bluuebunny/crossref_metadata_2025_split huggingface dataset:
OR15-03 Lower Hepatic Mitochondrial Respiration Relates To Dysmetabolism In Adolescents With Severe Obesity
Authors: Finn Erin , Fuller Kelly N Z , Knaub Leslie A , Reyes Yesenia Garcia , Derderian Sarkis C , Schoen Jonathan , Inge Thomas , Reusch Jane E , Nadeau Kristen , Cree Melanie 
Published: October 2023

Abstract
Disclosure: E. Finn: None. K.N. Fuller: None. L.A. Knaub: None. Y. Garcia Reyes: None. S.C. Derderian: None. J. Schoen: None. T. Inge: None. J.E. Reusch: Advisory Board Member; Self; Medtronic Diabetes. K. Nadeau: None. M. Cree: None.
Introduction: The severity of metabolic disease in youth with obesity is varied and determinants of disease progression are not known. Non-alcoholic fatty liver disease appears to be central to the development of cardiometabolic disease in youth with severe obesity. We tested the hypothesis that hepatic mitochondrial respiratory capacity would correlate with cardiometabolic measures in youth with severe obesity and a range of glycemia. Methods: Adolescents with severe obesity and a range of dysglycemia undergoing bariatric surgery were enrolled. Participants underwent anthropomorphic assessments, fasting labs, and a 4-hour mixed meal tolerance test (MMTT, 45 g carbs, 14 g protein, and 14 g fat) over 30 minutes followed by serial measures of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), and free fatty acids. Liver biopsies obtained at time of vertical sleeve gastrectomy surgery were analyzed for mitochondrial respiration. Permeabilized liver tissue was assessed for mitochondrial oxygen consumption by respirometry (Oxygraph-2k, OROBOROS) under both pyruvate (carbohydrate) and palmitoyl-carnitine (lipids) substrate conditions. Results: Fifteen youth with severe obesity (female=60%, mean age 16.9 ± 1.5 years, mean BMI 47.4 ± 7.2 kg/m2) were enrolled. Lower hepatic carbohydrate-supported respiration relates to higher serum glucose concentrations throughout the 4-hr MMTT (P=&lt; 0.001 to 0.05) as well as higher fasting serum triglycerides (p =&lt;0.001-0.05). Lower liver lipid-supported respiration is associated with higher C-peptide levels (p =0.001-0.01) throughout MMTT, increased Matsuda Index (p =0.001-0.05), and higher fasting hepatic transaminases, alanine aminotransferase (p =0.006-0.04), aspartame aminotransferase (p =0.007-0.02), and gamma-glutamyl transferase (p =0.01-0.03). Insulin, GLP-1, and free fatty acids are not correlated with mitochondrial respiration. Conclusion: Consistent with findings in adults and animals, youth with severe obesity have lower hepatic mitochondrial respiration which correlates with markers of poorer cardiometabolic health including higher triglycerides, higher glucose concentraions, lower insulin sensitivity, higher insulin secretion (C-peptide), and higher liver transaminases. Based on these findings, dysregulated hepatic mitochondrial respiration should be further explored as a possible contributor to the development of early liver disease and glucose dysregulation.
Presentation: Friday, June 16, 2023
OR15-05 Maternal Obesogenic Diet Exposure Leads To Transgenerational Worsening Of Offspring NAFLD In Male Mice
Authors: Hinrichs Holly , Ballentine Samuel J , Thompson Michael D 
Published: October 2023

Abstract
Disclosure: H. Hinrichs: None. S.J. Ballentine: None. M.D. Thompson: None.
