SUN-LB5 GnRHR ECL-2 Epitopes Targeted by Activating Autoantibodies in Polycystic Ovary Syndrome

Abstract Background: Activating autoantibodies (AAb) are directed to the gonadotropin releasing hormone receptor second extracellular loop (GnRHR-ECL2) and are pathogenic when induced in rats. We previously reported GnRHR-ECL2-AAb were elevated in sera from patients with PCOS (Rotterdam criteria) compared to ovulatory infertile controls (OIC). Methods:Human studies: ELISA detection of GnRHR Abs used a synthetic h-GnRHR-ECL2 28 mer peptide (LifeTein) as the target antigen. We assayed AAb activity in GnRHR transfected cells using a GeneBLAzer FRET assay (Invitrogen). ELISA AAb epitope locations on the ECL2 were identified on a minipin plate (pins 1-11 containing sequential 2 aa offsetting octapeptides, Mimotope, Inc) using sera from 30 PCOS subjects, 33 OIC and 18 normal controls (NC). Results:Human sera: An ELISA assay for GnRHR-ECL2-AAbs in the PCOS group was markedly higher than the NC group (P<0.0001) and the OIC subjects (P<0.003). The minipin data demonstrated one or more positive OD peaks on pins 4 (20%), 5 (47%) and 8 (47%) which shared L-aa sequences FSQC or CSFSQ. OIC had only 5 subjects with peaks at minipins 4 or 5 and NC had only 3 lower peaks and one with higher OD values over all minipins. GnRHR-AAb Specific Activity (SA) was estimated by measuring serum activity before and after suppression of AAb sensitive activity by addition of retro inverso D-aa (RID) peptides. These were specifically designed to mimic and decoy the AAb L-aa epitope sequences of pins 5 and 8). SA was measured in 10 selected PCOS and 10 OIC subjects who had positive ELISA values. The baseline activity in the PCOS group was significantly higher than OIC (P < 0.01) and dropped 50% with preincubation with peak 5 RID and 25% with peak 8 RID. The addition of both peak 5 and peak 8 RID suppressed the PCOS group activity to OIC levels (P > 0.2). There was no significant change in activity in the OIC subjects by the addition of peaks 5 + 8 RID peptides. Conclusion: These PCOS GnRHR-AAb data confirm the presence of significant activation of the GnRHR by AAb targeted to specific epitope(s) proximate to the disulfide GnRHR-ECL2 linkage to the nearby ECL1. These data are compatible with a pathophysiological role for GnRHR-AAb in PCOS and may provide both diagnostic and therapeutic opportunities.

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Bilateral Adrenal Hyperplasia as a Possible Mechanism for Hyperandrogenism in Women With Polycystic Ovary Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2015-4019 ◽

2016 ◽

Vol 101 (9) ◽

pp. 3353-3360 ◽

Cited By ~ 8

Author(s):

Evgenia Gourgari ◽

Maya Lodish ◽

Meg Keil ◽

Ninet Sinaii ◽

Evrim Turkbey ◽

...

Keyword(s):

