The effects of obesity and polycystic ovary syndrome on serum lipocalin-2 levels: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Lipocalin-2 is a novel adipokine that appears to play a role in the development of insulin resistance. Serum lipocalin-2 levels are elevated in obese patients. Obesity and insulin resistance are cardinal characteristics of the polycystic ovary syndrome (PCOS). However, there are limited data on serum lipocalin-2 levels in patients with PCOS. The aim of the present study was to assess serum lipocalin-2 levels in PCOS.</p> <p>Methods</p> <p>We studied 200 patients with PCOS and 50 healthy female volunteers.</p> <p>Results</p> <p>Serum lipocalin-2 levels were slightly higher in women with PCOS compared with controls (65.4 +/- 34.3 vs. 60.3 +/- 26.0 ng/ml, respectively) but this difference did not reach statistical significance. In contrast, lipocalin-2 levels were higher in overweight/obese women with PCOS than in normal weight women with the syndrome (76.2 +/- 37.3 vs. 54.5 +/- 27.2 ng/ml, respectively; p < 0.001). Serum lipocalin-2 levels were also higher in overweight/obese controls compared with normal weight controls (70.1 +/- 24.9 vs. 50.5 +/- 23.7 ng/ml, respectively; p = 0.004). In the total study population (patients with PCOS and controls), lipocalin-2 levels were independently correlated with the body mass index (p < 0.001). In women with PCOS, lipocalin-2 levels were independently correlated with the waist (p < 0.001).</p> <p>Conclusions</p> <p>Obesity is associated with elevated serum lipocalin-2 levels. In contrast, PCOS does not appear to affect lipocalin-2 levels.</p

Transcriptional regulation of endothelin-1 expression by advanced glycation end-products in human aortic endothelium is mediated via NF-kappaΒ and AP-1

Advanced Glycation End-products (AGEs) are produced by the non-enzymatic glycation of proteins, lipids and nucleic acids, resulting in an overload of highly reactive molecules of endogenous or exogenous (dietary) origin. Increased AGE levels in circulation and concomitant elevated tissue deposition have been associated with diabetic complications, atheromatosis, ageing and more recently with polycystic ovary syndrome pathogenesis. Interaction of AGEs with their receptor RAGE (Receptor for AGEs) activates intracellular signaling pathways which induce targeted gene expression in endothelium including upregulation of cell adhesion molecules and endothelin-1 (ET-1), implicated in vascular injury and endothelial dysfunction. The purpose of this study is to explore the molecular mechanism of AGE-induced regulation of ET-1 gene/protein expression in human endothelial cells and investigate its functional relevance in normal rat vascular endothelium

The importance of myo-inositol and D-chiro-inositol to support fertility and reproduction

This review details the physiologic roles of two insulin sensitizers, myo-inositol (MI) and D-chiro-inositol (DCI). In the human ovary, MI is a second messenger of follicle stimulating hormone (FSH) and DCI is an aromatase inhibitor. These activities allow a treatment for polycystic ovary syndrome (PCOS) to be defined based on the combined administration of MI and DCI, where the best MI:DCI ratio is 40:1. In addition, MI plays a pivotal role in the physiology of reproduction, and has beneficial effects on the development of oocytes, spermatozoa, and embryos. By contrast, DCI has little effect on spermatozoa, but high concentrations in the ovary can negatively affect the quality of oocytes and the blastocyst. Overall, the evidence in the literature supports the beneficial effects of MI in both female and male reproduction, warranting clinical use of MI in assisted reproductive treatment (ART).Cette revue détaille les rôles physiologiques de deux sensibilisateurs à l'insuline, le myo-inositol (MI) et le D-chiro-inositol (DCI). Dans l'ovaire humain, le MI est un second messager de l'hormone folliculostimulante (FSH) et le DCI est un inhibiteur de l'aromatase. Ces activités permettent de définir un traitement du syndrome des ovaires polykystiques (SOPK) basé sur l'administration combinée de MI et de DCI, où le meilleur rapport MI:DCI est de 40:1. En outre, le MI joue un rôle essentiel dans la physiologie de la reproduction et a des effets bénéfiques sur le développement des ovocytes, des spermatozoïdes et des embryons. En revanche, le DCI a peu d'effet sur les spermatozoïdes, mais des concentrations élevées dans l'ovaire peuvent avoir un effet négatif sur la qualité des ovocytes et du blastocyste. Dans l'ensemble, les données de la littérature confirment les effets bénéfiques du MI dans la reproduction féminine et masculine, ce qui justifie l'utilisation clinique du MI dans l'assistance médicale à la procréation

