bluuebunny/crossref_metadata_2025_split huggingface dataset:
PMON243 Metabolic Disorders Genetically Modify Polycystic Ovary Syndrome through its Candidate Hormones
Authors: Actkins Ky’Era , Davis Lea 
Published: November 2022

Abstract

Introduction
As the most common endocrine disorder in reproductive-aged women, polycystic ovary syndrome (PCOS) increases the risk of developing several cardiometabolic disorders like insulin resistance. However, Mendelian randomization (MR) studies provide little support for direct causal associations between PCOS and metabolic conditions with the exception of obesity and type 2 diabetes (T2D). As a result, secondary pathways and biological mediators increasingly emerge as a potential explanation for underlying mechanisms between traits.

Objective
To identify biomarkers that modify PCOS presentation and its comorbid conditions through MR, which uses significant genetic variants from genome-wide association studies to estimate causal effects between variables.

Methods
A bidirectional MR analysis was first implemented to identify associations between PCOS and metabolic traits (i.e., body mass index (BMI), T2D, blood pressure, coronary artery disease, and heart failure), with PCOS acting first as the exposure, then as the outcome. Next, MR was applied between significant metabolic phenotypes from the first analysis and thirty-two biomarkers from UK Biobank to identify any overlap with biomarkers that also significantly increased risk for PCOS. Mirroring biomarkers from a hospital population were used as a replication dataset and were further analyzed in a mediation analysis with clinical laboratory measurements.

Results
Testosterone from females (β = 0.83, p = 4.67e-04) and sex hormone-binding globulin (SHBG, β = -0.01, p = 5.00e-06) were identified as significant exposures for PCOS. These biomarkers also exhibited causal effects on BMI (βFT = 0.10, p = 5.81e-12; βSHBG = 0.001, p = 4.56e-10) and T2D (βSHBG = -0.004, p = 4.99e-26), which were the only two phenotypes that exerted causal risk for PCOS (p &lt; 0.001). Although SHBG had strong bidirectional effects on both traits, female-derived testosterone was the only testosterone exposure (vs sex-combined and male testosterone) that increased BMI (β = 0.04, p = 1.08e-16). This positive association with BMI was exclusively replicated for free testosterone as the outcome. Although no significant associations were observed in the mediation analysis for BMI and free testosterone, total testosterone mediated 29% of the genetic pathway from T2D to PCOS.

Conclusions
Overall, MR can expand our understanding on the phenotypic irregularities of PCOS through examination of biomarker etiology cross-traits. These results imply a strong interaction between prevalent PCOS characteristics, one that may mitigate the advancement of other chronic comorbidities. Therefore, further research is needed to elucidate PCOS regulation, which may reveal a more complex web of modifiable effects that have yet to be explored.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
PMON251 Loss of Constitutive Androstane Receptor, CAR reduces the serum androgens levels and alters reproductive function
Authors: Asokakumar Anjana , Hernandez Juan P , Xiao Rui , Moore David D , Anakk Sayeepriyadarshini 
Published: November 2022

Abstract
The nuclear receptor, Constitutive Androstane Receptor (CAR/NR1i3) is extensively known for its detoxification function in the liver. We have identified the role of CAR in regulating androgen levels and regulating testis function. Although the inactivation of CAR by the sex hormone axis via androstanol has been known for decades, its role in regulating reproduction has not been addressed. On examining the WT mice and the global CARKO mice, we found that CARKO mice have reduced serum testosterone and androstanol levels. Further, the levels of the steroidogenic gene, Srd5a1 was significantly reduced. This result correlated well with reduced anogenital distance in males, increased anxiety and subfertility. However, we did not find differences in the expression of detoxification genes in the CARKO testis. Histological analysis of the testis of the CARKO mice revealed abnormal Leydig cells and Oil Red O staining showed lipid accumulation in the Leydig cell island. We are currently examining the effect of the reduced androgens in the hypothalamic-pituitary-gonadal axis in the CARKO mice model.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
PMON255 Inflammation and Oxidative Stress in Seminal Plasma: Role of Free Light Chains of Immunoglobulins and Antioxidants as Biomarkers in Male Infertility
Authors: Bruno Carmine , Vergani Edoardo , Oliva Alessandro , Basile Umberto , Napodano Cecilia , Gulli Francesca , Silvestrini Andrea , Meucci Elisabetta , Orlando Patrick , Silvestri Sonia , Tiano Luca , Mancini Antonio 
Published: November 2022

