bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating HMGB1 Levels Are Associated With Glucose Clamp-Derived Measures of Insulin Resistance in Women With PCOS
Authors: Migazzi Matteo , Dauriz Marco , Cirillo Francesca , Catellani Cecilia , Villani Michela , Tosi Flavia , Street Maria Elisabeth , Moghetti Paolo 
Published: May 2021

Abstract
Context: High mobility group box 1 (HMGB1) is a nuclear constitutive and highly conserved mammalian protein which shows several important physiologic functions, playing a crucial role in local and systemic inflammation. It also seems to be implicated in the development of metabolic syndrome, whereas some in vitro and animal models and recent preliminary human studies suggested its potential role in polycystic ovary syndrome (PCOS) pathophysiology. In particular, some data suggested a potential role of HMGB1 in follicular maturation block. Moreover, increased blood and follicular fluid HMGB1 concentrations have been reported in PCOS women, showing a direct correlation with surrogate indexes of insulin-resistance (IR) (i.e. HOMA-IR).
Objective: The purpose of the present study was to investigate the relationships between serum HMGB1 levels and clinical, endocrine and metabolic parameters of PCOS patients.
Design and patients: Sixty women with PCOS, 30 with IR and 30 with normal insulin sensitivity (IS), and 30 healthy controls were included in the study. In these subjects, body fat was quantified by bioelectrical impedance; plasma HMGB1 levels were measured using a specific ELISA method (Tecan, Mannedorf, Switzerland); and serum androgens were measured by liquid chromatography/mass spectrometry and equilibrium dialysis. In PCOS women, IR was measured using the gold standard hyperinsulinemic-euglycemic clamp technique, combined with indirect calorimetry.
Results: HMGB1 levels did not differ between PCOS women and healthy controls (4.11 ± 3.22 vs 3.77 ± 2.50 ng/mL, respectively; p=0.61). Moreover, HMGB1 levels did not differ between PCOS phenotype subgroups. However, PCOS IR women showed higher levels of this protein as compared with PCOS IS (5.00 ± 3.53 vs 3.16 ± 2.59 ng/mL, respectively; p=0.017). In women with PCOS, HMGB1 levels were associated with several metabolic parameters, including IR measured by glucose utilization during the clamp (rho -0.37, p=0.005). This correlation was preserved after adjusting for potential confounding parameters, such as age, fat mass and serum free testosterone. HMGB1 levels did not change during glucose-clamp induced acute hyperinsulinemia, either in the whole cohort of patients or in IR and IS subgroups analyzed separately. Both in the whole population under study and in PCOS women, HMGB1 levels did not correlate with anthropometric parameters, hormonal features and ovarian morphology.
Conclusions: In women with PCOS, HMGB1 blood levels show an independent association with insulin resistance. However, no associations with other typical features of the syndrome were found. Further research is needed in order to establish whether this protein may play a role in the pathogenesis of PCOS.
Evaluation of Thyroid Function and Its Relationship With Metabolic Parameters in Indian Adolescents With PCOS
Authors: Talwar Vipan , Talwar Gourav 
Published: May 2021

Abstract
Background: Women with PCOS have high insulin resistance and a higher prevalence of raised TSH levels. Thyroid dysfunction can lead to the alterations in lipid and metabolic parameters. There is a very little data regarding the relationship between TSH and indices of insulin resistance in Indian adolescents with PCOS. Aim of Study: To assess the status of thyroid function and its impact on biochemical parameters and cardiovascular (CV) risk factors in Indian Adolescents with PCOS. Methods: Study group was 130 adolescents aged between 13 to 19 years, recently diagnosed with PCOS as per Revised Rotterdam criteria and a control group of 75 age matched, healthy, non PCOS females. Participants were subjected to an elaborate clinical, anthropometric