The effect of dietary glycotoxins (AGEs) on the tissues of female rats

INTRODUCTION: Advanced glycation end-products (AGEs) are highly reactive molecules, formed by non enzymatic glycation of proteins, lipids, and nucleic acids, which may induce structural and vascular changes. Glyoxalase detoxification system composed of glyoxalase-I and II (GLO-I, II), is the main clearing system implicated in the protection against cellular damage due to cytotoxic metabolites such as AGEs. Recently, ovarian tissue has emerged as a new target of excessive AGEs deposition been associated either with a high AGEs diet in experimental animals or hyperandrogenaemic disorders like Polycystic Ovarian Syndrome (PCOS) in humans.AIM OF THE STUDY: This study was designed to investigate the impact of dietary AGEs and androgens in rat tissues and specifically in the ovarian tissue. The ovarian GLO-I activity was also measured.MATERIALS AND METHODS: Two groups of female rats at 21 days of age were studied. The first composed of normal non-androgenized (NAN, Group A, n=18) and the second of androgenized prepubertal (AN) rats (Group B, n=29). Both groups were further randomly assigned, either to high (HA) or low (LA) AGE content diet for 3 months. Serum AGE levels (U/ml) were measured by AGE-specific competitive ELISA. Immunohistochemical analysis was performed to estimate accumulation of AGEs on ovarian homogenates. Determination of ovarian GLO-1 activity was assessed spectrophotometrically by following the formation of S-D-lactoylglutathione.RESULTS: High deposition of AGEs was observed mainly in the ovarian granulosa layers of female rats fed with high AGEs diet (p ≤ 0.001), as well as the granulosa of the androgenized rats. There was strong positive correlation between serum AGEs and androgens levels (rs=0.604, p≤0.001), whereas there was a negative correlation between serum AGEs and levels of Estrogens (rs=0.563, p≤0.001) and Progesterone (rs=0.609, p≤0.001). The activity of ovarian GLO-I was significantly reduced in normal NAN animals fed with HA diet compared to LA (p=0.006). Furthermore, GLO-I activity was markedly reduced in AN animals compared to NAN (p≤0.001) when fed with the corresponding diet type. In addition, ovarian GLO-I activity was positively correlated with the body weight gain (rs=0.533, p<0.001), Estradiol (rs=0.326, p=0.033) and progesterone levels (rs=0.500, p<0.001). A negative correlation was observed between GLO-I activity and AGEs expression in the ovarian granulosa cell layer of all groups with marginal statistical significance (rs=-0.263, p=0.07).CONCLUSION: The present study demonstrated that high AGEs diets, as well as high levels of androgens, alter the metabolic and hormonal profile of female rats, while they have an inhibitory effect on the ovarian GLO-1 activity. These results reveal a potential mechanism of reduced detoxification of AGEs regarding the ovarian impairment observed under conditions of deranged nutritional habits, such as a high AGEs diet and/or hormonal parameters, such as hyperandrogenaemia.