bluuebunny/crossref_metadata_2025_split huggingface dataset:
FRI455 Polycystic Ovary Syndrome-Associated DENND1A Non-Coding Risk Loci Alter Gene Expression
Authors: Sankaranarayanan Laavanya , Johnson Graham , Barrera Alejandro , Dunaif Andrea Elizabeth , Reddy Timothy 
Published: October 2023

Abstract
Disclosure: L. Sankaranarayanan: None. G. Johnson: None. A. Barrera: None. A.E. Dunaif: None. T. Reddy: None.
Polycystic ovary syndrome (PCOS) is a leading cause of infertility and type 2 diabetes affecting 10-15% of menstruating people worldwide. PCOS is characterized by increased circulating testosterone levels, ovulatory dysfunction and insulin resistance. Genome wide association studies (GWAS) have identified ∼20 replicated common PCOS susceptibility loci in European and Han Chinese cohorts. The associated variants are predominantly non-coding and implicate neuroendocrine, reproductive, and metabolic causal pathways. Rare non-coding variants in DENND1A, a GWAS candidate gene that regulates androgen biosynthesis, were present in ∼50% of PCOS families by whole genome sequencing. These associations suggest non-coding genetic contributions to the development of PCOS. We tested the hypothesis that PCOS GWAS risk loci contribute to PCOS pathogenesis by altering gene regulation. We first identified ∼1500 functioning regulatory elements across the GWAS associated regions using a high throughput reporter assay, STARR-seq, in two different cell lines. We used H295R, an adrenal cell line model for testosterone production and COV434, an ovarian granulosa cell line. We identified cell-line specific and overlapping regulatory regions suggesting that there is context specific gene regulation. Sixty percent of the identified regions are in previously documented open chromatin regions from DNase-seq and ATAC-seq studies supporting our hypothesis that these regulatory regions are functional. We additionally experimentally tested the regulatory effect of five of the regulatory regions identified in the DENND1A locus in H295R cells using CRISPR-based epigenetic editing tools. This endogenous perturbation increases DENND1A gene levels (measured by qPCR) and also increased testosterone produced by the H295R cells (measured by ELISA), suggesting that these regions are biologically relevant to PCOS pathogenesis.We investigated allele-specific regulatory activity in a multi-ethnic pool of five genomes from healthy individuals. We identified 21 common genetic variants (minor allele frequency in the population &gt;0.05) that alter regulatory activity in the DENND1A locus, including two that are ancestry-specific. Further, rs12237685 and rs28441318 are also eQTLS for DENND1A from the GTEX project and reside within open chromatin regions in ovarian cells. The functional consequences of non-coding genetic variants associated with complex traits has been exceptionally difficult to elucidate. Our findings suggest that both the common genetic variants and rare PCOS patient-associated DENND1A variants and altered gene expression. Further, some of those variants may contribute to allele-specific genetic risk for PCOS.
Presentation Date: Friday, June 16, 2023
FRI456 Endocrine and Non-Endocrine Causes of Fatigue in Adults With Turner Syndrome: Cohort Study and Review of the Literature
Authors: Rosenberg Anna G W , Dingemans Veerle D A , Bos-Roubos Anja G , Luijks Sanne , Dessens Arianne B , Dykgraaf Ramon , Roos-Hesselink Jolien W , van Rossum Elisabeth F C , van der Lely Aart J , de Graaff Laura C G 
Published: October 2023

Abstract
Disclosure: A.G. Rosenberg: None. V.D. Dingemans: None. A.G. Bos-Roubos: None. S. Luijks: None. A.B. Dessens: None. R. Dykgraaf: None. J.W. Roos-Hesselink: None. E.F. van Rossum: None. A.J. van der Lely: None. L.C. de Graaff: None.