Polycystic Ovary ◽

Hormone Secretion ◽

Urinary Free Cortisol ◽

Adrenocortical Function ◽

High Dose ◽

High Dose Dexamethasone ◽

Free Cortisol ◽

Before And After ◽

Pcos Group ◽

Adrenal Volume

Abstract Context: Androgen excess may be adrenal and/or ovarian in origin; we hypothesized that a subgroup of patients with polycystic ovarian syndrome (PCOS) may have some degree of abnormal adrenocortical function. Objective: The objective of the study was to evaluate the pituitary adrenal axis with an oral low- and high-dose dexamethasone-suppression test (Liddle's test) in women with PCOS. Design: This was a case-control study. Setting: The study was conducted at the National Institutes of Health Clinical Center. Participants: A total of 38 women with PCOS and 20 healthy volunteers (HV) aged 16–29 years participated in the study. Main Outcome Measures: Urinary free cortisol (UFC) and 17-hydroxysteroids (17OHS) before and after low- and high-dose dexamethasone and assessment of adrenal volume by computed tomography scan were measured. Results: Twenty-four-hour urinary 17OHS and UFC were measured during day 1 to day 6 of the Liddle's test. Baseline UFC levels were not different between PCOS and HVs; on the day after the completion of high-dose dexamethasone administration (d 6), UFC was higher in the PCOS group (2.0 ± 0.7 μg/m2·d) than the HV group (1.5 ± 0.5) (P = .038). On day 5, 17OHS and UFC were negatively correlated with adrenal volumes (left side, rp = −0.47, P = .009, and rp = −0.61, P < .001, respectively). PCOS patients above the 75th percentile for UFC and/or 17OHS after high-dose dexamethasone (n = 15) had a significantly smaller total adrenal volume (6.9 ± 1.9 cm3 vs 9.2 ± 1.8 cm3, P = .003) when compared with the remaining PCOS patients (n = 22), but they did not have worse insulin resistance or hyperandrogenism. Conclusions: In a subset of young women with PCOS, we detected a pattern of glucocorticoid secretion that mimicked that of patients with micronodular adrenocortical hyperplasia: they had smaller adrenal volumes and higher steroid hormone secretion after dexamethasone compared with the group of PCOS with appropriate response to dexamethasone.

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A Properly Balanced Reduction Diet and/or Supplementation Solve the Problem with the Deficiency of These Vitamins Soluble in Water in Patients with PCOS

Nutrients ◽

10.3390/nu13030746 ◽

2021 ◽

Vol 13 (3) ◽

pp. 746

Author(s):

Małgorzata Szczuko ◽

Iwona Szydłowska ◽

Jolanta Nawrocka-Rutkowska

Keyword(s):

Liquid Chromatography ◽

Vitamin C ◽

Dietary Intervention ◽

Polycystic Ovary ◽

Glycaemic Index ◽

Reproductive Age ◽

Control Group ◽

Before And After ◽

Pcos Group ◽

Biochemical Analyses

Polycystic ovary syndrome (PCOS) is an increasingly common problem for women in the reproductive age throughout the entire world. A reduction diet with a low glycaemic index (GI) has proved to support the treatment of PCOS. The aim of the study was to analyse the influence of the diet on the level of vitamins soluble in water. The study included 55 women, 40 of which suffered from PCOS (identified by means of the Rotterdam Criteria) and 15 healthy women of the Caucasian race. The level of vitamins before and after the dietary intervention was measured. The diet was a reduction diet with a reduced glycaemic index (GI). Biochemical analyses were made on the basis of liquid chromatography—Infinity 1260 Binary liquid chromatography (LC) Agilent Technology. The level of vitamins in the serum was analysed together with the consumption before and after the dietary intervention. A higher level of vitamin C in the plasma was observed before and after the dietary intervention in the PCOS group in comparison to the control group despite the lower intake of this vitamin in the PCOS group. The remaining vitamins were at a comparable or lower level (B1, B3, B5, B6 and B12). After the dietary intervention, only B1 and B9 were at a clearly lower level (a trend of p = 0.093 and p = 0.085). A properly balanced reduction diet with reduced GI improves the supply of vitamins in women with PCOS. An additional recommendation should be the additional supplementation of B1, niacinamide and the combination of folates with inositol. The level of vitamin C in the plasma may not be a good marker of its supply in the PCOS group.

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Evaluation of the pathophysiological role of Fetuin A levels in adolescents with polycystic ovary syndrome

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0524 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Elvan Bayramoğlu ◽

Semra Çetinkaya ◽

Servan Özalkak ◽

Erdal Kurnaz ◽

Gülşah Demirci ◽

...