Abstract
Oxidative and inflammatory damage are underlying mechanisms in various conditions related to male infertility, including varicocele. Free light chains of immunoglobulins (FLCs) are considered markers of low-grade inflammation in various conditions. Nowadays it is known that they may play enzymatic and proteolytic activities; they may activate complement cascade and mast cells, with crucial role in the development of contact sensibility; they may also inhibit the autonomous signaling ability of the B-cell receptor. Their detection in biological fluids may be useful as biomarker of inflammation or altered immune response. Coenzyme Q10 (CoQ10), a lipidic antioxidant and component of the mitochondrial respiratory chain, is involved in spermatozoa energy metabolism and motility.
Therefore, we aimed to evaluate FLCs seminal levels in patients with varicocele in comparison to control subjects and to correlate them with CoQ10 and Total Antioxidant Capacity (TAC) in human semen.
A total of 65 patients were enrolled, aged 18-50 years. Semen analysis was performed; patients were divided into three groups: controls (CTRL), 12 normozoospermic patients aged 34 (33-41) years; varicocele (VAR), 29 patients aged 33 (26-37) years; idiopathic (IDIO), 24 oligo-, astheno- and oligoasthenozoospermic patients aged 37 (33.5-40.5) years. FLCs were assayed by turbidimetric method; CoQ10 by HPLC; TAC by spectrophotometric method.
Λ FLCs showed a trend towards higher levels in VAR vs CTRL and IDIO. VAR showed a trend towards lower κ FLCs levels vs the other two groups. Comparing κ/λ ratio VAR showed significantly lower levels vs CTRL and IDIO (Mean±SEM 3.18±0.75; 8.28±1.71; 8.90±2.94, respectively; p&lt;0.05). CoQ10 seminal levels showed higher levels in VAR and IDIO compared to CTRL (57.7±4.13; 65.50±6.95 and 38.30±3.35 mcg/ml, respectively; p&lt;0.05) No different TAC values were found between groups.
Our data confirm lower levels of κ/λ ratio in VAR as previously reported and suggest a possible application as clinical biomarkers for male infertility.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
OR07-3 Hormone-Controlled Cooperative Binding of Transcription Factors Within Enhancer Clusters Drives Synergistic Induction of Fasting-Regulated Genes
Authors: Charni-Natan Meital , Goldberg Dana , Goldstein Ido 
Published: November 2022

Abstract
During fasting, hepatocytes produce glucose in response to hormonal signals. Glucagon and glucocorticoids are principal hormones secreted during fasting that cooperate in regulating glucose production via increasing hepatic gluconeogenesis. However, how these hormone signals are integrated in hepatocytes and translated to a biological output is unknown. We used genome-wide profiling of gene expression, enhancer dynamics and transcription factor binding in primary mouse hepatocytes to uncover the mode of cooperation between glucagon and corticosterone (the major glucocorticoid in mice). We found that compared to a single treatment with either hormone alone, a dual treatment initiates a pro-gluconeogenic gene program in hepatocytes by synergistically inducing gluconeogenic genes. We show that the mechanism driving synergistic gene expression is based on glucagon-mediated enhancer activation, leading to increased binding of the glucocorticoid receptor (GR) upon corticosterone stimulation. This was shown by glucagon-dependent increases in the active enhancer mark H3K27ac at GR binding sites (both signals were measured genome-wide via chromatin immunoprecipitation sequencing). Thus, glucagon-dependent enhancer activation, mediated by the glucagon-activated transcription factor CREB, assists GR loading to specific enhancers located near synergistic gluconeogenic genes. This 'assisted loading' mechanism is enhancer-specific as GR was able to efficiently bind other enhancers without assistance by CREB. Interestingly, we found that the glucagon-CREB axis does not only activate single enhancers but is also able to activate entire enhancer clusters. Indeed, CREB binding in one enhancer unit within a cluster, led to cluster-wide enhancer activation, thereby assisting the loading of GR in other enhancer units within the cluster that are unbound by CREB directly. These chromatin and gene expression changes collectively lead to synergistic glucose production from hepatocytes in the presence of glucagon and corticosterone. In summary, we show that hepatocytes integrate extracellular signals by an enhancer-specific mechanism: glucagon activates enhancers, thereby assisting the loading of GR upon stimulation by corticosterone. This chromatin-bound integration of endocrine signals leads to synergistic gene induction and a tailored response to fasting.
Presentation: Saturday, June 11, 2022 12:00 p.m. - 12:15 p.m.
OR26-5 Musashi-2 Regulatory Interactions Promote Adrenal Steroidogenesis
Authors: Baldwin Amber , Mukherjee Neelanjan , Murphy Elisabeth , Sajek Marcin , Walters Kathryn 
Published: November 2022