and biochemical assessment. Hormonal analysis included serum FT3, FT4, TSH, anti-TPO antibody, LH, FSH, prolactin, free testosterone, 17 OH progesterone, Lipid profile. Fasting plasma glucose and Insulin were used to calculate HOMA-IR. Statistical analysis was done by SPSS. P value of &lt;0.005 was significant. Results: Mean age of the subjects was 15.9 ± 3.1 years. Mean level of TSH was higher in PCOS group than in controls (4.1 ± 3.1 vs 2.8 ± 1.9; p-&lt;0.001). There was significantly higher prevalence of subclinical hypothyroidism (SCH) (19.2%vs 6.7%;p-0.01), Anti TPO antibody titre (18.6 vs 4.7%; p,0.01) and goitre (14.1%vs 3.2%; p - 0.02) in PCOS subjects compared to controls. BMI and Systolic BP were higher in PCOS with SCH. Free testosterone (p-0.002), HOMA-IR (p- 0.03) and dyslipidaemia (p &lt; 0.01) were significantly higher in PCOS subjects with SCH as compared to both euthyroid PCOS and euthyroid controls. Discussion: 50-70% women with PCOS, have been reported to have insulin resistance and hyperinsulinemia and are at a higher risk for developing metabolic and CV diseases. Literature supports the high prevalence of SCH/thyroid autoimmunity in PCOS. In this study we have found that Indian adolescents with PCOS have a high prevalence of SCH. Also we have observed significant changes in insulin resistance indices in PCOS subjects with SCH as compared to those with normal thyroid functions. The association between TSH level and insulin resistance indices is complex and one probable mechanism is that the hypothyroidism leads to increase in adiposity and pro inflammatory markers. This unique interplay of PCOS, adiposity, thyroid dysfunction and autoimmunity forms a complex pathophysiological pathway which leads to the potentiation of insulin resistance thereby resulting in a further increase in metabolic and CV risk in women with PCOS. Conclusion: There is a high prevalence of SCH in Indian Adolescents girls with PCOS and it is associated with significant changes in insulin resistance indices, which may increase the risk of metabolic and CV disorders in these already vulnerable young subjects.
Lifestyle and Weight Change in Women With Polycystic Ovary Syndrome During COVID19 Pandemic
Authors: Eyupoglu Nesrin Damla , Aksun Seren , Ozturk Mervenur , Yildiz Bulent Okan 
Published: May 2021

Abstract
Polycystic ovary syndrome (PCOS) is a complex disorder associated with obesity, sleep apnea, and disordered eating. We aimed to assess whether COVID19 related social isolation affects lifestyle and weight control in women with PCOS. We performed an online survey including 232 women with PCOS and 157 healthy controls on isolation characteristics, weight alterations, physical activity, sleeping and eating patterns by validated questionnaires. Three-Factor Eating Questionnaire (TFEQ-18), Pittsburgh Sleep Quality Index (PSQI), and International Physical Activity Questionnaire Short Form (IPAQ-SF) were used. PCOS-related quality of life questionnaire (PCOSQ) was also completed by patients. During over 14 weeks of isolation, 48.5% participants gained weight, 13.9% participants’ weight was stable, and 37.6% participants lost weight. The patient and control groups did not show any difference in weight alteration (p=0.44). Physical activity was reduced (p&lt;0.001 for both), eating patterns did not show a significant change in both groups, whereas sleep quality was reduced in PCOS group only (p&lt;0.001). Within the weight gainers, increase in BMI was more prominent in PCOS group (1.3±1 kg/m2) than controls (1.0±0.6 kg/m2) (p=0.01). In weight gainer group, delta BMI values showed positive correlations with delta PSQI scores (r = 0.24, p=0.004), delta sleep induction time (r=0.25, p=0.001) and delta TFEQ-18 scores (r=0.25, p=0.001). Weight changes during social isolation are similar in women with PCOS and healthy women. However, the increase in BMI of weight gainers is higher in PCOS and is mainly related to sleep quality and eating habits rather than reduced physical activity.
