Obesity and polycystic ovary syndrome influence on intestinal permeability at fasting, and modify the effect of diverse macronutrients on the gut barrier.

Women with the extremely prevalent polycystic ovary syndromegather multiple cardiovascular risk factors and chronic subclinical inflammation. Interactions between diet, adiposity, and gut microbiota modulate intestinal permeabilityand bacterial product translocation, and may contribute to the chronic inflammation process associated with the polycystic ovary syndrome. In the present study, we aimed to address the effects of obesity, functional hyperandrogenism, and diverse oral macronutrients on intestinal permeabilityby measuring circulating markers of gut barrier dysfunction and endotoxemia. Participants included 17 non-hyperandrogenic control women, 17 women with polycystic ovary syndrome, and 19 men that were submitted to glucose, lipid, and protein oral loads. Lipopolysaccharide-binding protein, plasma soluble CD14, succinate, zonulin family peptide, and glucagon-like peptide-2 were determined at fasting and after oral challenges. Macronutrient challenges induced diverse changes on circulating intestinal permeabilitybiomarkers in the acute postprancial period, with lipids and proteins showing the most unfavorable and favorable effects, respectively. Particularly, lipopolysaccharide-binding protein, zonulin family peptide, and glucagon-like peptide-2 responses were deregulated by the presence of obesity after glucose and lipid challenges. Obese subjects showed higher fasting intestinal permeabilitybiomarkers levels than non-obese individuals, except for plasma soluble CD14. The polycystic ovary syndromeexacerbated the effect of obesity further increasing fasting glucagon-like peptide-2, lipopolysaccharide-binding protein, and succinate concentrations. We observed specific interactions of the polycystic ovary syndromewith obesity in the postprandial response of succinate, zonulin family peptide, and glucagon-like peptide-2. In summary, obesity and polycystic ovary syndromemodify the effect of diverse macronutrients on the gut barrier, and alsoinfluence intestinal permeabilityat fasting,contributing to the morbidity of functional hyperandrogenism by inducing endotoxemia and subclinical chronic inflammation.

Serum metabolomics profiling by proton nuclear magnetic resonance spectroscopy reveals sexual dimorphism and masculinization of intermediate metabolism in women with polycystic ovary syndrome (PCOS).

BACKGROUND: The polycystic ovary syndrome (PCOS) is associated with insulin resistance, obesity and cardiometabolic comorbidities. We here challenged the hypothesis, using state-of-the art proton nuclear magnetic resonance spectroscopy metabolomics profiling, that androgen excess in women induces also a certain masculinization of intermediate metabolism that is modulated by obesity. METHODS: Participants were 53 Caucasian young adults, including 17 women with classic PCOS consisting of hyperandrogenism and ovulatory dysfunction, 17 non-hyperandrogenic women presenting with regular menses, and 19 healthy men, selected in order to be similar in terms of age and body mass index (BMI). Half of the subjects had obesity defined by a body mass index ≥ 30 kg/m2. Subjects maintained the same diet unrestricted in carbohydrates for 3 days before sampling and maintained their lifestyle and exercise patterns prior and during the study. Plasma samples were submitted to proton nuclear magnetic resonance spectroscopy metabolomics profiling. RESULTS: Obesity associated a metabolomics profile mainly characterized by increased branched chain and aromatic aminoacids. Regardless of obesity, this unfavorable profile also characterized men as compared with control women, and was shared by women with PCOS. Notably, the negative impact of obesity on metabolomics profile was restricted to women, with obese men showing no further deterioration when compared with their non-obese counterparts. CONCLUSIONS: Serum metabolomics profiling by proton nuclear magnetic resonance spectroscopy reveals sexual dimorphism, and masculinization of intermediate metabolism in women with PCOS, further suggesting a role for sex and sex hormones in the regulation of intermediate metabolism.

Bloodletting has no effect on the blood pressure abnormalities of hyperandrogenic women taking oral contraceptives in a randomized clinical trial.