Abstract
The adrenal gland is the site of steroid hormone synthesis. These hormones regulate many physiological processes including metabolism, blood pressure and volume, and sexual characteristic development. While signaling pathways, steroidogenic enzymes, and transcription factors have all been well characterized, little is known about the contribution of RNA-binding proteins (RBPs) in regulating steroidogenesis. We recently demonstrated that regulated RNA decay controls the timing of the steroidogenic gene expression response and identified 9 RBPs that regulate aldosterone production in an immortalized human cell line model for steroidogenesis, H295R. One of the RBPs we identified was Musashi-2 (MSI2), which is required for development of other steroidogenic tissues such as ovary and testis in mice. We found that MSI2 mRNA is enriched in human adrenal glands relative to other tissues, positively correlates in expression with mRNAs encoding steroidogenic enzymes, and abundantly expressed in H295R cells. Staining of normal human adrenal gland sections demonstrated that MSI2 protein is expressed in all three layers of the human adrenal cortex. Taken together, we hypothesized that MSI2 promotes steroidogenesis through regulating expression of target mRNAs encoding. Using the selective MSI2 inhibitor Ro-08-2750 (Ro) we found that aldosterone and cortisol production is decreased in a dosage dependent manner in H295R cells, which is consistent with siRNA knockdown of MSI2. We performed RNA-immunoprecipitation and sequencing and identified 1428 mRNA targets of MSI2 in H295R cells. A target of interest was Stearoyl-CoA Desaturase (SCD), which functions to convert saturated fatty acids to unsaturated fatty acids that promote formation of lipid droplets. Cholesterol esters in lipid droplets are a source of cholesterol used to produce all steroid hormones. Ro treatment of H295R cells resulted in a suppression of SCD mRNA and protein induction. Furthermore, inhibition of SCD with A939572 caused a dosage dependent decrease in aldosterone production. These data suggest that potentiation of stimulation dependent SCD induction is one mechanism by which MSI2 promotes steroidogenesis. It will be important to determine if and how MSI2 promotes steroidogenesis in primary human adrenal cells and mouse models. Since it is possible to deliver oligonucleotides to the adrenal cortex, disruption of MSI2-SCD mRNA regulatory interactions may open new therapeutic avenues for modulate aldosterone production.
Presentation: Monday, June 13, 2022 12:00 p.m. - 12:15 p.m.
RF03 | PMON296 Insulin-induced AKR1C3 Metabolizes Classical and 11-oxygenated Androgens in a Model of PCOS Adipocytes
Authors: Mesaros Clementina , Paulukinas Ryan , Penning Trevor 
Published: November 2022

Abstract
Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women. These patients commonly develop hyperandrogenism and this androgen excess (AE) is believed to drive the syndrome. PCOS women also characteristically develop insulin resistance (IR), which correlates with AE in PCOS women. Aldo-keto reductase family 1 member C3 (AKR1C3) catalyzes the conversion of peripheral androgens and is induced by insulin in adipocytes. Classically, AKR1C3 converts Δ4-androstene-3,17-dione (4AD) to testosterone (T) and 5α-androstane-3,17-dione (5AD) to 5α-dihydrotestosterone (DHT). As a result, androgen conversion in adipocytes may contribute to the AE of PCOS women. Additionally, the 11-oxygenated androgens of adrenal origin were reported as the dominant androgens of PCOS and may be an alternative source of AE. AKR1C3 can also convert 11-ketoandrostene-3,17-dione (11K-4AD) to 11-ketotestosterone (11K-T) and 11-ketoandrostane-3,17-dione (11K-5AD) to 11-ketodihydrotestosterone (11K-DHT). T, DHT, 11K-T and 11K-DHT are potent agonists for the androgen receptor (AR). Therefore, overexpression of AKR1C3 by insulin could increase AR activation through production of both classical and 11-keto potent androgens. We hypothesize that AKR1C3 induced by insulin will produce 11K-T and 11K-DHT in a model of PCOS adipocytes. We developed a stable-isotope-dilution liquid chromatography high resolution mass spectrometric assay (SID-LC-HRMS) for the quantification of both classical and 11-oxygenated androgens in differentiated Simpson-Golabi-Behmel Syndrome adipocytes. Cells were treated with 4AD, 11K-4AD, or 11β-hydroxy-androstene-3,17-dione (11β-OH-4AD), the adrenal precursor to 11K-4AD. Androgens were derivatized with Girard P to enhance sensitivity and specificity. Analyte peaks were quantified using calibration curves of analyte to internal standard ratios versus pg of authentic standard. Our data suggests that 11β-OH-4AD is converted to 11K-4AD, which is then converted by insulin-induced AKR1C3 to 11K-T. The conversion of 11K-4AD to 11K-T was AKR1C3 dependent since a panel of AKR1C3 inhibitors blocked 11K-T formation. We found that 11K-T is deactivated to 11β-hydroxy-testosterone (11β-OH-T) and 11K-4AD can be back converted to 11β-OH-4AD by 11β-hydroxy steroid dehydrogenase type 1 (HSD11B1). This suggests that HSD11B1 protects the AR from overactivation by converting potent 11-keto androgens to their less potent 11β-hydroxy counterparts. Both classical and 11-oxygenated androgens may be sources of AE in PCOS by their intracrine formation in adipocytes. Our work elucidates the role of AKR1C3 in the formation of both classical and 11-keto potent androgens in a model of PCOS adipocytes and supports AKR1C3 as a potential therapeutic target in mitigating the AE of PCOS.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
ODP436 Adrenal Insufficiency After Combined Treatment of Itraconazole and Triamcinolone
Authors: Sajan Alen , Mandhan Akash , Wong Beatrice , Abraham Smita , Stefan Simona 
Published: November 2022