Background: The Developmental Origins of Health and Disease (DOHaD) hypothesis states that development of chronic disease is impacted by early life or in utero exposures. Recent studies have found that exposure to maternal obesity/obesogenic diet increases the susceptibility of offspring to non-alcoholic fatty liver disease (NAFLD). We have shown that maternal obesogenic diet exposure (MODE) in mice leads to worse NAFLD progression to fibrosis in first generation offspring with associated changes in the microbiome. Evidence indicates that some developmentally programmed phenotypes are passed transgenerationally or to the third generation of offspring. The goal of the current study was to evaluate if MODE-induced programming of worse NAFLD progression is passed transgenerationally. Methods: F0 Female mice were fed chow (CON) or high fat-fructose-cholesterol (HFFC) diet for 6 weeks and bred with lean males. F1 and F2 females were fed chow diet and mated with chow-fed males to yield an F3 generation where only the F0 female was fed HFFC diet. F3 male offspring were weaned to HFFC diet for 7 weeks to induce progressive NAFLD. Liver was collected for histopathologic analysis. NAFLD activity scoring (NAS) was performed by a pathologist blinded to group. Results: F3 HFFC offspring had decreased liver weight and liver weight/body weight ratio compared to F3 CON offspring. F3 HFFC offspring had increased hepatic free fatty acids, but no difference in hepatic triglycerides and cholesterol. Mac-2 and CD45 staining was increased in F3 HFFC offspring. Sirius red staining for collagen was also increased in F3 HFFC offspring. NAS scoring confirmed histologic finding showing an increased frequency of higher inflammation and total NAS scores in F3 HFFC offspring. Fibrosis scores were also higher in F3 HFFC offspring. Conclusions: MODE leads to transgenerational transmission of worse NAFLD progression in male offspring. This suggests a role for an epigenetic mechanism involved in developmental programming of NAFLD. Future studies will focus on the mechanisms of this transgenerational event.
Presentation: Friday, June 16, 2023
THU256 Prevalence And Risk Factors Associated With Diabetes Mellitus Among Middle Aged Women In Southern Brazil: A Population Based Study
Authors: Oppermann Karen , Spritzer Poli Mara 
Published: October 2023

Abstract
Disclosure: K. Oppermann: None. P.M. Spritzer: None.
The prevalence of diabetes mellitus (DM) has been growing steeply. The early recognition of clinical characteristics related to DM may be determinant to reduce its prevalence in specific populations. The aim of this cross-sectional study, nested to the Passo Fundo cohort study, was to investigate the prevalence and the clinical factors associated with diabetes mellitus (DM) among middle-aged women. A total of 298 women were enrolled in which demographic, anthropometric characteristics, blood pressure (BP), use of hormone therapy (HT), physical activity (PA), smoking status, alcohol intake were obtained. Habitual PA was assessed by digital pedometer for 7 days, and participants were stratified into active and inactive (≥ 6,000 and &lt; 6,000 steps/day, respectively). Mean age was 57.1±5.4 years, 78.7% women were postmenopausal, 8.3 % menopausal transition, 7.3% pre-menopause and 5.6% were classified as “hysterectomy” that is, those women who had previously undergone hysterectomy which menopause status could not be classified. The prevalence of DM was 17.1% (n= 51): pre-menopause 9.1%, menopausal transition 20.0%, post-menopause 18.4% and hysterectomized women, 5.9% (p=0.53). Women with DM were older (58.7 ±5.2 vs. 56.8 ± 5.4 years, p=0.022), worked fewer hours per week in the last month (p= 0.040), had lower age at menarche (12.6 ±1.8 vs. 13.2 ± 1.9 years, p=0.026), were more frequently inactive (83.7 vs. 64.7 %, p=0.010), had higher BMI (30.9 ± 6.3 vs. 28.4 ± 6.4 kg/m2, p=0.012), waist circumference (WC) (98.5 ± 13.2 vs. 90.3 ±13.3 cm) p&lt;0.001), and higher visceral (218.5±85.2 vs. 164.9±71.6 p &lt; 0.001) and total fat, (534.9 ±167.8 vs. 451.8±170.2 p=0.003) but not subcutaneous fat (315.5±117.3 vs. 286.9±118.7 p=0.140), and systolic blood pressure (SBP) (138.7 ± 17.3 vs. 130.2 ± 18.7 mmHg, p=0.003). The prevalence of current smoking was 19.5%, alcohol use was 32.5%, HT current use was 16.1% and it was not statistically different between women with and without DM. Women with DM presented higher prevalence of metabolic syndrome, 76.5% (n=39) vs. 34.8 % (n=86), p&lt;0.001 as well as using statins more often (35.3% vs. 12.6%, p&lt;0.001). A higher prevalence ratio of DM was associated with physical inactivity (PR 2.137; 95% CI 1.056-4.325; p&lt;0.035). For each year of anticipated menarche, the risk of DM increases by 12% and for each mmHg there is an increase of 1.4% of DM diagnosis. Conclusion: The prevalence of DM among middle-aged women was 17.1%. Women with DM were older, have less working activity, earlier menarche, using statins more often and walk less. Also, they have higher BMI, waist circumference, visceral abdominal fat, and MS. Age, physical inactivity, early age at menarche, and systolic blood pressure were related independently to higher prevalence of DM in this unselected population of middle-aged women.
