hospital, Riga, Latvia, between January 2017 and December 2020. Genomic DNA was extracted from whole blood, and SNVs in the GNRHR, ESR2, LHCGR and FSHR genes were genotyped. The distributions of SNV genotypes were compared among the three groups and genotype-phenotype associations within the PCOS group were evaluated. Results: No statistically significant differences were found in the distributions of genotypes for GNRHR (rs104893837), ESR2 (rs4986938), LHCGR (rs2293275) and FSHR (rs6166, rs6165, rs2349415) among PCOS patients, risk patients and healthy controls. Within the PCOS group, ESR2 rs4986938 minor allele homozygous patients had a significantly higher level of total testosterone than major allele homozygous patients and heterozygous patients. A significantly higher total testosterone level was also observed in PCOS patients carrying the LHCGR rs2293275 minor allele compared with major allele homozygous patients. Conclusions: The SNVs ESR2 rs4986938 and LHCGR rs2293275 play a role in the phenotypic characteristics of PCOS. To fully uncover their influence on the development of PCOS and its symptoms, further studies of larger cohorts and a follow up of this study sample through to adulthood are required. Furthermore, studies of adolescent PCOS patients conducted prior to the latest European Society of Human Reproduction and Embryology (ESHRE) criteria (2018) should be re-evaluated as the study groups might include risk patients according to these updated criteria, thereby potentially significantly impacting the published results.

scholarly journals Evaluation of the Efficacy and Threshold of Serum Anti-mullerian Hormone (AMH) Levels for Diagnosis and Prediction of Polycystic Ovary Syndrome (PCOS) Among Indian Women.

2022 ◽  
Author(s):  
Sajad Sumji ◽  
Abid Bhat ◽  
Aafia Rashid ◽  
Imtiyaz wani ◽  
Vishnu Vasudevan ◽  
...  
Keyword(s):  
Operating Characteristic ◽  
Polycystic Ovary ◽  
Serum Testosterone ◽  
Ovary Syndrome ◽  
Indian Women ◽  
Menstrual Cycles ◽  
Diagnostic Threshold ◽  
Pcos Group ◽  
The Mean ◽  
Rotterdam Criteria

Abstract Purpose: PCOS women exhibit higher levels of AMH and has been proposed to add value to diagnosis of PCOS incase ambiguity. However, variable cutoffs of AHM for PCOS prediction have been reported. This study was designed to determine diagnostic threshold of serum AMH levels and its correlation with clinical, hormonal and ultrasonographic parameters among women with PCOS.Materials: In this prospective study, 113 women with PCOS as per Rotterdam criteria 2003 and 75 normo-ovulatory women were included. Clinical, biochemical, hormonal and sonographic assessment in addition to serum AMH levels were determined using standard methodology.Results: Mean age was comparable (23.43±3.42vs.24.21±3.18 years) between cases and controls. The mean number of menstrual cycles per year were lower while as mean BMI, FG score, and serum testosterone were higher in cases than controls (p<0.05). The mean serum AMH level was significantly higher in PCOS group (7.84±3.67vs. 3.23 ±1.56 ng/mL) than controls. The serum AMH levels showed a positive correlation(p<0.05) with LH/FSH ratio (r = 0.206, p = 0.029), number of ovarian follicles(r=0.461) and volume,(r=0.521), but no correlation significant with age and BMI. As per receiver operating characteristic (ROC) curve, cut-off was worked out to be 3.76 ng/mL with 86.7% sensitivity and 62.7% specificity. Conclusion: Serum AMH levels correlate positively with PCOM among PCOS women and may be a potent diagnostic marker of ovarian dysfunction either alone or in conjunction with other tools to ensure timely diagnosis and early treatment of the disorder.

scholarly journals Effects of Metformin on Reproductive, Endocrine, and Metabolic Characteristics of Female Offspring in a Rat Model of Letrozole-induced Polycystic Ovarian Syndrome With Insulin Resistant

2020 ◽  
Author(s):  
Yidong Xie ◽  
Li Xiao ◽  
Xiaohan Shi ◽  
Yifan Zhao ◽  
Xiaohong Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary Syndrome ◽  
Rat Model ◽  
Wistar Rats ◽  
Polycystic Ovary ◽  
Female Offspring ◽  
Ovary Syndrome ◽  
Metabolic Characteristics ◽  
Reproductive Endocrine ◽  
The Impact