Abstract

Introduction
Adrenal insufficiency (AI) has been reported due to the use of budesonide and itraconazole. We report an unusual presentation of adrenal insufficiency from the use of triamcinolone and itraconazole.

Clinical Case
46-year-old man with a history of NASH and alcoholic cirrhosis requiring liver transplant presented to ER with two weeks of progressive lower extremity weakness. He reported difficulty climbing stairs and getting up from a chair. He denied anorexia, nausea, vomiting, abdominal pain, or lightheadedness. He was treated with itraconazole for diffuse histoplasmosis for over one year and received one dose of intra-articular triamcinolone 40mg for shoulder pain 2 weeks prior to the hospital admission. Physical exam was significant for proximal weakness, ecchymoses on upper and lower bilateral extremities, mild truncal obesity, but no violaceous striae, moon facies, dorsocervical fat pad or supraclavicular fullness. Laboratory evaluation was notable for sodium 129 mEq/L (n: 135-145), potassium 5.9 mEq/dl (n: 3.5-5), albumin 2.9 g/dl (n: 3.5-5) and glucose 345 mg/dl (n: 70-140), ACTH of 6 pg/ml (6-20) AM cortisol of &lt;1 ug/dl (n: 4-20), aldosterone &lt;1 ng/dl (n: 3-16), and plasma renin activity (PRA)20.54 ng/mL/h (n: 0.25-5.82). Serum cortisol increased to 3.4 ug/dl at 60 minutes of cosyntropin stimulation test, consistent with adrenal insufficiency. Synthetic glucocorticoid panel detected triamcinolone. Patient was discharged on hydrocortisone and fludrocortisone with marked clinical improvement. Abdominal MRI 3 months after admission did not show any adrenal involvement by histoplasmosis. Fludrocortisone was slowly titrated off and only hydrocortisone continued. Repeat evaluation 6 months after last triamcinolone injection demonstrated recovery of HPA axis with peak cosyntropin stimulation cortisol level 16.3 ug/dL (assay by Abbott Alinity) and recovery of renin/angiotensin/aldosterone axis (AM aldosterone 7 ng/dl, renin 2 ng/ml/h). Repeat synthetic glucocorticoid testing confirmed clearance of triamcinolone.

Conclusion
Itraconazole is CYP3A inhibitor that has been shown to decrease the metabolism and clearance of different corticosteroids. While our patient's lab results supported a diagnosis of AI, it was unclear if the etiology was primary (PAI) or central AI (CAI). The Na+, K+, aldosterone and PRA levels support a diagnosis of PAI; whereas the suppressed ACTH level supports CAI. We believe that our patient had an atypical presentation of both PAI due to histoplasmosis and CAI due to itraconazole/triamcinolone. This confounding picture can potentially be explained by an underlying PAI that may have been masked and exacerbated by the HPA axis suppression of the itraconazole/triamcinolone combination.
Presentation: No date and time listed
LBODP092 Proposal Of Indication For Completion Thyroidectomy In Follicular Thyroid Carcinoma Using TERT Promoter Mutational Status
Authors: Park Hyunju , Heo Jung , Ki Chang-Seok , Shin Jung Hee , Oh Young Lyun , Son Young I , Kim Jee Soo , Kim Sun Wook , Chung Jae Hoon , Kim Tae Young , Kim Tae Hyuk , Kim Jung-Han 
Published: November 2022

Abstract

Background
Stepwise surgical approach with hemithyroidectomy and completion thyroidectomy was used to solve the dilemma of definite characterization of follicular thyroid carcinoma (FTC). However, which patients will be candidates for completion thyroidectomy has been controversial. The aim of this study is to clarify the selection criteria for completion thyroidectomy using TERT promoter mutation.