Presentation: Thursday, June 15, 2023
THU631 Steroyl-CoA Desaturase Is A Progesterone Receptor Target Gene In Uterine Leiomyoma
Authors: Komorowski Allison S , Zuberi Azna , Coon V John S , Anton Melania Lidia , Bulun Serdar Ekrem , Yin Ping 
Published: October 2023

Abstract
Disclosure: A.S. Komorowski: None. A. Zuberi: None. J.S. Coon V: None. M.L. Anton: None. S.E. Bulun: None. P. Yin: None.
Uterine leiomyomas (LM) are common benign neoplasms affecting approximately one in four reproductive-age women. LM can cause menorrhagia, dysmenorrhea, anemia, and infertility. Steroyl-CoA desaturase (SCD) is a delta-9 fatty acid desaturase which converts saturated fatty acids to monounsaturated fatty acids in a reaction that is critical to maintenance of fatty acid homeostasis. Prior work has demonstrated upregulation of SCD in multiple cancer types as part of lipid metabolic reprogramming, and SCD has been identified as a potential drug target for cancer and non-alcoholic steatohepatitis. Growth of LM tumors is progesterone-dependent, and we found that progesterone receptor (PR)-binding sites were enriched in the SCD gene locus. Normalized RNA-seq count demonstrated that knockdown of PR decreased SCD expression in LM cells. Further experiments with knockdown of PR in LM cells demonstrated decreased SCD expression on both quantitative real-time PCR and Western blot. Treatment of LM cells with progesterone for 6 hours lead to mild upregulation of SCD expression. In summary, steroyl-CoA desaturase, an enzyme involved in lipid homeostasis, is upregulated by progesterone and may represent a novel target for treatment of uterine LM.
Presentation: Thursday, June 15, 2023
THU637 The Effects Of Polyphenol On Insulin Resistance And Hormonal Parameters On Women With Polycystic Ovary Syndrome: A Systematic Review And Meta-analysis Of Randomized Controlled Trials
Authors: Almeida Balieiro Caroline Cristine , Hespanhol Larissa C , Araújo Freitas Marcos Aurélio , de Oliveira Lilia Maria Lima 
Published: October 2023

Abstract
Disclosure: C.A. Balieiro: None. L.C. Hespanhol: None. M. Araújo Freitas: None. L. Lima de Oliveira: None.
Introduction: Polycystic ovary syndrome (PCOS) is an endocrinopathy with a high prevalence in women of reproductive age. This syndrome is characterized by ovarian cysts, anovulation, infertility, skin disorders, increased Body Mass Index (BMI), insulin resistance, and altered hormone levels. The most commonly affected hormones include testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and insulin. Different treatments have been tested to increase insulin sensitivity and hormone regulation, and recently polyphenols have emerged as a promising option for these women. We aimed to perform a systematic review and meta-analysis of randomized clinical trials (RCTs) comparing polyphenols to placebo in women with PCOS. Methods: The PubMed, Cochrane, and Embase databases were searched for RCTs comparing polyphenols to placebo. Data were extracted from published reports, and quality assessment was performed according to PRISMA guidelines. Endpoints included were: changes in levels of serum insulin, changes in BMI, LH, and testosterone levels. We used a random-effects model to calculate the Mean Difference (MD), Standardized Mean Difference (SMD), and 95% confidence interval (CI). Heterogeneity was examined with the Cochrane Q test and I² statistics: p values inferior to 0.05 and I² &gt; 25% were considered significant for heterogeneity. Results: A total of 15 studies involving 916 patients were included. Of all participants, 445 (49%) received polyphenols. Polyphenols resulted in a significant decrease in serum insulin level (MD -2.49 [-3.72, -1.25] 95% CI; p &lt; 0.0001, I² = 64%), in comparison to placebo. In addition, BMI levels were significantly reduced in patients treated with polyphenols when compared to placebo (MD -0.12 [-0.18, -0.06] 95% CI; p = 0.0002, I² = 0%). There was a reduction in LH levels in the intervention group, when compared with the baseline levels to the final levels (MD -0.87 [-1.54, 0.20] 95% CI; p = 0.01, I² = 46%). The decrease in testosterone levels was not significantly different when comparing polyphenols and placebo (SMD -0.14 [-0.53, 0.25] 95% CI; p = 0.48, I² = 73%). Conclusion: This meta-analysis provided evidence of the effectiveness of polyphenols in reducing serum insulin, LH and BMI in women with polycystic ovary syndrome compared to placebo. There was no statistically significant difference in the reduction of testosterone levels between polyphenols and placebo. This study represents the most current evidence on this promising treatment.
