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      Oxidative stress and metabolic markers in pre- and postnatal polycystic ovary syndrome rat protocols

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          Abstract

          Background

          Several studies have described an enhanced inflammatory status and oxidative stress balance disruption in women with polycystic ovary syndrome (PCOS). However, there is scarce information about redox markers in the blood of androgenized animal models. Here, we evaluated the serum/plasma oxidative stress marker and metabolic parameter characteristics of prenatal (PreN) and postnatal (PostN) androgenized rat models of PCOS.

          Materials and methods

          For PreN androgenization (n=8), 2.5 mg of testosterone propionate was subcutaneously administered to dams at embryonic days 16, 17, and 18, whereas PostN androgenization (n=7) was accomplished by subcutaneously injecting 1.25 mg of testosterone propionate to animals at PostN day 5. A unique control group (n=8) was constituted for comparison.

          Results

          Our results indicate that PostN group rats exhibited particular modifications in the oxidative stress marker, an increased plasma ferric-reducing ability of plasma, and an increased antioxidant capacity reflected by higher albumin serum levels. PostN animals also presented increased total cholesterol and triglyceride–glucose levels, suggesting severe metabolic disarrangement.

          Conclusion

          Study findings indicate that changes in oxidative stress could be promoted by testosterone propionate exposure after birth, which is likely associated with anovulation and/or lipid disarrangement.

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          Most cited references40

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          Circulating markers of oxidative stress and polycystic ovary syndrome (PCOS): a systematic review and meta-analysis.

          BACKGROUND Oxidative stress might be associated with polycystic ovary syndrome (PCOS), but relatively small studies published to date do not permit reaching a definitive conclusion. We aimed at conducting a systematic review and meta-analysis of studies evaluating circulating markers of oxidative stress in patients with PCOS. METHODS We conducted a systematic review of studies reporting circulating markers of oxidative stress in women with PCOS and controls published up to June 2012, using Entrez PubMed and EMBASE online facilities. Meta-analysis calculated standardized mean differences (SMDs) and 95% confidence intervals (95CI). RESULTS From 1633 potential studies identified electronically, 68 studies, including 4933 PCOS patients and 3671 controls, were selected. For each of nine circulating markers of oxidative stress, an individual meta-analysis was conducted. Compared with control women, patients with PCOS presented higher circulating concentrations of homocysteine (23% increase, SMD 0.6, 95CI, 0.4-0.8), malondialdehyde (47% increase, SMD 1.9, 95CI 1.2-2.6) and asymmetric dimethylarginine (36% increase, SMD 1.1, 95CI 0.6-1.6), and increased superoxide dismutase activity (34% increase, SMD 1.0, 95CI 0.5-1.4) and decreased glutathione levels (50% decrease, SMD -3.7, 95CI -6.2 to -1.2) and paraoxonase-1 activity (32% decrease, SMD -0.9, 95CI -1.3 to -0.4). Similar results were found when restricting the analyses to studies in which patients and controls were matched for age and body mass index. CONCLUSIONS Circulating markers of oxidative stress are abnormal in women with PCOS independent of weight excess. This finding suggests that oxidative stress may participate in the pathophysiology of this common disorder.
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            A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome.

            Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, abdominal obesity, and insulin resistance. However, its etiology is unclear, and its management is often unsatisfactory or requires a diversified approach. Here, we describe a new rat PCOS model, the first to exhibit both ovarian and metabolic characteristics of the syndrome. Female rats received the nonaromatizable androgen dihydrotestosterone (DHT) or the aromatase inhibitor letrozole by continuous administration, beginning before puberty, to activate androgen receptors. Adult DHT rats had irregular cycles, polycystic ovaries characterized by cysts formed from atretic follicles, and a diminished granulosa layer. They also displayed metabolic features, including increased body weight, increased body fat, and enlarged mesenteric adipocytes, as well as elevated leptin levels and insulin resistance. All letrozole rats were anovulatory and developed polycystic ovaries with structural changes strikingly similar to those in human PCOS. Our findings suggest that the formation of a "hyperplastic" theca interna reflects the inclusion of luteinized granulosa cells in the cyst wall rather than true hyperplasia. We conclude that the letrozole model is suitable for studies of the ovarian features of human PCOS, while the DHT model is suitable for studies of both ovarian and metabolic features of the syndrome.
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              Adipose tissue has aberrant morphology and function in PCOS: enlarged adipocytes and low serum adiponectin, but not circulating sex steroids, are strongly associated with insulin resistance.