Normoferritinemic women with functional hyperandrogenism show a mild iron overload. Iron excess, hyperandrogenism, and cardioautonomic dysfunction contribute to blood pressure (BP) abnormalities in these patients. Furthermore, combined oral contraceptives (COC) prescribed for hyperandrogenic symptoms may worse BP recordings. Iron depletion by phlebotomy appears to lower BP in other acquired iron overload conditions. We aimed to determine the effect of iron depletion on the office BP, ambulatory BP monitoring, and frequency of hypertension in patients with functional hyperandrogenism submitted to standard therapy with COC. We conducted a phase 2 randomized, controlled, parallel, open-label clinical trial (NCT02460445) in adult women with functional hyperandrogenism including hyperandrogenic polycystic ovary syndrome and idiopathic hyperandrogenism. After a 3-month run-in period of treatment with 35 µg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to three scheduled bloodlettings or observation for another 9 months. Main outcome measures were the changes in office BP, 24-h-ambulatory BP, and frequency of hypertension in both study arms. From June 2015 to June 2019, 33 women were included in the intention-to-treat analyses. We observed an increase in mean office systolic BP [mean of the differences (MD): 2.5 (0.3-4.8) mmHg] and night-time ambulatory systolic BP [MD 4.1 (1.4-6.8) mmHg] after 3 months on COC. The percentage of nocturnal BP non-dippers also increased, from 28.1 to 92.3% (P < 0.001). Office and ambulatory BP did not change throughout the experimental period of the trial, both when considering all women as a whole or as a function of the study arm. The frequency of the non-dipping pattern in BP decreased during the experimental period [OR 0.694 (0.577-0.835), P < 0.001], regardless of the study arm. Decreasing iron stores by scheduled bloodletting does not override the BP abnormalities caused by COC in women with functional hyperandrogenism.

Postprandial responses of circulating energy homeostasis mediators to single macronutrient challenges: influence of obesity and sex hormones.

We analysed the influence of obesity, sex and sex steroids on the postprandial responses of circulating energy homeostasis mediators and their receptors to different macronutrient challenges. Seventeen women with polycystic ovary syndrome (PCOS, 8 with obesity), 17 non-hyperandrogenic control women (8 with obesity) and 19 control men (9 with obesity) were submitted, on alternate days, to isocaloric (300 kcal) oral glucose, lipid and protein loads. We evaluated serum ghrelin, leptin, soluble leptin receptor and adiponectin levels and the leukocyte gene expression of ghrelin (GHRL) and its receptor (GHSR), leptin receptor (LEPR) and adiponectin receptor 1 (ADIPOR1) during the macronutrient challenges. The postprandial responses of circulating energy homeostasis mediators were entirely different than those of their related genes. After macronutrient loads the postprandial response of serum energy homeostasis mediators showed a generalized physiological decrease that was blunted in subjects with obesity but was not influenced by sex, sex hormones or PCOS. However, gene expression of GHRL, LEPR and ADIPOR1 showed a marked increase following the ingestion of glucose compared with lipids and proteins, regardless of obesity and sex steroids. The physiological decrease after macronutrient loads, that was deregulated in obesity, did not reflect the acute leukocyte gene expression mainly after glucose, and may suggest a possible role for ghrelin, leptin and adiponectin in the postprandial inflammatory process.

Acute-phase glycoprotein profile responses to different oral macronutrient challenges: Influence of sex, functional hyperandrogenism and obesity.

Acute-phase glycoprotein 1H-NMR spectroscopy profiles serve as surrogate markers of chronic inflammation in metabolic disorders such as obesity, diabetes and polycystic ovary syndrome (PCOS). The latter is associated with increased height-to-width (H/W) ratios of GlycA and GlycB after fasting, but not to glycoprotein areas, regardless of obesity. We studied the responses to separate glucose, lipid and protein oral challenges of five glycoprotein variables (GlycA, GlycB, and GlycF areas and the GlycA and GlycB H/W ratios) in 17 women with PCOS, 17 control women, and 19 healthy men. Glucose and protein ingestion resulted into decreases in all glycoprotein variables, whereas lipid ingestion increased GlycA, GlycF and induced minimal changes in GlycB and GlycB H/W. We found no effects of obesity or group of subjects on postprandial glycoprotein variables regardless of the macronutrient being ingested. However, a statistically significant interaction indicated that obesity blunted the decrease in some of these variables in control women and men, whereas obese women with PCOS showed larger changes when compared with their non-obese counterparts. In conclusion, acute-phase glycoprotein profiles indicate an anti-inflammatory response during postprandial phase that is less pronounced after lipid ingestion, and is counteracted by the chronic inflammatory background associated with obesity and PCOS.