Abstract Background: Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disorder that has many characteristic features including hyperandrogenemia, insulin resistance and obesity. The beneficial effects of metformin on reproduction, metabolism and endocrine, especially with the capacity to ameliorate insulin resistance (IR) in polycystic ovary syndrome (PCOS), place it as a good alternative for its widely prescribed, but its association with PCOS offspring remains uncertain. We aim to investigate the impact of metformin on reproductive, endocrine and metabolic characteristics in female offspring born to letrozole-induced PCOS-IR rats.Methods: 45 female wistar rats were implanted with letrozole-continuous-release pellets or placebo, subsequently treated with metformin or vehicle control, then mated with healthy male wistar rats. Estrous cycle, endocrine hormone profile, fasting insulin measurements and glucose tolerance test have been investigated and the expression of INSR in pancreas, FSHR and LHCGR in ovaries have been analyzed with Quantitative Real-time Polymerase Chain Reaction and Western Blotting assay.Results: Decreased conception rate and increased multiple pregnancy rates were found in PCOS-IR rats, which significantly improved after metformin treatment. Metformin significantly decreased the risk of body weight gain and increased INSR expression of pancreas in female F1 offspring in PCOS-IR rats. Decreased FSHR and increased LHCGR expressions in ovary were observed in female F1 rats of PCOS-IR and PCOS-IR+Met group. Nevertheless, there were no significant differences of INSR, FSHR and LHCGR expressions in female F2 offspring of PCOS-IR rats, as well as other PCOS phenotypes.Conclusions: The current study indicates that widespread reproductive, endocrine and metabolic changes in letrozole induced PCOS-IR rat model, but those PCOS phenotypes could not be inherit to offspring generations stably. Metformin may contribute to improve obesity, hyperinsulinemia and insulin resistance of female F1 offspring in PCOS-IR. The results of this study can be used as a theoretical basis for supporting metformin-using in the treatment of PCOS-IR patients.

scholarly journals Circulating ANGPTL8 Is Associated with the Presence of Metabolic Syndrome and Insulin Resistance in Polycystic Ovary Syndrome Young Women

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Danlan Pu ◽  
Ling Li ◽  
Jingxia Yin ◽  
Rui Liu ◽  
Gangyi Yang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Lipid Metabolism ◽  
Polycystic Ovary Syndrome ◽  
Young Women ◽  
Metabolic Disorders ◽  
Polycystic Ovary ◽  
Serum Marker ◽  
Healthy Controls ◽  
Ovary Syndrome

Background. ANGPTL8 has been reported to be a regulator of lipid metabolism, and it is associated with insulin resistance (IR) and metabolic syndrome (MetS). We investigated whether ANGPTL8 plays a role in MetS. Methods. ANGPTL8 and adiponectin concentrations were measured in PCOS patients with or without MetS and in their corresponding healthy controls. The association of circulating ANGPTL8 with adiponectin and other parameters was also examined. Results. Circulating ANGPTL8 concentrations were higher in PCOS women with MetS than in those without MetS and in the controls (P<0.01). ANGPTL8 was positively correlated with age, BMI, FAT%, WHR, SBP, TG, FBG, HbA1c, Fins, and HOMA-IR (all P<0.01) in the study populations and negatively associated with adiponectin and M-values (P<0.001). In addition, ANGPTL8 was positively correlated with PRL, LH, TEST, and FAI and negatively correlated with SHBG (all P<0.01). ROC curve analyses showed that the AUCMetS was 0.87 (P<0.001), with a sensitivity of 92.4% and specificity of 75.4%, and the AUCIR was 0.82 (P<0.01), with a sensitivity of 76.4% and specificity of 75.6%. Conclusion. ANGPTL8 levels progressively decrease from PCOS patients with MetS to those without MetS and may be a serum marker associated with the degree of metabolic disorders.

scholarly journals Anti-Müllerian Hormone as a Diagnostic Marker in Egyptian Infertile Polycystic Ovary Syndrome Females: Correlations with Vitamin D, Total Testosterone, Dyslipidemia and Anthropometric Parameters

