bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-690 Euglycemic Diabetic Ketoacidosis Associated with SGLT-2 Inhibitors- an Under-recognized Diagnosis
Authors: Chhabra Sarah , Manzano Alex , Garg Neha
Published: May 2020

Background

Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are a promising class of oral anti-hyperglycemic agents with mounting evidence of reduced cardiovascular risk and renal failure, in patients with type 2 diabetes mellitus. Recent increase in their use has led to identification of hitherto unknown side effects of these drugs. Euglycemic Diabetic Ketoacidosis (eDKA), found to be associated with SGLT-2i use, is a life-threatening condition and commonly goes unrecognized due to absence of the cardinal sign of hyperglycemia.

Clinical Case

We describe a 47 year old male with history of coronary artery disease and recently diagnosed type 2 diabetes mellitus who presented to our hospital with one week history of nausea, lethargy, progressive fatigue, and shortness of breath. He was diagnosed with type 2 diabetes three weeks prior, with HBA1c of 12%.

His regimen included basal insulin and recent transition to empagliflozin due to severe GI intolerance with metformin use.

On arrival he was noted to be tachycardic with a heart rate of 113/min, afebrile and normotensive. Physical exam was mostly unremarkable except for dry oral mucous membranes. Serum chemistry was consistent with high anion gap metabolic acidosis with bicarbonate of 6.9 mmol/L (21-32 mmol/L), anion gap of 29 mmol/L (10-20 mmol/L), mildly elevated blood glucose of 132 mg/dl (74-106 mg/dl), acute kidney injury with creatinine of 1.47 mg/dl (0.7- 1.3 mg/dl), and a beta hydroxybutyrate level of 82.7 mg/dl (0.20- 5.63 mg/dl). Urine analysis showed ketonuria. This was consistent with a clinical and biochemical diagnosis of eDKA. He was treated with IV D5%NS-20mEq/L KCL and an insulin drip. Upon resolution of his acidosis and normalization of the anion gap he was switched to subcutaneous Insulin Glargine and Lispro. Empagliflozin was held as it was thought to be contributing to the diagnosis of eDKA.

Conclusion

Our case yet again illustrates the importance of recognition of EDKA to aid prompt management, especially with the rising popularity of SGLT-2 inhibitors. It is also important to educate patients about this condition, mostly notable in the first two months of starting the medication, to recognize the concerning symptoms and precipitating factors like dehydration, improper insulin dosing, low calorie diet, alcohol, infection, surgery. An acceptable alternative to SGLT-2i can be glucagon like peptide receptor (GLP- 1) agonists, also associated with good cardiovascular outcomes.
SUN-632 The Impact of Vitamin D Deficiency on Pregnancy in Type 1 Diabetes
Authors: Kolpakova Evgenia , Ibragimova Liudmila , Derevyanko Olga , Ragimov Magomed , Bostanova Fatima , Nikankina Larisa , Nikonova Tatiana
Published: May 2020

Vitamin D deficiency during pregnancy may not only impair maternal skeletal preservation and fetal skeletal formation but also influence fetal “imprinting” that may affect chronic disease susceptibility soon after birth as well as later in life.

Vitamin D deficiency has been linked to multiple adverse perinatal outcomes in pregnancy including; pre-eclampsia, gestational diabetes, low birth weight, bacterial vaginosis, pre-term delivery and caesarean section. Aim: to assess 25-hydroxy vitamin D (25OHD) concentrations in women with type 1 diabetes (T1DM) during pregnancy, post-delivery and also foetal (cord blood) 25OHD concentrations and to examine relationships between these. The second aim of the study to examine potential relationships between maternal 25OHD and glycosylated haemoglobin (HbA1c) throughout pregnancy. Materials and methods: This was an observational study of 42 pregnant controls without diabetes and 39 pregnant women with T1DM. Maternal serum 25OHD was measured serially throughout the pregnancy and post-delivery. Cord blood 25OHD was measured at delivery. 25OHD was measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). HbA1c was measured serially throughout the pregnancy. Control and T1DM groups were not significantly different in age or number of previous miscarriages. As expected, the T1DM group exhibited significantly higher HbA1c levels, and also had significantly increased incidence of preeclampsia (2 of 42 cases (4,8%) in control group and 5 of 39 cases in T1DM group (12,8%)) (p= 0,03). Delivery gestational age was significantly lower for babies born to mothers with T1DM (39,6±1,4 weeks in control group and 37,6±2,1 in T1DM group (p= 0,001).