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Free Testosterone ◽

Ovary Syndrome ◽

Fetuin A ◽

Pathophysiological Role ◽

Pcos Group ◽

Natural Inhibitor

Abstract Objectives Polycystic ovary syndrome (PCOS) is an endocrinopathy, in which hyperandrogenism and hyperinsulinism have both occurred. Fetuin-A, a natural inhibitor of tyrosine kinase, leads to insulin resistance. The aim was to evaluate the relationship between fetuin-A and hyperandrogenism and hyperinsulinism and the role of fetuin-A in the pathophysiology of PCOS. Methods Thirty-eight cases with PCOS and 40 healthy adolescents were included in the study. PCOS and controls were divided into obese/non-obese subgroups. LH, FSH, total and free testosterone (TT, FT), SHBG, androstenedione, DHEAS were measured in patients with PCOS. Fasting glucose, insulin, lipid profile, AST, ALT, HsCRP, and fetuin levels of PCOS patients and healthy controls were also measured. Results Fetuin-A levels were higher in PCOS patients than in controls. In the obese-PCOS group, when compared to non-obese PCOS patients; the levels of SHBG and HDL were low while cholesterol, LDL, triglyceride, HOMA-IR, FT, FAI, and HSCRP levels were high, but Fetuin-A levels were similar. In the obese-PCOS group, fetuin-A levels were higher than in obese-controls. HOMA-IR and fetuin-A levels were higher in non-obese PCOS patients than in non-obese controls. In the PCOS group, fetuin-A was positively correlated with TT, FT, FAI and androstenedione and negatively correlated with SHBG. Regression analysis demonstrated that FT, SHBG, and androstenedione significantly predicted fetuin-A levels (R2=54%). In non-obese PCOS patients and controls, fetuin-A was positively correlated with insulin and HOMA-IR. Conclusions These results suggest a relationship between androgen levels and fetuin-A in PCOS cases, independent of insulin resistance, and may shed light on further studies.

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Oxidative Stress Status in Patients with Choledocholithiasis: Before and After Endoscopic Sphincterotomy and Biliary Clearance

Revista de Chimie ◽

10.37358/rc.18.8.6493 ◽

2018 ◽

Vol 69 (8) ◽

pp. 2172-2176

Author(s):

Catalin Victor Sfarti ◽

Alin Ciobica ◽

Carol Stanciu ◽

Gheorghe G. Balan ◽

Irina Garleanu ◽

...

Keyword(s):

Oxidative Stress ◽

Endoscopic Sphincterotomy ◽

Specific Activity ◽

Oxidative Stress Marker ◽

Control Group ◽

Oxidative Stress Parameter ◽

Extrahepatic Cholestasis ◽

Biliary Clearance ◽

Oxidative Stress Status ◽

Before And After

Choledocholithiasis may cause biliary obstruction which leads to hepatocellular injury. Oxidative stress has been proposed as a possible mechanism involved in this disorder. This study evaluates the oxidative stress burden in patients with choledocholithiasis and secondary cholestasis, before and after endoscopic sphincterotomy. Experimental part: Patients diagnosed with choledocholithiasis and secondary extrahepatic cholestasis were included in the study between January 1st 2016 and October 31st 2016. In all patients oxidative stress markers were collected within 2 hours before and 48 hours after therapeutic ERCP. Selected markers were superoxide dismutase (SOD), glutathione peroxidase (GPX) and malondialdehyde (MDA). The results were compared to those from a group of 40 healthy subjects. Significantly lower concentrations of SOD (p = 0.03) and GPX (p [ 0.0001) activities, associated with an increased level of MDA level (p [ 0.0001) were shown in patients before biliary clearance compared with the healthy control group. After ERCP the only oxidative stress parameter which showed improvement was the SOD specific activity (p = 0.037). This study shows that extrahepatic cholestasis secondary to choledocholithiasis is associated with increased oxidative stress status. After biliary clearance one oxidative stress marker was significantly improved (SOD), suggesting a possible antioxidant effect of such procedure.