ΕΙΣΑΓΩΓΗ: Τα προϊόντα προχωρημένης μη ενζυματικής γλυκοζυλίωσης (Advanced glycation end-products, AGEs) είναι μόρια υψηλής αντιδραστικής ικανότητας που σχηματίζονται από την μη ενζυμική γλυκοζυλίωση πρωτεϊνών, λιπιδίων και νουκλεϊκών οξέων και μπορούν να επάγουν δομικές αλλαγές των κυττάρων. Το σύστημα της Γλυοξαλάσης αποτελείται από την Γλυοξαλάση-1 και -2 (Glyoxalase-1,-2, GLO-1,-2), είναι το βασικό σύστημα κάθαρσης που εμπλέκεται στην προστασία της κυτταρικής βλάβης λόγω τοξικών μεταβολιτών όπως τα AGEs. Πρόσφατα, ο ωοθηκικός ιστός έχει αναδειχθεί ως ένας νέος ιστό-στόχος εναπόθεσης AGEs, γεγονός που έχει συσχετισθεί τόσο με διατροφή υψηλής περιεκτικότητας σε γλυκοτοξίνες (AGEs) σε πειραματόζωα, όσο και σε καταστάσεις υπερανδρογοναιμίας στους ανθρώπους, όπως το Σύνδρομο των Πολυκυστικών Ωοθηκών (ΣΠΩ).ΣΚΟΠΟΣ ΜΕΛΕΤΗΣ: Η μελέτη σχεδιάστηκε προς διερεύνηση της επίδρασης των διατροφικών γλυκοτοξινών (AGEs) καθώς και της περίσσειας ανδρογόνων στους ιστούς θηλέων επιμύων και ειδικότερα στον ωοθηκικό ιστό, ενώ μελετήθηκε και η δραστικότητα του ενζύμου κάθαρσης, της ωοθηκικής Γλυοξαλάσης-1 (GLO-1).ΥΛΙΚΑ ΚΑΙ ΜΕΘΟΔΟΙ: Μελετήθηκαν δύο ομάδες θηλέων επιμύων, η πρώτη από φυσιολογικούς, μη αρρενοποιημένους επίμυες και η δεύτερη από αρρενοποιημένους προεφηβικούς επίμυες. Και οι δύο ομάδες χωρίστηκαν σε δύο υπο-ομάδες και η κάθε υπο-ομάδα αντιστοιχήθηκε σε δίαιτα υψηλής ή χαμηλής περιεκτικότητας σε γλυκοτοξίνες για 3 μήνες. Τα AGEs του ορού (U/ml) μετρήθηκαν με AGE-ειδική ανταγωνιστική ELISA. Ανοσοϊστοχημική ανάλυση πραγματοποιήθηκε για την εκτίμηση της εναπόθεσης των AGEs στα παρασκευάσματα ωοθηκικού ιστού. Ο προσδιορισμός της δραστικότητας της ωοθηκικής Γλυοξαλάσης-1 έγινε με τη χρήση φασματοφωτομετρίας προσμετρώντας το σχηματισμό προϊόντος S-D-λακτουλογλουταθειόνης.ΑΠΟΤΕΛΕΣΜΑΤΑ: Βρέθηκε υψηλή εναπόθεση των AGEs κυρίως στην κοκκιώδη στιβάδα των επιμύων υπό διατροφή υψηλή σε γλυκοτοξίνες (p ≤ 0.001), καθώς και στους αρρενοποιημένους επίμυες. Υπήρχε ισχυρή θετική συσχέτιση μεταξύ των AGEs του ορού και των επιπέδων των ανδρογόνων (rs=0.604, p≤0.001), ενώ αρνητική ήταν η συσχέτισή των επιπέδων τους με τα επίπεδα Οιστραδιόλης (rs=0.563, p≤0.001) και Προγεστερόνης (rs=0.609, p≤0.001). Η δραστικότητας της ωοθηκικής Γλυοξαλάσης-1 βρέθηκε σημαντικά μειωμένη στους φυσιολογικούς μη αρρενοποιημένους επίμυες υπό διατροφή υψηλή σε γλυκοτοξίνες συγκριτικά με εκείνους σε διατροφή χαμηλής σε γλυκοτοξίνες (p=0.006). Επίσης, η δραστικότητα του ενζύμου ήταν μειωμένη στους αρρενοποιημένους επίμυες συγκριτικά με τους μη αρρενοποιημένους (p≤0.001) με την αντίστοιχη διατροφή. Η δραστικότητα της GLO-1 έδειξε θετική συσχέτιση με την αύξηση του σωματικού βάρους των επιμύων (rs=0.533, p<0.001), τα επίπεδα Οιστραδιόλης (rs=0.326, p=0.033) και Προγεστερόνης (rs=0.500, p<0.001). Αρνητική συσχέτιση παρατηρήθηκε ανάμεσα στην εναπόθεση των AGEs στην κοκκιώδη στιβάδα των ωοθυλακίων σε όλες τις ομάδες με οριακή στατιστική σημαντικότητα (rs=-0.263, p=0.07).ΣΥΜΠΕΡΑΣΜΑΤΑ: Η μελέτη αυτή έδειξε πως τροφή υψηλής περιεκτικότητας σε γλυκοτοξίνες (AGEs) καθώς και οι υψηλές συγκεντρώσεις ανδρογόνων, διαταράσσουν το μεταβολισμό και το ορμονικό προφίλ των πειραματόζωων, ενώ επιδρούν ανασταλτικά στην δραστικότητα του ενζύμου κάθαρσης των AGEs, της Γλυοξαλάσης-1 (GLO-1). Τα αποτελέσματα αυτά αναδεικνύουν έναν πιθανό μηχανισμό μειωμένης κάθαρσης των AGEs σε σχέση με την ωοθηκική δυσλειτουργία που παρατηρείται σε περιπτώσεις τόσο διαταραγμένων διατροφικών συνηθειών, όσο και ορμονικών παραμέτρων, όπως η υπερανδρογοναιμία