Lifestyle, Anxiety,Depression, and Clinical Profile in Women With Polycystic Ovary Syndrome: Initial Results From the Brazilian PCOS Study
Authors: Spritzer Poli Mara , Marchesan Lucas Bandeira , dos Santos Betania Rodrigues , Oppermann Karen , dos Reis Rosana Maria , Ferriani Rui A , Weiss Rita Vasconcellos , Meirelles Ricardo , Candido Ana L , Reis Fernando M 
Published: May 2021

Abstract
Brazil is a large country with rich cultural and ethnic diversity among its different regions. In this ongoing nationwide collaborative study, we are evaluating modifiable lifestyle factors, metabolic and reproductive abnormalities and prevalence of anxiety/depression in a less-well represented population of women with PCOS from Brazil. The design of the Brazilian PCOS study has been published previously1. Briefly, the study is being conducted in the outpatient clinics of university hospitals within the public health care network (Unified Health System - SUS) across the country. The sample includes women with PCOS diagnosed according to Rotterdam criteria and a control group of healthy women matched by age and geographic region. Collected data are being incorporated into a unified cloud database. Two hundred five participants have been enrolled thus far (17% of an expected sample size of 1,200 women). Age, years of formal education and socioeconomic class were similar among PCOS phenotypes and the control group. The prevalence of PCOS phenotypes in this sample was 64.7% for phenotypes A + B, 25% for phenotype C, and 10.3% for phenotype D. Phenotypes A + B and D had higher prevalence of obesity (BMI&gt;30) (p=0.001) and metabolic syndrome as compared to the other groups (32.4% in A + B and 50% in D vs. 16% in C and 5.9% in controls; p=0.002). Total testosterone levels, determined by mass spectrometry were higher in PCOS A+B than in the other phenotypes, even after adjustment for BMI (p&lt;0.001). Sedentariness (&lt;150 min/week of physical activity) was present in more than 60% of participants in all PCOS phenotypes and in controls, with no difference between the groups. More than 70% of participants in all PCOS phenotypes had a fruit and vegetable intake below 5 portions/day. Anxiety/depression (SRQ-20) was frequent in phenotypes A + B (41.6%) and D (56.3%) vs. phenotype C (23.1%) and controls (28.6%) (p=0.062). These initial results suggest that PCOS participants, besides often presenting metabolic abnormalities have an unhealthy lifestyle and high prevalence of psychological distress. Analysis of the full study sample will be useful to guide specific public strategies for primary and secondary prevention of psychological, metabolic and reproductive comorbidities in the PCOS population of Brazil. 1Spritzer PM, et al. BMJ Open. 2019; 9:e029191.
Contribution of Copy Number Variation in Idiopathic Hypogonadotropic Hypogonadism
Authors: Stamou* Maria , Brand* Harrison , Lippincott Margaret Flynn , Wong Isaac , Plummer Lacey , Balasubramanian Ravikumar , Talkowski Michael , Seminara Stephanie Beth 
Published: May 2021

Abstract
Introduction: While the role of single nucleotide variants (SNVs) in causal genes for Idiopathic Hypogonadotropic hypogonadism (IHH) is known, the contribution of copy number variants (CNVs) to IHH has not been systematically studied. Here, we examined the prevalence of CNVs in a large IHH cohort and their associated phenotypic spectrum.
Methods: Exome sequencing (ES) from 1,441 IHH probands was analyzed using the GATK-gCNV pipeline to identify CNVs that spanned known IHH genes with a site frequency of &lt;1%. ES data was also analyzed for rare SNVs in all IHH genes. IHH subjects were evaluated for reproductive and non-reproductive phenotypes (kidney, eye, cardiovascular, midline/ facial, bone and neurological abnormalities).
Results: (i) CNV prevalence in IHH: Three percent of the IHH probands (46/1441 probands, 38 males and 8 females) harbored CNVs in 19/36 high confidence IHH genes (26 deletions 20 duplications). The vast majority of CNVs disrupted either the ANOS1 (26%) or FGFR1 (17%) genes. Intriguingly, CHD7 (a gene that carries SNVs in ~12% of our IHH subjects) did not harbor any CNVs. (ii) Phenotypic analysis: We found that CNVs were more common in IHH subjects with anosmia (Kallmann syndrome, N=33) compared to normosmic IHH (N=13). More than half of the subjects with CNVs affecting IHH genes carried at least 1 non-reproductive feature (26/46 IHH subjects, 56%). A syndromic presentation with multiple non-reproductive phenotypes was more common in IHH subjects harboring multigenic CNVs (IHH gene & additional genes) compared to IHH subjects with single IHH gene CNV or SNV in a single IHH gene (61% vs. 12% or 18%, respectively; p 0.0006).
Conclusions: CNVs in known IHH genes contribute to 3% of the IHH genetic architecture in our cohort. IHH subjects with larger multigenic CNVs displayed phenotypes consistent with contiguous gene syndromes. The absence of genic CNVs in genes frequently found to carry SNVs, such as CHD7, requires additional analysis to establish the biologic or mechanistic reasons for their rarity.