Methods
A total of 87 FTC patients who had information about TERT promoter mutation from August 1995 to November 2020 were investigated. The cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each of the WHO 2017 classifications were calculated.

Results
Of the 87 patients, 8 patients (9.2%) had initial distant metastasis, and 15 patients (17.2%) had persistent disease or developed structural recurrence. Threshold diameter for initial distant metastasis, disease recurrence, and cancer-specific death was 2cm in minimally invasive FTC (MI-FTC) with mutant TERT (M-TERT) and in encapsulated angioinvasive FTC (EA-FTC) with M-TERT, while in MI-FTC with wild-type TERT (WT-TERT) and EA-FTC with WT-TERT it was 4cm. Cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each WHO 2017 classification were significantly different only in patients with WT-TERT (P = 0. 001, P = 0. 019, and P = 0. 005, respectively).

Conclusions
The data suggested that 2 cm may be a critical threshold diameter for deciding completion thyroidectomy in MI-FTC with M-TERT and EA-FTC with M-TERT. TERT promoter mutational status can be a game changer for selecting candidates for completion thyroidectomy.
Presentation: No date and time listed
LBODP103 Ectopic Thyroid Tissue In A Pediatric Patient After Total Thyroidectomy
Authors: Gurnurkar Shilpa , Vyas Neha , Seekford Jennifer Leigh 
Published: November 2022

Abstract

Introduction
Ectopic thyroid tissue is defined as any functional thyroid tissue outside the normal anatomical location. It is rare and occurs with a frequency of 1 in 100,000-300,000. Most commonly, it is located along the normal track of thyroid development along the floor of the primitive gut to the pre-tracheal region of the neck; however, rarely it has been found in other areas. Malignancy is very rare in ectopic thyroid tissue (&lt;1%) and when it occurs, papillary carcinoma is the most common type. Maki et al have reported multiple cases of lateral neck ectopic thyroid tissue in the presence of an orthotopic thyroid gland in the adult population. Only 2 pediatric cases have been reported in the literature so far.

Clinical Case
A 11-year-old male presented with concerns of morbid obesity and a neck swelling. He endorsed a previous history of thyroid nodules measuring over 2 cm that were being monitored by his previous endocrinologist. On exam, he was noted to have a goiter. Labs were obtained which indicated normal thyroid function tests (TSH 3. 040 uIU/mL, nl 0.45-4.5 uIU/mL and free T4 0.96 ng/dL, nl 0.93-1.6 ng/dL) and negative anti thyroid antibodies (TPO antibody &lt;9 IU/mL, nl 0-26 IU/mL and thyroglobulin ab &lt;1 IU/mL, nl 0. 0-0.9 IU/mL). His previous medical records revealed that a FNA was completed 2 years prior which was reported as benign. A repeat thyroid ultrasound revealed a multinodular goiter with 5 nodules measuring 3.3 x1.5×1.3cm and 5×6×5mm in the right lobe and 7×6×4cm, 2.4×2.1×1.8cm, and 5×6×5cm in the left lobe. After reviewing different management approaches, the family preferred thyroidectomy. He was referred to general surgery and subsequently underwent total thyroidectomy. Post-operatively, he was started on levothyroxine and calcium carbonate supplementation. The calcium supplementation was subsequently weaned and discontinued. Final pathology was reported as benign. Unfortunately, he was lost to follow up and presented to his primary care provider 6 months post-operatively with continued weight gain and a right sided neck mass. Labs obtained showed an elevated TSH (9.820 uIU/mL, nl 0.45-4.5 uIU/mL) and normal free T4 (1. 07 ng/dL, nl 0.93-1.6 ng/dL). Ultrasound of the neck revealed a 2.5 cm heterogeneous nodule in the right neck adjacent to the thyroid bed, concerning for recurrent/residual disease. FNA was completed and was consistent with normal appearing thyroid tissue. Ultrasound monitoring will continue to assess for change in size and need, if any for surgical removal in the future.

Discussion
Ectopic thyroid tissue with an orthotopic thyroid is a very rare finding in the pediatric population. Ectopic thyroid tissue outside of the thyroglossal duct is rare as well. We present an 11-year-old male who underwent thyroidectomy for multiple large thyroid nodules and subsequently developed a new neck mass diagnosed as ectopic thyroid tissue.
Presentation: No date and time listed