Background: Turner syndrome (TS) is a rare genetic developmental disorder characterized by gonadal dysfunction, short stature and heart defects, among others. Women with TS often suffer from severe fatigue, for which they are typically referred to endocrinologists. The diagnostic work-up is generally time-consuming and invasive, but it rarely solves the problem. To prevent the personal and financial burden of unnecessary diagnostic procedures, it is crucial to understand fatigue in TS. Therefore, in this study, we explored the association between fatigue and endocrine and non-endocrine comorbidities in a - for rare disorders - large group of TS women. Design: Cross-sectional study. Methods: 170 genetically confirmed TS women who attended the TS reference center underwent a systematic health screening, including a structured interview, complete physical examination, biochemical measurements, perceived stress and fatigue questionnaires and additional tests when indicated. Results: Median age was 32.6 years (IQR 23.9 - 41.4 years) and median BMI was 25.4 kg/m2 (IQR 22.6 - 28.5 kg/m2). One in three TS women experienced severe fatigue. Liver enzyme disturbances and body mass index were significantly associated with higher fatigue scores, while childhood growth hormone treatment was associated with lower fatigue scores. Perceived stress was highly correlated with fatigue (ρ = 0.71; P &lt; 0.001). Conclusions: There was no association between fatigue and most endocrine and non-endocrine disorders, which implies that fatigue is only partly explained by somatic disorders. The high correlation between perceived stress and fatigue suggests that TS-specific neuropsychological processes may play an important role in the etiology of fatigue in TS women. We provide a practical algorithm for the endocrine, non-endocrine and psychological approach to fatigue in TS women.
Presentation Date: Friday, June 16, 2023
FRI458 Rare Pathogenic Missense Variants in LMNA Identified in Women with Polycystic Ovary Syndrome (PCOS)
Authors: Bauer Rosemary , Gorsic Lidija , Legro Richard S , Ehrmann David , Geoffrey Hayes M , Urbanek Margrit 
Published: October 2023

Abstract
Disclosure: R. Bauer: None. L. Gorsic: None. R.S. Legro: None. M.G. Hayes: None. M. Urbanek: None.
Background: Polycystic ovary syndrome (PCOS) is the most common form of anovulatory infertility among reproductive age women. In addition to experiencing reproductive symptoms, women with PCOS are at elevated risk of developing obesity, insulin resistance (IR), and type 2 diabetes. Familial partial lipodystrophy type 2 (FPLD2) is a disorder of lipid storage and insulin resistance caused by dominant missense alleles in the gene encoding the intermediate filaments lamin A/C (LMNA). Women with this Mendelian disorder of IR also experience symptoms of PCOS such as amenorrhea and hyperandrogenism. We, therefore, hypothesize that genetic variation in LMNA also contributes to PCOS, which is a common form of IR. In other words, we hypothesize that PCOS falls into the phenotypic spectrum of disorders caused by variation in LMNA.Objective: We aim to identify and evaluate variation in LMNA that underlies PCOS pathogenesis. Methods: To test our hypothesis, we sequenced the LMNA gene in 602 women with PCOS and 125 reproductively healthy women. We comprehensively screened LMNA for genetic variation that is likely to alter the lamin A/C proteins, including missense, nonsense, splicing or frameshift variants. We identified 7 missense variants in 8 cases and no variants in reproductively healthy controls (χ2= 3.1, p=0.081, OR &gt; 1.78, with study controls; χ2= 46.8, p&lt;1x10-8, OR= 8.5 with gnomAD non-Finnish European cohort population controls). To determine which of these variants are pathogenic, we systematically evaluated them according to criteria outlined by the American College of Medical Genetics (ACMG). These guidelines evaluate pathogenicity of variants through multiple lines of evidence, including population data, computational predictions, and functional studies. Results: We identified 5 pathogenic variants in LMNA and 2 that are likely pathogenic. When assessed individually, 6 of the 7 variants are significantly enriched in our cohort when compared to gnomAD non-Finnish European population controls (OR &gt; 5.0). All of the LMNA variants are likely damaging as predicted by 3 computational methods: CADD score ≥ 15, FATHMM prediction of “Damaging”, and MutationTaster classification as “disease causing.” Additionally, many of the variants have previously been identified in individuals with lipodystrophy. Conclusion: Together with previous identification of LMNA variants in women with PCOS by our lab (Urbanek et al. 2009 JCEM) and others (Crespo et al. 2022 JES), this work further establishes LMNA variation as a pathogenic mechanism for PCOS.