Novel Oral Testosterone Formulation Improves Male Well Being Without Compromising International Prostate Symptom Scores
Authors: Dhingra Om P , Bernstein James , Barnes Shaina D , VanLaanen Hannah , Wadlington Natasha , Chang Jessica 
Published: May 2021

Abstract
Introduction: Male hypogonadism results from insufficient secretion of testosterone (T) and is characterized by low serum T concentrations. Common symptoms of hypogonadism include decreased libido, impotence, weakness, low energy, depression and/or loss of motivation, memory and concentrating issues, and sleep disturbances. Several forms of T replacement are available. Testosterone undecanoate (TU) is a testosterone prodrug available in oral formulations. A novel TU formulation, SOV2012-F1, has been submitted for FDA consideration under the name KYZATREX®. While TU efficacy is measured by serum total T, patientfocused endpoints such as Patient Reported Outcomes (PROs) are valuable indicators of well-being and psychosexual symptom abatement. Methods: A Phase 3, randomized, multicenter, open-label, active-controlled trial, comparing SOV2012F1 (testosterone undecanoate capsules) (n=214) with AndroGel® (1.62% topical testosterone gel) (n=100) enrolled males aged 18 to 65 years with hypogonadism (serum total T levels ≤281 ng/dL). A key exploratory endpoint was change from Baseline (ΔBL) after 52 weeks of treatment in the following PROs: International Prostate Symptom Score (IPSS), Psychosexual Daily Questionnaire (PDQ), Short Form Health Survey 36 item (SF-36), and the International Index of Erectile Function (IIEF). Results: Total or overall scores for all PROs (IPSS, PDQ, SF-36 and IIEF) showed increased improvement in the SOV2012-F1 group relative to the Androgel group, and all but IPSS demonstrated improvement relative to BL. For IPSS, due to the potential that T could worsen urinary symptoms, the ΔBL would ideally be small to reflect minimal impact. Change for the SOV2012-F1 and AndroGel groups was, respectively, 0.6 and 1.0. Further, the IPSS total score was not significantly different from BL in the patients receiving SOV20212-F1 (p = 0.5659). For PDQ, a clinically meaningful improvement of sexual desire in hypogonadal men age ≥65 years is ≥0.7; mean ΔBL was 1.6 in the SOV2012-F1 group versus 1.4 in the AndroGel group. In the SF-36, the mean ΔBL total score was 83.7 in the SOV2012-F1 group and 70.2 in the AndroGel group. Further, post hoc analysis of the Health Change category found a significant (p ≤ 0.05) improvement in patient perspectives on health over the course of the study. The overall satisfaction score of the IIEF trended towards significance for the SOV2012-F1 group with a mean ΔBL score of 2.3 versus and 1.6 in the AndroGel group. The ΔBL for the 4 domains of male sexual function were small and consistent between the SOV2012-F1 and AndroGel groups. Comparable results were noted for Early Withdrawals and All Subjects across all PROs. Conclusion: Treatment with SOV2012-F1 for 52 weeks exceeded AndroGel patient satisfaction as measured by PROs including IPSS, PDQ, SF-36 and IIEF, demonstrating clinical distinction. Further analysis of SOV2012-F1 will be forthcoming.
Prohibitin-1 Transgenic Mice Revealed an Important Role of Prohibitin in Testicular Steroidogenesis
Authors: Bassi Geetika , Mishra Suresh 
Published: May 2021

Abstract
Testosterone, the male sex hormone, plays an important role in the sexual development and fertility. Consequently, its deficiency causes infertility, obesity, osteoporosis and cardiovascular diseases. Leydig cells (LCs) are the testicular interstitial cells responsible for the biosynthesis of testosterone in response to luteinizing hormone (LH) from the pituitary. Cholesterol is the essential substrate for steroidogenesis which is translocated from the cytosol to the mitochondria where it gets converted to pregnenolone (by P450 side chain cleavage enzyme). Subsequently, pregnenolone translocate to endoplasmic reticulum where action of various enzymes results in the biosynthesis of testosterone. Prohibitin-1 (PHB1) is an evolutionary conserved ubiquitously expressed protein with cell compartment and cell-type specific functions. Mitochondrial function of PHB1 has been widely studied but its role in testicular steroidogenesis is unexplored. Recently, we have reported two transgenic mice models of PHB1, PHB-Tg and mutant-PHB-Tg (mPHB-Tg), expressing PHB1 or Y114F (mutant PHB1) respectively under the control of Fabp-4 gene promoter. During phenotypic characterization of these mice models, we observed a drastic size/weight difference in the testis of PHB-Tg and mPHB-Tg when compared with wild type mice. The mPHB-Tg mice testis was significantly smaller than the PHB-Tg and wild type mice. Further analysis of mPHB-Tg testis revealed wider testicular interstitium with LC hyperplasia and elongated seminiferous tubules. Ultrastructure investigation revealed that LCs of mPHB-Tg mice have prominent nucleus with increased number of mitochondria and lipid droplets. In addition, electron microscopic images of mPHB-Tg mice LCs revealed a sign of lipophagy and mitophagy. This prompted us to measure testosterone levels in these mice; surprisingly mPHB-Tg mice showed significantly higher testosterone levels as compared to PHB-Tg and wild type mice. Furthermore, testicular lysates and primary LCs cell lysates from transgenic mice models revealed that overexpression of PHB/mPHB in LCs inversely effect expression levels of steroidogenic acute regulatory protein (StAR). Moreover, co-immunoprecipitation of PHB1 displayed an interaction with StAR, P450scc and LC3 further revealing a key role of PHB1 in cholesterol translocation, testicular steroidogenesis and autophagy. Taken together, this finding suggests that PHB1 plays a multifaceted role in testicular steroidogenesis from determining testis size to the translocation of cholesterol into the mitochondria, in maintaining lipid homeostasis and biosynthesis of testosterone. Implications of our findings are broad because cholesterol translocation to the mitochondria and its subsequent utilization for steroidogenesis is conserved in all steroidogenic tissues.