2D Diffusion-Ordered 1 H-NMR Spectroscopy Lipidomic Profiling after Oral Single Macronutrient Loads: Influence of Obesity, Sex, and Female Androgen Excess.

SCOPE: Postprandial dysmetabolism plays a major role in the pathogenesis of metabolic disorders such as obesity and the polycystic ovary syndrome (PCOS). The aim is to characterize the circulating lipoprotein particle profiles in response to oral glucose, lipid, and protein challenges. METHODS AND RESULTS: 17 women with PCOS, 17 control women, and 19 healthy men selected to have similar age and body mass index are studied. Blood samples are collected following the ingestion of 300 kcal in the form of glucose, lipids, or proteins, and they are submitted to two-dimensional (2D) diffusion-ordered 1 H-NMR spectroscopy. Regardless of macronutrient administered, the number of very low-density (VLDL) particles increases whereas low density-lipoprotein (LDL) decreases. High density-lipoprotein (HDL) particles increase only after lipid ingestion. Obese subjects show an increase in the number of large VLDL particles and a decrease in large LDL particles, with a significant reduction in the average particle size of LDL. Patients with PCOS show a particularly unfavorably smaller LDL particle size response to oral lipid intake, regardless of obesity. CONCLUSIONS: Oral macronutrient challenges induce immediate class-specific postprandial changes in particle number and size of lipoproteins, with lipids inducing a more pro-atherogenic lipoprotein profile compared to glucose and proteins, particularly in obese subjects and women with PCOS.

TLR2 and TLR4 Surface and Gene Expression in White Blood Cells after Fasting and Oral Glucose, Lipid and Protein Challenges: Influence of Obesity and Sex Hormones.

We studied if macronutrients of the diet have different effects on leukocyte activation, and if these effects are influenced by sex hormones or obesity. We analyzed leukocyte cell surface and gene expression of toll-like receptors 2 and 4 (TLR2 and TLR4) during fasting and after macronutrient loads in women with polycystic ovary syndrome and female and male controls. Fasting TLR2 surface expression in neutrophils was higher in men than in women. Obese subjects presented higher TLR2 gene expression than nonobese individuals, particularly in men. In contrast, surface TLR4 expression was lower in men and in obese individuals. Postprandial cell-surface expression decreased similarly after all macronutrient loads. Neutrophil TLR2 decreased only in obese subjects whereas TLR4 showed a greater decrease in nonobese individuals. However, TLR2 gene expression increased after glucose ingestion and decreased during the lipid load, while TLR4 was induced in response to lipids and mostly to glucose. Postprandial TLR gene expression was not influenced by group of subjects or obesity. Both cell-surface and gene postprandial expression inversely correlated with their fasting levels. These responses suggest a transient compensatory response aiming to prevent postprandial inflammation. However, obesity and sex hormones showed opposite influences on surface expression of TLR2 and TLR4, but not on their gene expression, pointing to regulatory posttranscriptional mechanisms.

Postprandial inflammatory responses after oral glucose, lipid and protein challenges: Influence of obesity, sex and polycystic ovary syndrome.