Presentation Date: Friday, June 16, 2023
OR19-02 DIS3 Variants Are Associated with Primary Ovarian Insufficiency
Authors: Johnstone Erica Boiman , Gorsi Bushra , Coelho Emily , Moore Barry , Chow Clement , Yandell Mark , Welt Corrine Kolka 
Published: October 2023

Abstract
Disclosure: E.B. Johnstone: None. B. Gorsi: None. E. Coelho: None. B. Moore: Consulting Fee; Self; Fabric Genomics. C. Chow: None. M. Yandell: Consulting Fee; Self; Fabric Genomics. Stock Owner; Self; Fabric Genomics. C.K. Welt: None.
Context: A genetic etiology accounts for the majority of unexplained primary ovarian insufficiency (POI). Objective: We hypothesized a genetic cause of POI for a sister pair with primary amenorrhea.Design: The study was an observational study.Setting: Subjects were recruited at an academic institution.Subjects: Subjects were sisters with primary amenorrhea caused by POI, and their parents. Additional subjects included women with POI analyzed previously (n=291). Controls were recruited for health in old age or were from the 1000 Genomes Project (total n=233). Intervention: We performed whole exome sequencing (WES) and data were analyzed using the Pedigree Variant Annotation, Analysis and Search Tool (pVAAST), which identifies genes harboring pathogenic variants in families. We performed functional studies in a D. melanogaster model.Main Outcome: Genes with rare pathogenic variants were identified. Results: The sisters carried compound heterozygous variants in DIS3. The sisters did not carry additional rare variants that were absent in publicly available datasets. DIS3 knockdown in the ovary of D. melanogaster resulted in lack of oocyte production and complete infertility.Conclusions: Compound heterozygous variants in highly conserved amino acids in DIS3 and failure of oocyte production in a functional model suggest that mutations in DIS3 cause POI. DIS3 is a 3’ to 5’ exoribonuclease that is the catalytic subunit of the exosome involved in RNA degradation and metabolism in the nucleus. The findings provide further evidence that mutations in genes important for transcription and translation are associated with POI.
Presentation Date: Saturday, June 17, 2023
SAT358 Race And Ethnicity Of Women With 21-hydroxylase Deficient Non-classic Adrenal Hyperplasia (NCAH) Compared With PCOS
Authors: Pace Lauren Arielle , VanHise Katherine L , Chan Jessica Loretta , Pisarska Margareta Danuta , Azziz Ricardo 
Published: October 2023

Abstract
Disclosure: L.A. Pace: None. K.L. VanHise: None. J.L. Chan: None. M.D. Pisarska: None. R. Azziz: Advisory Board Member; Self; Arora Forge. Consulting Fee; Self; Rani Therapeutics, Fortress Biotech, Spruce Biosciences, Core Access Surgical Technologies. Grant Recipient; Self; Foundation for Research and Education Excellence, Ferring Pharmaceuticals. Stock Owner; Self; Martin Imaging.
Background: 21-hydroxylase (21-OH) deficient non-classic adrenal hyperplasia (NCAH) is found in 1-10% of androgen excess patients and is one of the most common autosomal recessive disorders in humans. In turn, PCOS has complex inheritance and is one of the most common endocrine disorders of women. Objective: To compare the racial and ethnic distribution of NCAH vs. PCOS in a referral population. Methods: We analyzed data from a database collected prospectively of consecutive female patients presenting with androgen excess at a tertiary care referral clinic. Results: Among 645 consecutive female patients with androgen excess who completed their evaluation, 15 (2.3%) had NCAH and 619 (96.0%) had PCOS defined by the Rotterdam 2003 criteria. Of 15 women with NCAH, 13 (86.7%) were White (10 White Non-Hispanic [WNH] and 3 White Hispanic [WH]), one (6.7%) was Asian, and one (6.7%) was of mixed race. Of PCOS subjects, 479 (77.4%) were White (347 WNH, 121 WH, and 11 of undocumented ethnicity), 65 (10.5%) were Black (55 Black