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Evaluation of Ovaries in Patients with Polycystic Ovary Syndrome using Shear Wave Elastography

Current Medical Imaging Formerly Current Medical Imaging Reviews ◽

10.2174/1573405615666190114150538 ◽

2020 ◽

Vol 16 (5) ◽

pp. 578-583

Author(s):

Aysegul Altunkeser ◽

Zeynep Ozturk Inal ◽

Nahide Baran

Keyword(s):

Shear Wave ◽

Large Scale ◽

Polycystic Ovary ◽

Shear Wave Elastography ◽

Left Ovary ◽

Control Group ◽

Tissue Elasticity ◽

Group I ◽

Pcos Group ◽

The Right

Background: Shear wave electrography (SWE) is a novel non-invasive imaging technique which demonstrate tissue elasticity. Recent research evaluating the elasticity properties of normal and pathological tissues emphasize the diagnostic importance of this technique. Aims: Polycystic ovarian syndrome (PCOS), which is characterized by menstrual irregularity, hyperandrogenism, and polycystic overgrowth, may cause infertility. The aim of this study was to evaluate the elasticity of ovaries in patients with PCOS using SWE. Methods: 66 patients diagnosed with PCOS according to the Rotterdam criteria (PCOS = group I) and 72 patients with non-PCOS (Control = group II), were included in the study. Demographic and clinical characteristics of the participants were recorded. Ovarian elasticity was assessed in all patients with SWE, and speed values were obtained from the ovaries. The elasticity of the ovaries was compared between the two groups. Results: While there were statistically significant differences between the groups in body mass index (BMI), right and left ovarian volumes, luteinizing hormone and testosterone levels (p<0.05), no significant differences were found between groups I and II in the velocity (for the right ovary 3.89±1.81 vs. 2.93±0.72, p=0.301; for the left ovary 2.88±0.65 vs. 2.95±0.80, p=0.577) and elastography (for the right ovary 36.62±17.78 vs. 36.79±14.32, p=0.3952; for the left ovary 36.56±14.15 vs. 36.26±15.10, p=0.903) values, respectively. Conclusion: We could not obtain different velocity and elastography values from the ovaries of the patients with PCOS using SWE. Therefore, further large-scale studies are needed to elucidate this issue.

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Physical Performance Regarding Handgrip Strength in Women with Polycystic Ovary Syndrome

Revista Brasileira de Ginecologia e Obstetrícia / RBGO Gynecology and Obstetrics ◽

10.1055/s-0040-1718953 ◽

2020 ◽

Vol 42 (12) ◽

pp. 811-819

Author(s):

Gislaine Satyko Kogure ◽

Victor Barbosa Ribeiro ◽

Flávia Ganoa de Oliveira Gennaro ◽

Rui Alberto Ferriani ◽

Cristiana Libardi Miranda-Furtado ◽

...

Keyword(s):