BACKGROUND & AIMS: Most evidence linking the polycystic ovary syndrome (PCOS) with chronic low-grade inflammation has been obtained in the fasting state. We have studied the postprandial inflammatory response to oral glucose, lipid and protein challenges and the possible influences of obesity, sex and PCOS on these responses. METHODS: On alternate days, we submitted 17 women with PCOS (9 non-obese, 8 obese), 17 control women (9 non-obese, 8 obese) and 19 control men (10 non-obese, 9 obese) to isocaloric (300 Kcal) oral macronutrient loads. We assayed serum for TNF-α, IL-6, IL-18, IL-10, pentraxin-3 and galectin-3 concentrations and leukocytes for expression of TNF, IL6, IL10 and their receptors TNFRSF1B, IL6R and IL10RA. RESULTS: Circulating IL-6 levels decreased after glucose and protein ingestion but slightly increased after oral lipid intake. Leukocyte IL6 expression did not change after the ingestion of any macronutrient yet IL6R expression increased during all macronutrient challenges, the largest increase being observed after glucose ingestion. Serum TNF-α similarly decreased during either macronutrient load, whereas TNF expression increased after macronutrient ingestion, the highest increase observed after oral glucose. TNFRSF1B expression also increased after glucose intake but not after lipid or protein ingestion. No global effect of obesity or group on postprandial circulating IL-6, TNF-α, or IL6, IL6R, TNF and TNFRSF1B expression was found. Circulating IL-18 concentrations decreased during all oral challenges, whereas in case of galectin-3 and pentraxin-3 only the protein load caused a reduction in its concentrations. Of the genes studied here, IL10 showed the largest increase in expression throughout all the postprandial curves, particularly after glucose. Obesity blunted the increase in IL10 expression. IL10RA expression decreased after glucose ingestion but remained unchanged during lipid and protein loads. CONCLUSIONS: Glucose ingestion, as opposed to lipid and protein intake, results into the largest increase in leukocyte gene expression of inflammatory mediators. The expression of the anti-inflammatory cytokine IL10 was the largest observed here, suggesting a compensatory mechanisms against postprandial inflammation that may be blunted in obesity. However, these responses did not translate into the circulating concentrations of these inflammatory mediators during the immediate postprandial phase.

Metabolic Cytokines at Fasting and During Macronutrient Challenges: Influence of Obesity, Female Androgen Excess and Sex.

SCOPE: Cytokines have pleiotropic functions within the organism and their levels may be influenced by obesity, visceral adiposity and sex hormones. Diet composition may also affect their systemic concentrations during fasting and in the postprandial period. Hence, we studied the influence of sex steroids and obesity on the circulating levels of a panel of metabolic cytokines in the fasting state and after single macronutrient challenges. METHODS: On alternate days we submitted 17 women with polycystic ovary syndrome (PCOS) (9 non-obese, 8 obese), 17 non-hyperandrogenic control women (9 non-obese, 8 obese) and 19 control men (10 non-obese, 9 obese) to isocaloric oral glucose, lipid and protein loads. Serum levels of omentin-1, vaspin, lipocalin-2, adipsin, PAI-1, chemerin, FGF-21 and FGF-23 were determined by Luminex multiplex technology. RESULTS: During fasting, obese patients presented higher levels of PAI-1, chemerin and adipsin but decreased FGF-23 and omentin-1 compared with non-obese subjects. Vaspin showed sexual dimorphism with lower levels in men than women with PCOS and female controls. Following macronutrient ingestion, most metabolic cytokines presented a similar physiological response consisting of a decrease in circulating concentrations, which was inversely associated with the fasting levels of these molecules. Protein intake caused the major postprandial decrease whereas glucose did not significantly reduce PAI-1, FGF-23 and vaspin, and even increased FGF-21. Regardless of the macronutrient administered, vaspin levels showed a larger reduction in non-obese individuals while the decrease in PAI-1 was particularly noticeable in the obese subgroup. The postprandial reductions of omentin-1 and FGF-23 after glucose and protein loads were influenced by obesity. No major differences were found between patients with PCOS and male and female controls. CONCLUSIONS: Obesity, but not PCOS or sex, markedly influences metabolic cytokine levels at fasting and after macronutrient ingestion. The observed postprandial decrease in their circulating concentrations might represent a physiological compensatory mechanism against food-induced inflammation and oxidative stress. This mechanism is altered by obesity and is differently modulated by macronutrients, suggesting a larger contribution of glucose to stressful postprandial responses.

Glycoprotein A and B Height-to-Width Ratios as Obesity-Independent Novel Biomarkers of Low-Grade Chronic Inflammation in Women with Polycystic Ovary Syndrome (PCOS).

The polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women in reproductive age. Obesity and low-grade chronic inflammation are frequently associated with PCOS. Recently, proton nuclear magnetic resonance (1H-NMR)-derived glycoprotein profiles have emerged as potential biomarkers that reflect systemic inflammation in type 2 diabetes, obesity, and other pathological processes. The aim of this work is to study plasma glycoprotein profiles as metabolic/inflammatory biomarkers underlying PCOS and its association with inflammation and obesity. We used 1H-NMR spectroscopy to study five glycoprotein variables, namely GlycA, GlycB, and GlycF and the height-to-width (H/W) ratio of GlycA and GlycB, in 17 women with PCOS (9 non-obese and 8 obese), 17 control women (9 non-obese and 8 obese), and 19 healthy men (10 non-obese and 9 obese). H/W ratios of GlycA and GlycB, but not glycoprotein areas, were specifically associated with PCOS independently of obesity. When considered as a whole, obese subjects presented higher GlycA, GlycB, and GlycF areas and higher H/W GlycA and GlycB ratios than their non-obese counterparts. All glycoprotein variables were associated with hsCRP, IL-6, and TNF-α, showing different correlations among PCOS, women, and men. Our present exploratory results suggest that 1H-NMR-derived glycoprotein profiles might serve as novel diagnostic markers of low-grade chronic inflammation in women with PCOS.

Gut Microbiota and the Polycystic Ovary Syndrome: Influence of Sex, Sex Hormones, and Obesity.

Context: Gut microbiota play a major role in health and disease by influencing physiology, metabolism, nutrition, and immune function. Objective: To evaluate the composition of gut microbiota in women with polycystic ovary syndrome (PCOS), focusing on the influence of sex, sex hormones and obesity on the associations found. Design: Cross-sectional study. Setting: Academic hospital. Participants: We recruited 15 women with PCOS, 16 nonhyperandrogenic control women, and 15 control men. Participants were classified as nonobese (<30 kg/m2) or obese (≥30 kg/m2) according to their body mass index. Interventions: Standardization of diet for 3 consecutive days (at least 300 g of carbohydrates per day) followed by fecal sampling and a standard 75-g oral glucose tolerance test. Main Outcome Measures: Analysis of bacterial abundance and composition of gut microbiota by massive sequencing of 16S ribosomal DNA amplicons in a MiSeq platform (Illumina). Results: α Bacterial diversity was reduced in women compared with men, and ß diversity was reduced particularly in obese patients with PCOS. Women with PCOS presented with specific abnormalities in gut microbiota consisting of an increased abundance of the Catenibacterium and Kandleria genera. When all participants as a whole were considered, indexes of bacterial diversity and the abundance of several bacterial genera correlated positively with serum androgen concentrations and negatively with estradiol levels. Conclusions: The diversity and composition of the gut microbiota of young adults are influenced by the combined effects of sex, sex hormone concentrations, and obesity, presenting with specific abnormalities in women with PCOS.

Effects of glucose ingestion on circulating inflammatory mediators: Influence of sex and weight excess.

BACKGROUND & AIMS: Low-grade chronic inflammation is involved in the pathophysiology of obesity. However, little is known about the influence of sex and sex hormones on surrogate inflammatory markers and mediators, particularly after glucose ingestion. DESIGN: Observational study. METHODS: We measured the circulating concentrations of interleukin-6, interleukin-18, macrophage migration inhibitory factor, matrix metallopeptidase-9, monocyte chemotactic protein-1 and pentraxin-3, in the fasting state and during a 75 g oral glucose tolerance test, in 24 women and 25 men. Eleven men and 11 women were lean whereas 14 men and 13 women had weight excess. RESULTS: Anti-inflammatory cytokines (interleukin-6 and interleukin-18) were increased in the fasting state and/or decreased in some women during the oral glucose tolerance test, as opposed to inflammatory mediators such as macrophage migration inhibitory factor and matrix metallopeptidase-9 that increased during the oral glucose tolerance test especially in subjects with weight excess. Body mass index and waist circumference were the main determinants of these changes. Fasting pentraxin-3 levels were especially increased in lean women in parallel to a decrease in free testosterone levels, and decreased during the oral glucose tolerance test as opposed to the increase in insulin concentrations. CONCLUSIONS: The circulating concentrations of markers of low-grade chronic inflammation in young healthy adults are not only influenced by obesity but also by abdominal adiposity, fasting and glucose ingestion and, in some cases, by sex and sex hormones. These influences should be considered when these markers are used as surrogate markers of the inflammatory milieu associated with obesity.