Non-Hispanic [BNH], 5 Black Hispanic [BH], and 5 were Black of undocumented ethnicity), 47 (7.6%) were Asian Non-Hispanic (ANH), 6 (1.0%) were Native Hawaiian/Pacific Islander Non-Hispanic, 14 (2.3%) were of mixed race (4 Hispanic and 10 Non-Hispanic), and 7 (1.1%) were other or undocumented race. Comparing key phenotypic features, the mean (±SD) age at first visit for NCAH patients was 33.1 (±14.1) years vs. 28.9 (±6.9) for PCOS (p=0.03); mean BMI of NCAH patients was 27.7 (±8.2) kg/M2 vs. 30.2 (±8.2) in PCOS (p=0.26); mean Ferriman-Gallwey (FG) score for NCAH patients was 8.6 (± 6.2) vs. 6.7 (±5.1) PCOS (p=0.19); and mean menstrual cycles per year were 7.8 (±5.2) in NCAH vs. 6.0 (±3.9) in PCOS (p=0.12). Conclusions: Phenotypically, patients with NCAH were slightly older, but did not differ in BMI, degree of hirsutism, or menstrual dysfunction vs. PCOS patients, emphasizing the need to screen for NCAH using basal follicular-phase measurements of 17-hydroxyprogesterone. However, there were notable racial differences between the NCAH and PCOS cohorts. While 10% of PCOS patients were Black in this referral clinic database, no patient with NCAH was Black. The paucity of NCAH among Black individuals evaluated for androgen excess mirrors the ethnic/racial distribution in the classic form of 21-OH deficient adrenal hyperplasia. These data question whether Black women suspected of androgen excess or PCOS should be routinely screened for NCAH.
Presentation Date: Saturday, June 17, 2023
SAT380 Clinical, Metabolic And Hormonal Profile In Women Carrying Cyp21a2 Mutations
Authors: Livadas Sarantis , Goulis Dimitrios G , Belardinelli Elisabetta , Armeni Eleni , Solmi Beatrice , Veneti Stavroula , Lambrinoudaki Irene , Cecchetti Carolina , Macut Djuro P , Gambineri Alessandra 
Published: October 2023

Abstract
Disclosure: S. Livadas: None. D.G. Goulis: None. E. Belardinelli: None. E. Armeni: None. B. Solmi: None. S. veneti: None. I. Lambrinoudaki: None. C. Cecchetti: None. D.P. Macut: None. A. Gambineri: None.
Background: Heterozygote (HET) CYP21A2 gene mutations are present in 5-10% of the general Mediterranean population. Despite that homozygotes suffer from classical or non-classical congenital adrenal hyperplasia (NC-CAH), a survival advantage has been suggested for heterozygote carriers. The aim of this study was to describe the clinical, metabolic and hormonal profile in reproductive age women with CYP21A2 HET. Methods: Data from 56 HET women were compared with 105 controls, 64 untreated women with NC-CAH and 63 women with polycystic ovary syndrome (PCOS) of similar age and body mass index. Results: The prevalence of hirsutism (54 vs. 8%) and acne (44 vs. 4%) was higher in HET than controls. The degree of menstrual irregularities was similar between HET and NC-CAH and worse than controls. The lipid profile was better in HET than PCOS (Cholesterol 170.2±37.1 vs. 187. 7±39.3 mg/dl, HDL 61.4±26.1 vs. 46.8±8.6 mg/dl), but similar to NC-CAH. Testosterone (0.78±0.45 vs. 0.50±0.25 ng/dl), SHBG (38.2±20.1 vs. 56.2±31.4 nmol/l), FAI (9.56±3.45 vs. 5.37±1.24) and DHEAS concentrations (2.62±1.31 vs. 1.27±0.94 nmol/l) were similar to HET, NC-CAH and PCOS and significantly higher than controls as well as insulin (13.88±7.96 vs. 7.51±2.82 IU/l) and HOMA-IR (2.95±1.60 vs. 1.65±0.67). Δ4- androstenedione (5.97±2.88 vs. 8.80±3.45 ng/ml) and 17(OH)-progesterone (4.32±2.02 vs. 13.75±8.34 ng/ml) concentrations were lower in HET than in NC-CAH, but higher than PCOS and controls. Finally, ovarian PCO morphology prevalence was similar in HET than NC-CAH and PCOS. Conclusions: HET display a favorable lipidemic profile, but a similar degree of hyperandrogenic signs, menstrual disturbances, insulin resistance, hyperandrogenemia and ovarian morphology than women with PCOS or NC-CAH. Therefore, these women, when identified, should be followed-up.