Polycystic Ovary Syndrome ◽

Physical Performance ◽

Lean Mass ◽

Polycystic Ovary ◽

Handgrip Strength ◽

Serum Levels ◽

Total Testosterone ◽

Dominant Hand ◽

Ovary Syndrome ◽

Pcos Group

Abstract Objective The present study aimed to investigate the physical performance of handgrip strength (HGS) in women with polycystic ovary syndrome (PCOS). Methods A case-control study that included 70 women with PCOS and 93 age-matched healthy women aged between 18 and 47 years with body mass index (BMI) between 18 Kg/m2–39.9 Kg/m2. The serum levels of total testosterone, androstenedione, insulin, estradiol, thyroid-stimulating hormone (TSH), prolactin, sex hormone-binding globulin (SHBG), and 17-hydroxyprogesterone (17-OHP) were measured. The free androgen index (FAI) and the homeostatic model assessment of insulin resistance (HOMA-IR) were calculated. The body composition regions of interest (ROIs) were assessed by dual-energy X-ray absorptiometry (DXA), and the handgrip strength (HGS) was evaluated for both the dominant and the non-dominant hands with a manual Sammons Preston (Bolingbrook, IL, US) bulb dynamometer. Results Women with PCOS had high serum levels of total testosterone (p < 0.01), androstenedione (p = 0.03), and insulin (p < 0.01), as well as high FAI (p < 0.01) and HOMA-IR (p = 0.01) scores. Compared with the non-PCOS group, the PCOS group had greater total lean mass in the dominant hand (p < 0.03) and greater HGS in both the dominant and the non-dominant hands (p < 0.01). The HGS was correlated with lean mass (p < 0.01). Conclusion Women with PCOS have greater HGS. This may be associated with age and BMI, and it may be related to lean mass. In addition, the dominance effect on muscle mass may influence the physical performance regarding HGS in women with PCOS.

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Indirect Predictors of Visceral Adipose Tissue in Women with Polycystic Ovary Syndrome: A Comparison of Methods

Nutrients ◽

10.3390/nu13082494 ◽

2021 ◽

Vol 13 (8) ◽

pp. 2494

Author(s):

Małgorzata Kałużna ◽

Magdalena Czlapka-Matyasik ◽

Aleksandra Bykowska-Derda ◽

Jerzy Moczko ◽

Marek Ruchala ◽

...

Keyword(s):

Adipose Tissue ◽

Polycystic Ovary Syndrome ◽

Visceral Adipose Tissue ◽

Polycystic Ovary ◽

Age Groups ◽

Ovary Syndrome ◽

Women Subjects ◽

Pcos Group ◽

Total Body ◽

Visceral Adipose

Visceral adipose tissue (VAT) accumulation, is a part of a polycystic ovary syndrome (PCOS) phenotype. Dual-energy x-ray absorptiometry (DXA) provides a gold standard measurement of VAT. This study aimed to compare ten different indirect methods of VAT estimation in PCOS women. The study included 154 PCOS and 68 age- and BMI-matched control women. Subjects were divided into age groups: 18–30 y.o. and 30–40 y.o. Analysis included: body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), waist/height 0.5 (WHT.5R), visceral adipose index (VAI), lipid accumulation product (LAP), and fat mass index (FMI). VAT accumulation, android-to-gynoid ratio (A/G), and total body fat (TBF) was measured by DXA. ROC analysis revealed that WHtR, WHT.5R, WC, BMI, and LAP demonstrated the highest predictive value in identifying VAT in the PCOS group. Lower cut-off values of BMI (23.43 kg/m2) and WHtR (0.45) were determined in the younger PCOS group and higher thresholds of WHtR (0.52) in the older PCOS group than commonly used. Measuring either: WHtR, WHT.5R, WC, BMI, or LAP, could help identify a subgroup of PCOS patients at high cardiometabolic risk. The current observations reinforce the importance of using special cut-offs to identify VAT, dependent on age and PCOS presence.

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Age-specific cut-off levels of anti-Müllerian hormone can be used as diagnostic markers for polycystic ovary syndrome

Reproductive Biology and Endocrinology ◽

10.1186/s12958-021-00755-8 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Fahimeh Ramezani Tehrani ◽

Maryam Rahmati ◽

Fatemeh Mahboobifard ◽

Faezeh Firouzi ◽

Nazanin Hashemi ◽

...