Metabolic syndrome and polycystic ovary syndrome ... and vice versa

The metabolic syndrome (MS) and the polycystic ovary syndrome (PCOS) appear to be interrelated, although they are distinct entities. Women with PCOS appear to be commonly affected by MS, while women with MS may display reproductive or endocrine features of PCOS. These clinical observations appear to be only partly attributable to the association of both syndromes with obesity and imply a reciprocal pathophysiologic relationship between PCOS and MS with potentially significant clinical sequelae. Adult women with MS are at a greater risk of developing cardiovascular disease; women with PCOS also appear to carry such an increased risk in their postmenopausal life. Conversely, women with MS may experience reproductive disturbances, reminiscent of PCOS, more commonly than their counterparts from the general population. This review presented the current epidemiology of MS in adults and adolescents with PCOS, as well as the limited amount of data on the prevalence of features of PCOS among women with MS or MS features. We also discuss the potential pathophysiologic mechanisms underlying the relationship between these interweaving, but distinct, syndromes. Arq Bras Endocrinol Metab. 2009;53(2):227-237

Endocrine Disrupting Chemicals: An Occult Mediator of Metabolic Disease

Endocrine disrupting chemicals (EDCs), a heterogeneous group of exogenous chemicals that can interfere with any aspect of endogenous hormones, represent an emerging global threat for human metabolism. There is now considerable evidence that the observed upsurge of metabolic disease cannot be fully attributed to increased caloric intake, physical inactivity, sleep deficit, and ageing. Among environmental factors implicated in the global deterioration of metabolic health, EDCs have drawn the biggest attention of scientific community, and not unjustifiably. EDCs unleash a coordinated attack toward multiple components of human metabolism, including crucial, metabolically-active organs such as hypothalamus, adipose tissue, pancreatic beta cells, skeletal muscle, and liver. Specifically, EDCs' impact during critical developmental windows can promote the disruption of individual or multiple systems involved in metabolism, via inducing epigenetic changes that can permanently alter the epigenome in the germline, enabling changes to be transmitted to the subsequent generations. The clear effect of this multifaceted attack is the manifestation of metabolic disease, clinically expressed as obesity, metabolic syndrome, diabetes mellitus, and non-alcoholic fatty liver disease. Although limitations of EDCs research do exist, there is no doubt that EDCs constitute a crucial parameter of the global deterioration of metabolic health we currently encounter

Defects in insulin signaling pathways in ovarian steroidogenesis and other tissues in polycystic ovary syndrome (PCOS)

The polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age today. Women with PCOS often demonstrate defective ovarian steroid biosynthesis and present with hyperandrogenemia. Moreover, 50-70% of PCOS women are insulin resistant and hyperinsulinemic. Insulin acts on the ovary via its own receptor and interacts with gonadotrophins, modulating steroidogenesis. The precise role of insulin and the molecular mechanisms that take place are not yet completely explicated. This review will be focused on insulin’s action on the ovary and other target tissues, describing the intracellular signaling pathways implicated in steroidogenesis and their defects in women with PCOS. (C) 2008 Elsevier Ltd. All rights reserved