              Comprehensive characterization of the adipose tissue in women with polycystic ovary syndrome (PCOS), over a wide range of body mass indices (BMIs), is lacking. Mechanisms behind insulin resistance in PCOS are unclear. To characterize the adipose tissue of women with PCOS and controls matched pair-wise for age and BMI, and to identify factors, among adipose tissue characteristics and serum sex steroids, that are associated with insulin sensitivity in PCOS. Seventy-four PCOS women and 31 controls were included. BMI was 18-47 (PCOS) and 19-41 kg/m(2) (controls). Anthropometric variables, volumes of subcutaneous/visceral adipose tissue (magnetic resonance imaging; MRI), and insulin sensitivity (clamp) were investigated. Adipose tissue biopsies were obtained to determine adipocyte size, lipoprotein lipase (LPL) activity, and macrophage density. Circulating testosterone, free testosterone, free 17β-estradiol, SHBG, glycerol, adiponectin, and serum amyloid A were measured/calculated. Comparison of 31 pairs revealed lower insulin sensitivity, hyperandrogenemia, and higher free 17β-estradiol in PCOS. Abdominal adipose tissue volumes/distribution did not differ in the groups, but PCOS women had higher waist-to-hip ratio, enlarged adipocytes, reduced adiponectin, and lower LPL activity. In regression analysis, adipocyte size, adiponectin, and waist circumference were the factors most strongly associated with insulin sensitivity in PCOS (R(2)=0.681, P < 0.001). In PCOS, adipose tissue has aberrant morphology/function. Increased waist-to-hip ratio indicates abdominal/visceral fat accumulation, but this is not supported by MRI. Enlarged adipocytes and reduced serum adiponectin, together with a large waistline, rather than androgen excess, may be central factors in the pathogenesis/maintenance of insulin resistance in PCOS.
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                Author and article information

                Journal
                J Inflamm Res
                J Inflamm Res
                Journal of Inflammation Research
                Journal of Inflammation Research
                Dove Medical Press
                1178-7031
                2018
                15 May 2018
                : 11
                : 193-202
                Affiliations
                [1 ]Laboratory of Biotechnology and Animal Reproduction, BioRep, Federal University of Santa Maria, Santa Maria, Rio Grande do Sul
                [2 ]Department of Veterinary Medicine, University of São Paulo, São Paulo
                [3 ]Laboratory of Clinical Biochemistry, Department of Clinical and Toxicological Analysis
                [4 ]Department of Clinical Medicine, Federal University of Santa Maria, Santa Maria, Rio Grande do Sul, Brazil
                Author notes
                Correspondence: Fabio Vasconcellos Comim, Department of Clinical Medicine, Federal University of Santa Maria, Av Roraima 1000, Building 26, Room 1337, Santa Maria, Rio Grande do Sul 97105900, Brazil, Tel +55 55 3220 8752, Email fabio.comim@ 123456ufsm.br
                Article
                jir-11-193
                10.2147/JIR.S160264
                5960249
                29805266
                2bdb82fb-5c15-4168-a560-bc3a3da2248f
                © 2018 Serrano Mujica et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Categories
                Original Research

                Immunology
                animal models of pcos,oxidative stress,prenatal,postnatal
                Immunology
                animal models of pcos, oxidative stress, prenatal, postnatal

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