Association of TLR2 S450S and ICAM1 K469E polymorphisms with polycystic ovary syndrome (PCOS) and obesity.

Toll-like receptors (TLRs) are activated by inflammatory stimuli and influence endothelial functions, contributing to the pathogenesis of atherosclerosis. We investigate the influence of polymorphisms in the genes encoding toll-like receptor 2 (TLR2) and 4 (TLR4) and endothelial adhesion molecules on polycystic ovary syndrome (PCOS) and its interaction with obesity. Ten single nucleotide polymorphisms were genotyped in 305 women with PCOS and 166 non-hyperandrogenic control women. In obese women, TLR2 S450S and ICAM1 K469E polymorphisms differently influenced metabolic variables and PCOS, respectively. Irrespective of PCOS, variant alleles of TLR2 S450S increased triglycerides, fasting insulin levels, and insulin resistance in obese women. TLR2 S450S interacted with obesity and PCOS on androstenedione levels, mutant alleles were associated with increased androstenedione concentrations in all women, with the exception of obese patients with PCOS (P=0.034). Regarding ICAM1 K469E, homozygosis for K469 alleles was more frequent in PCOS, but only in obese women (P=0.014). K469 alleles were also related to increased body mass index (P=0.017) and diastolic blood pressure (P=0.034). Moreover, ICAM1 K469E interacted with obesity and PCOS on serum triglyceride levels (P=0.019) and with PCOS on serum sex hormone-binding globulin concentrations (P=0.006). In conclusion, TLR2 S450S and ICAM1 K469E polymorphisms may be associated with PCOS and metabolic comorbidities in obese women.

A nontargeted study of muscle proteome in severely obese women with androgen excess compared with severely obese men and nonhyperandrogenic women.

OBJECTIVE: Androgen excess in women is frequently associated with muscle insulin resistance, especially in obese women with polycystic ovary syndrome. However, whether this is a primary event or the result of indirect mechanisms is currently debated. DESIGN: This is an observational study. METHODS: We obtained skeletal muscle biopsies during bariatric surgery from severely obese men (n=6) and women with (n=5) or without (n=5) androgen excess. We used two-dimensional differential gel electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight mass spectrometry to identify muscle proteins showing differences in abundance between the groups of obese subjects. RESULTS: Women with hyperandrogenism presented the lowest abundances of glycogen phosphorylase, pyruvate kinase, ß-enolase, glycerol-3-phosphate dehydrogenase, creatine kinase M-type, and desmin, whereas the abundances of these molecules were similar in control women and men. CONCLUSION: According to our nontargeted proteomic approach, women with hyperandrogenism show a specific alteration of the skeletal muscle proteome that could contribute to their insulin resistance. Because men do not show similar results, this alteration does not appear to be the direct effect on muscle of androgen excess, but rather the consequence of indirect mechanisms that merit further studies.

Influence of adrenal hyperandrogenism on the clinical and metabolic phenotype of women with polycystic ovary syndrome.

OBJECTIVE: To study the impact of adrenal hyperandrogenism (AH; defined as DHEAS concentration >95th percentile of a healthy female control population) on cardiometabolic risk factors associated with polycystic ovary syndrome (PCOS). DESIGN: Cross-sectional study. SETTING: Academic hospital. PATIENT(S): Two-hundred ninety-eight consecutive women with PCOS, of whom 120 were obese (body mass index [BMI] ≥30 kg/m(2)) and 178 nonobese (BMI <30 kg/m(2)). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Comprehensive evaluation of cardiovascular risk factors, including 75-g oral glucose tolerance test, office blood pressure, lipid profile, and low-grade inflammatory markers. RESULT(S): Patients with AH (AH-PCOS) had higher insulin circulating levels and lower insulin sensitivity than their counterparts without AH (non-AH-PCOS). Obesity, but not AH, was the main contributor to the presence of glucose tolerance disorders. Both obesity and AH increased the prevalence of prehypertension and hypertension. AH diminished high-density lipoprotein (HDL) levels in nonobese PCOS women in parallel with a decrease in total cholesterol levels, leading to a total to HDL cholesterol ratio similar to that of nonobese non-AH-PCOS patients. Furthermore, AH blunted the deleterious effect of obesity on the total cholesterol/HDL ratio, with the ratio of obese AH-PCOS patients being similar to that of nonobese PCOS patients with or without AH. CONCLUSION(S): The presence of AH in women with PCOS is associated with reduced insulin sensitivity and increased blood pressure but may have beneficial impact on the lipid profile. Obesity is the main determinant of the clustering of cardiovascular risk factors in PCOS women.