A Case of Autoimmune Polyglandular Syndrome Type 3b Initially Presenting as Generalized Weakness in an Elderly Patient
Authors: Ayesh Hazem , Burmeister Cameron , Abdelrahman Ahmed , Beran Azizullah , Suri Pooja 
Published: May 2021

Abstract
Introduction: Autoimmune polyglandular syndrome (APS) is a multiorgan genetic autoimmune disease. APS-3B subtype is autoimmune thyroiditis with pernicious anemia. In this case, we will discuss an elderly female patient diagnosed with APS-3B.
Case Presentation: A 69-year-old Caucasian female patient with a past medical history of autoimmune thyroiditis presented to the emergency department with a two-month history of generalized weakness and nausea. Associated symptoms included shortness of breath and diarrhea. Review of systems was otherwise unremarkable. Physical exam was positive for depigmented skin macules over the upper extremities. Lab results showed hemoglobin 8.2 [11.7 - 15.5 g/dL], MCV 121[80 - 100 fL], platelets 144,000 [150 - 450 X10E9/L], WBC 1.9 [4.0 - 11.0 X10E9/L], LDH 1153[100 - 235 U/L], TSH 0.28[0.49 - 4.67 uIU/mL], free T4 1.7 [0.61 - 1.60 ng/dL], direct Coombs test negative. Iron saturation 55%, vitamin B12 level &lt;50 [180 - 914 pg/mL], folate &gt;25[&gt;5.8 ng/mL], total bilirubin 2.3 [0.3 - 1.2 mg/dL], haptoglobin &lt;30 [32 - 228 mg/dL], AST 43 [0 - 41 U/L], reticulocyte 1.4%. Blood smear showed absolute neutropenia with flow cytometry unremarkable. Chest x-ray and urinalysis were negative. Immunofixation showed low IgM 44 [45 - 281 mg/dL], low IgG 619 [635 - 1,741 mg/dL]. Intrinsic factor antibodies (IF-Ab) were positive. Hematology reported that hemolytic anemia is less likely given Coombs test was negative. About 1.5% of Vitamin B12 deficiency present with a hemolytic picture due to ineffective erythropoiesis while Coombs test help to differentiate it from autoimmune hemolytic anemia. Diagnosis of pernicious anemia was made and the patient started on vitamin B12 injections. The combination of pernicious anemia, autoimmune thyroiditis, and vitiligo supported the diagnosis of autoimmune APS-3B. There was a normalization of vitamin B12 level and symptomatic improvement on a one-week follow-up.
Discussion: The patient was diagnosed with autoimmune thyroiditis in 2014 with positive anti-TPO antibodies and elevated TSH; she required levothyroxine supplementation since diagnosis. Hypothyroidism causes macrocytic anemia, which may delay pernicious anemia diagnosis. APS-3B is associated with HLA-B8 and/or DR3 and DR5. Many studies reported that autoantibodies can be detected before developing symptoms of organ involvement. Thorough family history provides support for autoantibody testing to detect cases of APS-3B earlier. Active surveillance and early diagnosis will help minimize invasive testing such as bone marrow biopsy, so proper history taking is a key factor to early diagnose these conditions.
Conclusion: APS-3B is a rare disorder. Diagnosis is difficult hypothyroidism causes macrocytic anemia. Early detection of APS-3B may help to prevent complications that increase the risk of mortality and morbidity, particularly in the elderly population.