Presentation Date: Saturday, June 17, 2023
FRI176 Integrated Profiling Analysis Of Serum Steroids And Catecholamines In A Single Run With LC-MS
Authors: Noh Jongsung , Lee Chaelin , Park Seung Shin , Ahn Chang Ho , Myung Seung-Woon , Kim Jung Hee , Choi Man Ho 
Published: October 2023

Abstract
Disclosure: J. Noh: None. C. Lee: None. S. Park: None. C. Ahn: None. S. Myung: None. J. Kim: None. M. Choi: None.
Adrenal steroids and catecholamines are associated with the response against biochemical stress and adrenal disorders. Metabolic alteration of these hormones could be quantitatively evaluated in diagnostic process, but both adrenal cortex and medullary hormones have been measured in different analytical platforms. To increase the bio-analytical validity, liquid chromatography-mass spectrometry (LC-MS) based simultaneous profiling of 29 steroids and 6 catecholamines was developed. After alkyloxycarbonylation with isobutyl chloroformate, catecholamines and steroids were extracted simultaneously in liquid-liquid extraction. The limit of quantification ranged from 0.1 to 25 ng/mL with extraction recoveries of 78.5-97.0%, while the precision and accuracy were 4.8-7.9% and 98.0-110.9%, respectively. The validated LC-MS assay was then applied to serum samples obtained from 20 individual patients with primary aldosteronism (PA), Cushing’s syndrome (CS) and pheochromocytoma and paraganglioma (PPGL). The significantly increased serum levels of 18-hydroxycorticosterone (p &lt; 0.005), corticosterone (p &lt; 0.05), and 18-hydroxycortisol (p &lt; 0.002) were observed in PA group, while PPGL group showed decreased level of 11-deoxycortisol (p &lt; 0.007). Higher levels of glucocorticoids including 21-deoxycortisol (p &lt; 0.002), 6β-hydroxycortisol (p &lt; 0.001), and tetrahydrocortisone (p &lt; 0.001) and lower levels of androgens including DHEA (p &lt; 0.00001) and DHEA sulfate (p &lt; 0.03) were detected in CS group. Catecholamines, such as norepinephrine (p &lt; 0.0001) and normetanephrine (p &lt; 0.0001), were significantly increased in PPGL patients. The present novel assay was successfully applied to discriminate three different adrenal diseases in a single analytical run.
Presentation: Friday, June 16, 2023
OR35-06 Polycystic Ovary Syndrome Is Associated With an Increased Mortality Risk
Authors: Ollila Meri-Maija , Arffman Riikka K , Morin-Papunen Laure , Korhonen Elisa , Gissler Mika , Piltonen Terhi T 
Published: October 2023

Abstract
Disclosure: M. Ollila: None. R.K. Arffman: None. L. Morin-Papunen: None. E. Korhonen: None. M. Gissler: None. T.T. Piltonen: None.