2018 ◽  
Vol 37 (4) ◽  
pp. 448-455 ◽  
Author(s):  
Engy Bakeer ◽  
Rasha Radwan ◽  
Ahmed El Mandoury ◽  
Abdullah Abd El Rahman ◽  
Mohamed Gad ◽  
...  
Keyword(s):  
Vitamin D ◽  
Polycystic Ovary Syndrome ◽  
Diagnostic Marker ◽  
Polycystic Ovary ◽  
Characteristic Curve ◽  
Total Testosterone ◽  
Healthy Controls ◽  
Anthropometric Parameters ◽  
Ovary Syndrome ◽  
Pcos Group

Summary Background: Recent studies have highlighted the role of anti-Müllerian hormone (AMH) in numerous ovarian disorders. Polycystic Ovary Syndrome (PCOS) is one of the major causes of infertility in Egypt. Several reports have linked PCOS with vitamin D deficiency. This investigation illustrates the possibility of using serum AMH for PCOS diagnosis in infertile Egyptian females, determines the variables affecting it and correlates it with serum 25(OH)D, testosterone, dyslipidemia and anthropometric parameters. Methods: All parameters were assessed either with ELISA or colorimetrically in 53 infertile PCOS women and 17 age matched apparently healthy controls diagnosed according to Rotterdam consensus. Results: Serum AMH, total testosterone, triacylglycerol (TG) levels and BMI were significantly higher in PCOS group compared to healthy controls (p=0.0239, p=0.0381, p=0.0457, and p=0.0067, respectively), while serum 25(OH)D levels and HDL-cholesterol (HDL-C) were significantly lower (p=0.0397 and p=0.0443, respectively). No significant correlation existed between AMH and 25(OH) D, BMI and dyslipidemia markers. AMH was found to have a significant negative correlation with age and a highly significant positive one with total testosterone in PCOS group (r=-0.303, p=0.027 and r=0.370, p=0.008, respectively). In the receiver operating characteristic curve of AMH, the cut-off value was 42.63 pmol/L with a specificity of 59% and a sensitivity of 82%. Multivariate regression analysis showed total testosterone to be the only determinant for AMH (β=0.381 and p=0.038). Conclusions: There should be a future trend of using AMH as a diagnostic marker for PCOS in Egyptian females. The variation in serum AMH levels is determined by total testosterone.

scholarly journals Dysbiosis of the Saliva Microbiome in Patients With Polycystic Ovary Syndrome

2021 ◽  
Vol 10 ◽  
Author(s):  
Na Li ◽  
Yangyang Li ◽  
Chen Qian ◽  
Qing Liu ◽  
Wei Cao ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Diurnal Rhythm ◽  
Polycystic Ovary ◽  
Control Group ◽  
Healthy Controls ◽  
Ovary Syndrome ◽  
Time Points ◽  
Diurnal Oscillation ◽  
Salivary Microbiota ◽  
Pcos Group

Significant differences in salivary microbiota communities between polycystic ovary syndrome (PCOS) patients and healthy controls have been reported, and interestingly, some salivary microbiota exhibit diurnal oscillation in healthy people. However, whether the diurnal oscillation of salivary microbiota is present in PCOS patients is unknown. In this study, we describe the differences in the saliva microbiome between the PCOS group and the control group at different time points over 24 h. 16S rRNA gene amplicon sequencing was performed on salivary and fecal samples from 10 PCOS patients and 10 healthy controls, and salivary samples were collected at 6-h intervals over 24 h (Zeitgeber (ZT)0, ZT6, ZT12, and ZT18). Among the salivary samples, those from the PCOS group showed significant differences from those of the control group at each time point. Differences were evident in taxa level and metabolic pathways. Interestingly, we found that PCOS disrupted the diurnal rhythm of the salivary microbiota abundance, as determined in the group of healthy women. In addition, no similar changes were found in PCOS patients and controls between the oral and fecal microbiota, including differential microbiota at the phylum level. In this study, significant differences in the composition of the salivary microbiota between PCOS and healthy women were detected at different time points. We also showed that the diurnal rhythm of relative abundance of the salivary microbiota was disrupted in patients with PCOS, which might be related to development of oral-related diseases and systematic metabolic disorders.

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