Presentation: Thursday, June 15, 2023
THU640 Clustering Of Genetic Loci Identifies 4 Distinct Polycystic Ovarian Syndrome Physiologic Pathways
Authors: Stamou Maria , Smith Kirk T , Kim Hyunkyung , Balasubramanian Ravikumar , Gray Kathryn , Udler Miriam 
Published: October 2023

Abstract
Disclosure: M. Stamou: None. K.T. Smith: None. H. Kim: None. R. Balasubramanian: None. K. Gray: None. M. Udler: Other; Self; Dr. Udler receives royalties from UpToDate, Inc and is part of an unpaid research collaboration with AstraZeneca, Inc.
Introduction: Genome-wide association studies (GWAS) have implicated severe genetic loci with polycystic ovarian syndrome (PCOS), with disease pathogenesis remaining largely unknown. Methods: To group PCOS GWAS loci into genetic clusters driven by disease physiology we performed a cluster analysis for 60 PCOS-associated genetic variants and 49 traits using GWAS summary statistics. Cluster-specific PCOS partitioned polygenic scores (pPS) were generated and tested for association with clinical phenotypes in the Mass General Brigham Biobank (MGBB, N=62,252). Associations with clinical outcomes (type 2 diabetes/T2D, coronary artery disease/CAD and female reproductive traits) were assessed using both GWAS-based pPS (DIAMANTE, N=898,130, CARDIOGRAM/UKBB, N=547,261) and individual-level pPS in MGBB.Results: Four PCOS genetic clusters were identified with top loci indicated as following: (i) Cluster 1, obesity (FTO); (ii) Cluster 2, hormonal changes (FSHB); (iii) Cluster 3, inflammatory markers (ATXN2/SH2B3); (iv) Cluster 4, insulin resistance/liver enzymes (MAF, SLC38A11). Cluster pPS’s were associated with distinct clinical traits in MGBB females: Cluster 1 with increased body mass index (BMI; p=6.63x10-29); Cluster 2 with increased age of menarche (p= p=1.5x10-4); Cluster 3 with decreased mean platelet volume (MPV; p= p=3.07 x10-6); and Cluster 4 with increased ALP & ALT (p=0.007 & 0.02). Cluster 1 pPS was associated with increased T2D (OR 1.067; p=7.31x10-50) in GWAS, with replication in MGBB all participants (OR 1.088, p=7.63x10-7) and females only (OR 1.107, 9.59x10-5).Conclusions: Distinct genetic clusters in PCOS individuals may underlie the clinical heterogeneity of the disease.
Presentation: Thursday, June 15, 2023
THU646 Postmenopausal Hyperandrogenism Secondary To Ovarian Leydig Cell Tumor
Authors: Batch Jennifer Tania , Gandhi Gunjan Yogendra 
Published: October 2023

Abstract
Disclosure: J.T. Batch: None. G.Y. Gandhi: None.
Introduction: Hirsutism is typically the initial presentation of virilization, including male pattern balding, deepening of the voice, and clitoromegaly. Postmenopausal hyperandrogenism can originate from adrenal or ovarian causes. This report describes marked hirsutism and scalp hair loss in a patient, leading to significant negative psychological and social impacts. Case Report: A 73-year-old female presented to the clinic complaining of scalp hair loss and increased facial hair in the upper lip and chin. She has hypertension (treated with amlodipine, losartan, metoprolol tartrate, and hydrochlorothiazide), dyslipidemia (treated with omega-3 fatty acids), hypothyroidism (treated with levothyroxine), and transvaginal hysterectomy without oophorectomy in 1994 for menorrhagia (no hormonal replacement therapy after surgery). The patient reported regular menstrual periods before the hysterectomy but developed menorrhagia during her early 50s. For the past five years, she noted bitemporal scalp hair loss that progressed significantly and created recession of the hairline and thinning of hair in her crown area. She developed dark pigmented hair on her upper lip and chin area, lower abdomen, and chest. Due to the significant impact of these physical changes, she became socially withdrawn and admitted to only leaving home to attend doctors’ appointments. She denied using supplements or physical contact with anyone using topical testosterone. She denied enlargement of her clitoris. She did note a deepening of her voice, although she is a chronic smoker. A hormonal work-up revealed a significantly high total testosterone of 511 ng/dL (normal range 2-45 ng/dL). DHEA-sulfate was normal at 62 mcg/dL (4-157 mcg/dL), and 17-hydroxyprogesterone was not significantly high at 192 ng/dL. MRI abdominal and pelvis with and without contrast revealed a 1.8 cm avidly enhancing left ovarian nodule. The patient underwent bilateral salpingo-oophorectomy. Pathology showed tumor cells with eosinophilic cytoplasm, central nucleus, and prominent nucleolus, consistent with a Leydig cell tumor measuring 1 cm and was confined to the left ovary. Four weeks after surgery, a repeat hormonal work-up revealed a normal total testosterone level of 23 ng/dL (normal range 2-45 ng/dL). Discussion: Hyperandrogenism with rapidly progressing hirsutism indicates a tumoral etiology. Leydig cell ovarian tumors are uncommon neoplasms arising from the gonadal stroma, accounting for &lt;0.1% of all primary ovarian tumors. The diagnosis is based mainly on clinical and laboratory data since imaging studies may not show the small androgen-producing lesion. Bilateral oophorectomy should be recommended in postmenopausal women when an ovarian source is suspected. Most ovarian virilizing tumors are benign, and bilateral salpingo-oophorectomy results in a cure.