Identification of reduced circulating haptoglobin concentration as a biomarker of the severity of pulmonary embolism: a nontargeted proteomic study.

Risk stratification of patients with pulmonary embolism (PE) may identify patients at high risk of early death who may benefit from more intensive surveillance or aggressive therapy. Nontargeted proteomics may identify biomarkers useful for the risk stratification of patients with acute symptomatic pulmonary embolism (PE). We studied 6 patients presenting with low-risk PE and 6 patients presenting with intermediate (n = 3) or high-risk (n = 3) PE. Two-dimensional difference gel electrophoresis was used to compare their plasma protein abundances. Candidate protein markers were identified by matrix assisted laser desorption ionization time-of-flight mass spectrometry. A panel of four biomarkers (haptoglobin, hemopexin, α2-macroglobulin, and Ig α1-chain C region) showed differences in plasma abundance among patients with acute symptomatic PE of different severity. Haptoglobin and hemopexin were decreased, whereas α2-macroglobulin and Ig α1-chain C region were increased, in patients with high or intermediate-risk PE compared with low-risk PE patient. In a separate clinical population consisting of 104 adults with acute PE, serum haptoglobin concentrations had an 85% chance of correctly identifying patients with high-risk PE according to receiving operating characteristics curve analysis. Moreover, serum haptoglobin concentrations ≤1 g/l showed an 80% sensitivity and a 96% specificity for the diagnosis of high-risk PE. Nontargeted proteomics identified protein biomarkers for the severity of PE that are involved in iron metabolism pathways and acute-phase response. Among them, reduced serum haptoglobin concentrations show a high accuracy for the biochemical detection of high-risk PE.

Sexual dimorphism in adipose tissue function as evidenced by circulating adipokine concentrations in the fasting state and after an oral glucose challenge.

STUDY QUESTION: Do the circulating levels of a panel of adipokines involved in glucose metabolism exhibit sexual dimorphism in the fasting state and after an oral glucose load? SUMMARY ANSWER: Our results indicate sexual dimorphism in the circulating concentrations of adipokines involved in intermediate metabolism in the fasting state and during an oral glucose load. This finding suggests an influence of sex steroids on adipose tissue function. WHAT IS KNOWN ALREADY: Sexual dimorphism in adipose tissue distribution fully develops after puberty and modulates the risk for cardiometabolic disorders. However, the possibility that adipose tissue function exhibits sexual dimorphism as well as its distribution is unproved. STUDY DESIGN, SIZE, DURATION: Cross-sectional case-control study including 32 subjects. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sixteen subjects with weight excess (8 men and 8 women, including 4 overweight and 4 obese subjects in each group) and 16 normal weight healthy volunteers (8 men and 8 women) presenting with similar age were submitted to a 75-g oral glucose tolerance test (oGTT). We measured circulating concentrations of insulin, glucose, chemerin, lipocalin-2, omentin-1, leptin and adiponectin and calculated their areas under the oGTT curve (AUC). MAIN RESULTS AND THE ROLE OF CHANCE: Leptin and adiponectin concentrations were higher throughout the oGTT in women compared with men. Lipocalin-2 concentrations decreased during the oGTT in the whole group of study subjects. However, these levels remained higher in men with weight excess compared with normal weight men, whereas in women with weight excess lipocalin-2 levels at the end of the oGTT were lower compared with normal weight women. Sex was among the main determinants of the AUC of omentin-1 and leptin in linear regression models, and lower estradiol and testosterone concentrations were related to higher AUC of chemerin and omentin-1, respectively. Subjects with weight excess had higher AUC of chemerin and leptin and lower AUC of omentin-1 and adiponectin levels, independently of sex. LIMITATIONS, REASONS FOR CAUTION: We included a relatively small sample size and, because this was a cross-sectional study, we cannot infer causality to the associations between the changes in circulating adipokine concentrations and the variables studied here. WIDER IMPLICATIONS OF THE FINDINGS: Sexual dimorphism in adipose tissue function should be considered when studying adiposity and obesity, and also when designing strategies for their diagnosis and management.