Women with polycystic ovary syndrome (PCOS) are burdened with multimorbidity, but there is only limited knowledge on mortality. Here, we investigated in a register-based 1:3 matched case-control study, whether women with PCOS have increased all-cause, or cause-specific mortality compared to women without PCOS. Women with PCOS (i.e., cases) were identified from the Finnish Care Register for Health Care using the International Classification of Diseases, Revisions 8, 9, and 10 (ICD-8, ICD-9, and ICD-10, respectively) codes for PCOS (ICD-10: E28.2, ICD-9: 256.4, ICD-8: 256.9). Control women were matched according to the year of birth and residential area. The time and cause of death as well as the highest level of education were extracted from the register of Statistics Finland. The registers covered the years 1969-2019. Crude and education-adjusted Cox proportional hazard models were applied, and the results were reported as hazard ratio (HR) with 95% confidence intervals. The study included 9,839 women with PCOS and 70,705 controls. Overall, 1,003 controls and 177 women with PCOS died during the follow-up period. The women with PCOS died significantly younger than the controls (51.4 ± 16.4 versus 52.9 ± 16.6 years, p&lt;0.001). In the unadjusted analysis, women with PCOS had increased overall mortality (HR=1.53 [1.28-1.84]) as well as increased mortality due to tumors (HR=1.42 [1.06-1.90]), endocrine, nutrition, or metabolic diseases (HR=2.45 [1.02-5.96]), and diseases of the circulatory system (HR=1.77 [1.19-2.62]). In the adjusted analysis, women with PCOS had increased overall mortality (HR=1.47 [1.23-1.76]), as well as increased mortality due to diseases of the circulatory system (HR=1.67 [1.13-2.48]) and tumors (HR=1.38 [1.04-1.85]). Regarding more specific causes of death, women with PCOS had increased mortality due to diabetes (HR=3.07 [1.16-8.08]), other diseases of the circulatory system (HR=2.07 [1.00-4.25]), and bronchitis (HR=3.61 [1.01-12.88]) in the adjusted analyses. In conclusion, PCOS is a severe lifelong syndrome that increases mortality. More emphasis should be targeted on the prevention and treatment of diabetes, circulatory diseases, tumors, and respiratory diseases in women with PCOS to reduce the mortality risk.
Presentation Date: Sunday, June 18, 2023
THU574 Hsd17b1 Partially Compensates For The Lack Of Hsd17b3 In Testicular Testosterone Production In Fetal Mice, But Not In Adults
Authors: Poutanen Matti , Junnila Arttu , Sipilä Petra , Huhtaniemi Ilpo T 
Published: October 2023

Abstract
Disclosure: M. Poutanen: None. A. Junnila: None. P. Sipilä: None. I.T. Huhtaniemi: None.
Hydroxysteroid (17β) dehydrogenase type 3 (Hsd17b3) is the primary enzyme converting androstenedione to testosterone in human testes. HSD17B3 deficiency is a known cause of a disorder of sex development (DSD), where XY individuals are born with a female appearance, but are virilized during puberty as testosterone starts to suddenly rise due to unknown compensatory mechanisms. We have previously established and characterized an Hsd17b3 knockout mouse line (HSD17B3KO). HSD17B3KO males were born phenotypically normal, but presented various signs of under-masculinization at later ages. However, although they have very high circulating androstenedione at adulthood, they also maintain normal-to-high concentrations of testosterone. Indeed, testosterone was only seen to be low during certain fetal and pubertal time points. We suspected that Hsd17b1, capable of catalyzing the same reaction and expressed in testes towards the end of the fetal development, could be responsible for the compensation in the testosterone production, especially in the presence of higher than normal concentrations of androstenedione. To test this, we created an Hsd17b1-Hsd17b3 double KO (DKO) mouse line. The loss of both Hsd17b1 and Hsd17b3 had a more drastic effect on the phenotype of the male animals than was observed in HSD17B3KO. The outward appearance of the DKO males was completely feminized both as newborns and at adulthood, with an anogenital distance comparable to females. The male internal genitalia were present, but compared to HSD17B3KO they were further reduced in size, as were several other androgen-sensitive tissues. However, the testes and epididymides of the DKO contained high number of mature spermatozoa. The loss of both enzymes had a clear effect on the testis steroidogenesis of the newborn animals, with a 2-fold increase in intra testis androstenedione and 6-fold decrease in testosterone concentration compared to WT and HSD17B3KO males. In contrast, at the age of 3 months, no difference in the circulating steroid concentrations was observed between the DKO and HSD17B3KO, and high concentrations of androstenedione and testosterone was present in both mice. This, along with the active spermatogenesis, imply that in a presence of high LH, a further compensatory mechanism of testosterone production is present in the adult testes. In conclusion, our results demonstrate that in the absence of Hsd17b3, Hsd17b1 is crucial for the remaining testosterone production capacity in fetal mouse testis. However, in adult animals, the compensatory role is taken over by other, so far unknown, enzymes. Compared to HSD17B3KO, the overall phenotype of the DKO male mice is more similar to that of the humans with HSD17B3 deficiency, while the phenotype of HSD17B3KO is less feminized.
Presentation Date: Thursday, June 15, 2023