Presentation: Thursday, June 15, 2023
OR04-04 Sexually Dimorphic Impact Of Gestational Hyperandrogenism On Offspring Growth Trajectory
Authors: Topaktas Eylem , Ghnenis Adel B G , Ciarelli Joseph Norman , Domke Stephanie , Padmanabhan Vasantha , Kalla Vyas Arpita 
Published: October 2023

Abstract
Disclosure: E. Topaktas: None. A.B. Ghnenis: None. J.N. Ciarelli: None. S. Domke: None. V. Padmanabhan: None. A.K. Vyas: None.
Gestational hyperandrogenism, as seen in polycystic ovary syndrome, adversely programs birth weight and small for gestational babies. In our established sheep model of PCOS phenotype, gestational testosterone (T) excess from days 30-90 of gestation (sexually dimorphic window where male fetuses naturally are exposed to elevated T) had no effect on fetal weight in early and mid-gestation (day 65 and 90; term 147 days) but manifested in intrauterine growth restriction (IUGR) on day 140 gestation followed by catch up growth in the early postnatal period in female lambs. The impact of T excess on IUGR and postnatal catch up seen in female may not be seen in the male due the elevated T it is naturally exposed to. We hypothesized that gestational T excess will have sexually dimorphic impact on late gestational fetal weights, a period of maximal fetal growth and the postnatal growth trajectory. Pregnant ewes were injected with T propionate (T), or oil-vehicle (CON), 100 mg I.M. twice weekly from gestational day 30 to 90 to obtain CON female (CF), T females (TF), CON males (CM), and T males (TM) fetuses on day 120 of gestation(GD120). In a the follow up study, lambs were delivered and weekly weights from CF, TF, CM, and TM were obtained till early adulthood. GD120 data and neonatal cytokine profile was analyzed by 2-way ANOVA and Cohen D (d) analysis while the postnatal growth data was subjected to mixed model ANOVA. T fetuses at GD120 weighed less then CON (P&lt;0.05); prenatal T excess reduced body weight (BW in kg) in both sexes compared to CON (CM 3.38±0.15 vs.TM 2.68±0.14, p=0.001; CF 3.27±0.21 vs.TF 2.72±0.11, p=0.03). There was a large magnitude increase in IL4 (d=0.92) and moderate in IL6 (d=0.78), IL1α (d=0.74), TNFα (d=0.77) and MIPβ (d=0.74) in TF compared to CF. TF also has large magnitude increase in MIPβ (d=0.97) and moderate magnitude increase in IL36RA (d=0.78), IL6 (d=0.70) compared to TM. TM has large magnitude increase in MIPβ (d=0.99) and IL6 (d=0.80) compared to CM. In contrast, during postnatal life, a significant age x treatment interaction (p =0.029) in average weight gain over time was evident. Growth was significantly higher in CM, TM and TF than CF and did not differ between CM and TM. Presence of IUGR in both sexes in late gestation, as opposed to catchup growth in the postnatal period only in TF not TM could have implication in sex-specific impact on the cardiometabolic function in the lambs. Supported by NIH R01HL139639.
Presentation: Thursday, June 15, 2023