Prevalence of hyperprolactinaemia in female premenopausal blood donors.

OBJECTIVE: The prevalence of asymptomatic hyperprolactinaemia has been widely studied in certain populations such as antipsychotic drugs users, infertile women or patients with primary hypothyroidism, but data on the prevalence of hyperprolactinaemia and macroprolactinaemia in the healthy population are very scarce in the literature. We aimed to obtain an unbiased estimation of the prevalence in premenopausal women of: (i) hyperprolactinaemia and (ii) its aetiology, including macroprolactinaemia and stress-related hyperprolactinaemia, while considering simultaneously the use of hormonal contraceptives. DESIGN: Prevalence survey. SUBJECTS: Three-hundred and ninety-three consecutive premenopausal women reporting spontaneously for blood donation. MEASUREMENTS: We performed an exhaustive clinical history and physical examination, establishing the presence of hirsutism, acne, alopecia, menstrual dysfunction and reproductive history. We also measured serum prolactin (PRL) (ruling out macroprolactinaemia when indicated), thyrotrophin, total testosterone, androstendione, sex hormone binding globulin and dehydroepiandrosterone sulphate concentrations. RESULTS: Serum PRL concentrations were increased in 16 of 393 women (4·1% prevalence, 95% CI: 2·1-6·0). The prevalence of macroprolactinaemia was 0·6% (95% CI: 0-1) in the total female blood donor population and was 12·5% (95% CI: 6-31) among hyperprolactinaemic patients. The remaining hyperprolactinaemic women had stress-related hyperprolactinaemia as the more likely aetiology. Finally, the frequency of hyperprolactinaemia was similar in users and nonusers of hormonal contraceptives (4·5% and 3·9% respectively, P = 0·209). CONCLUSIONS: The prevalence of hyperprolactinaemia in healthy female blood donors is low and is not influenced by the use of hormonal contraceptives. Pathological causes are very rare with stress-related hyperprolactinaemia and macroprolactinaemia being the most frequent causes of hyperprolactinaemia in these women.

A nontargeted proteomic study of the influence of androgen excess on human visceral and subcutaneous adipose tissue proteomes.

CONTEXT: Sex hormones, particularly androgens, may influence not only adipose tissue distribution but also its functions. OBJECTIVE: We aimed to evaluate if sexual dimorphism in body composition is accompanied by differences in the protein abundance of adipose tissue by applying a nontargeted proteomic approach. DESIGN: This was a case-control study. SETTINGS: The setting was an academic hospital. PATIENTS: Twenty-one morbidly obese patients, including 7 men, 7 women showing no evidence of androgen excess, and 7 hyperandrogenic women with polycystic ovary syndrome. INTERVENTIONS: We obtained subcutaneous (SAT) and visceral (VAT) adipose tissue samples during bariatric surgery. MAIN OUTCOME MEASURES: Protein abundance in VAT and SAT was analyzed by 2-dimensional differential gel electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight coupled to mass spectrometry. Results were validated by RT-PCR. RESULTS: The abundance of 2 spots of peroxiredoxin 6, creatine kinase B-type, 2 spots of selenium-binding protein 1, ruvB-like 2, 4-trimethylaminobutyraldehyde dehydrogenase, and albumin were higher in VAT compared with SAT in women with polycystic ovary syndrome. Men showed a similar pattern, whereas no difference between adipose tissue depots was observed in control women. Other proteins showed differences between VAT and SAT, confirming previous studies, or between the groups of subjects, without interaction between both effects. Several findings were confirmed by RT-PCR. CONCLUSIONS: Sexual dimorphism influences the abundance of several proteins in VAT and SAT. The patterns of abundance in adipose tissue depots of several proteins involved in metabolic processes were similar in women with androgen excess and in men, suggesting that androgens influence adipose tissue function.