Keyword(s):

Bayesian Method ◽

Polycystic Ovary ◽

Characteristic Curve ◽

Generalized Additive Models ◽

Additive Models ◽

Control Group ◽

Age Group ◽

Predictive Values ◽

Pcos Group

Abstract Background The majority of available studies on the AMH thresholds were not age-specific and performed the receiver operating characteristic curve (ROC) analysis, based on variations in sensitivity and specificity rather than positive and negative predictive values (PPV and NPV, respectively), which are more clinically applicable. Moreover, all of these studies used a pre-specified age categorization to report the age-specific cut-off values of AMH. Methods A total of 803 women, including 303 PCOS patients and 500 eumenorrheic non-hirsute control women, were enrolled in the present study. The PCOS group included PCOS women, aged 20–40 years, who were referred to the Reproductive Endocrinology Research Center, Tehran, Iran. The Rotterdam consensus criteria were used for diagnosis of PCOS. The control group was selected among women, aged 20–40 years, who participated in Tehran Lipid and Glucose cohort Study (TLGS). Generalized additive models (GAMs) were used to identify the optimal cut-off points for various age categories. The cut-off levels of AMH in different age categories were estimated, using the Bayesian method. Main results and the role of chance Two optimal cut-off levels of AMH (ng/ml) were identified at the age of 27 and 35 years, based on GAMs. The cut-off levels for the prediction of PCOS in the age categories of 20–27, 27–35, and 35–40 years were 5.7 (95 % CI: 5.48–6.19), 4.55 (95 % CI: 4.52–4.64), and 3.72 (95 % CI: 3.55–3.80), respectively. Based on the Bayesian method, the PPV and NPV of these cut-off levels were as follows: PPV = 0.98 (95 % CI: 0.96–0.99) and NPV = 0.40 (95 % CI: 0.30–0.51) for the age group of 20–27 years; PPV = 0.96 (95 % CI: 0.91–0.99) and NPV = 0.82 (95 % CI: 0.78–0.86) for the age group of 27–35 years; and PPV = 0.86 (95 % CI: 0.80–0.94) and NPV = 0.96 (95 % CI: 0.93–0.98) for the age group of 35–40 years. Conclusions Application of age-specific cut-off levels of AMH, according to the GAMs and Bayesian method, could elegantly assess the value of AMH in discriminating PCOS patients in all age categories.

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Correlation between steroid levels in follicular fluid and hormone synthesis related substances in its exosomes and embryo quality in patients with polycystic ovary syndrome

Reproductive Biology and Endocrinology ◽

10.1186/s12958-021-00749-6 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Li Yu ◽

Miao Liu ◽

Zhenxin Wang ◽

Te Liu ◽

Suying Liu ◽

...

Keyword(s):

Polycystic Ovary Syndrome ◽

Follicular Fluid ◽

Polycystic Ovary ◽

Mrna Levels ◽

Hormonal Changes ◽

Male Factor ◽

Expression Change ◽

Ovary Syndrome ◽

Steroid Synthesis ◽

Pcos Group

Abstract Background Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder with various manifestations and complex etiology. Follicular fluid (FF) serves as the complex microenvironment for follicular development. However, the correlation between the concentration of steroid in FF and the pathogenesis of PCOS is still unclear. Methods Twenty steroid levels in FF from ten patients with PCOS and ten women with male-factor infertility undergoing in vitro fertilization were tested by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in order to explore their possibly correlation with PCOS. Meanwhile, the mRNA levels of core enzymes in steroid synthesis pathway from exosomes of FF were also detected by qPCR. Results The estriol (p < 0.01), estradiol (p < 0.05) and prenenolone (p < 0.01) levels in FF of PCOS group were significantly increased, compared to the normal group, and the progesterone levels (p < 0.05) were decreased in PCOS group. Increased mRNA levels of CYP11A, CYP19A and HSD17B2 of exosomes were accompanied by the hormonal changes in FF. Correlation analysis showed that mRNA levels of CYP11A and HSD17B2 were negatively correlated with percent of top-quality embryos and rate of embryos develop to blastocyst. Conclusion Our results suggest that increased levels of estrogen and pregnenolone in follicular fluid may affect follicle development in PCOS patients, and the mechanism is partially related to HSD17B1, CYP19A1 and CYP11A1 expression change in FF exosomes.

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