Vitamin D deficiency, defined as 25OHD levels,25 nmol/L, was apparent in both the control and the T1DM groups across the entire pregnancy. Greater than 90% of pregnant women were classified as insufficient at each time-point, regardless of whether they had T1DM or not. This meant that 10% of this pregnant population were at a sufficient level at some point throughout pregnancy. Similar to maternal vitamin D levels, the neonates had a high incidence of 25OHD deficiency at birth. Also were shown correlations between cord blood and maternal vitamin D. Maternal 25OHD correlated positively with cord 25OHD at all 3 trimesters in the T1DM group. Conclusions: in T1DM pregnancy, low vitamin D levels persist throughout gestation and post-delivery; maternal vitamin D levels exhibit a significant negative relationship with HbA1c levels, supporting a potential role for this vitamin in maintaining glycaemic control; larger studies investigating whether low vitamin D levels are a risk factor for preterm delivery and preeclampsia in women with diabetes are needed.
OR26-04 Immediate Post-Operative Insulin Requirements May Predict Metabolic Outcome After Total Pancreatectomy and Islet Autologous Cell Transplant (TPIAT)
Authors: Verma Neha , Rajab Amer , Buss Jill , Lara Luis , Porter Kyle , Hart Philip , Conwell Darwin , Washburn W Kenneth , Black Sylvester , Kuntz Kristin , Meng Shumei
Published: May 2020

Immediate Post-Operative Insulin Requirements may Predict Metabolic Outcome after Total Pancreatectomy and Islet Autologous Cell Transplant (TPIAT) Introduction: Chronic pancreatitis (CP) is a progressive disease that leads to eventual loss of endocrine and exocrine function. Patients with CP experience abdominal pain, which in some instances can be refractory to medical and endoscopic intervention. Total pancreatectomy and islet auto transplantation (TPIAT) is a treatment option however predicting postoperative metabolic outcomes remains elusive. In this single-center retrospective study, we report pre-TPIAT characteristics, beta cell function indices, islet yield as well as post-TPIAT glucose management data to further understand their relationship.Methods:A total of 13 TPIAT subjects were included who underwent beta cell function assessment via intravenous glucose tolerance tests and oral mixed meal tolerance tests. Islet yield, glucose level and insulin requirement for 72 hours postoperatively were collected. In addition, their glucose control and insulin requirements at 3, 6 and 12-month post TPIAT were analyzed.Results:The median age was 45 years with median duration of CP for 5 years. The main cause of CP was idiopathic. All 13 subjects had normal baseline fasting glucose levels. Median islet yield was 4882 IEq/kg (interquartile range 3412 to 8987). Median post-operative total insulin requirement on day 3 was 0.43 units/kg. Pre-TPIAT baseline glucose, insulin or c-peptide level did not have a significant correlation with the islet yield. Similarly, there was no correlation between islet yield and insulin requirement at 72-hour post operatively. However, there was an inverse correlation between the absolute islet yield (IEq) and insulin requirement at 6 months and 12 months following post-TPIAT. Further analysis of the relationship between 72-hour post-op insulin requirement and insulin requirement at discharge, 3, 6 and 12 month showed a positive correlation. Despite the new finding of inverse correlation of islet yield with long-term insulin requirement, this study was not able to detect a correlation between the preoperative parameters to postoperative short-term or long-term outcome as noted in other studies.Conclusion: The 72-hour postoperative insulin requirement is a helpful postoperative predictor of patients needing long term insulin management following TPIAT. This observation may identify a high risk group of patients in need of more intensive diabetes education and treatment prior to hospital discharge.
SUN-355 Associations of Trabecular Bone Score and Bone Mineral Density with Cardiorespiratory Fitness and Body Composition in Men with and Without Paraplegia
Authors: Usuga Daniela , McMillan David W , Jacobs Kevin A , Nash Mark S , Valderrabano Rodrigo J
Published: May 2020

Introduction: Following spinal cord injury (SCI) lower extremity bone mineral density (BMD) losses are as high as 40% due to mechanical unloading and autonomic dysfunction. While lumbar spine (LS) BMD appears to be relatively spared, evidence suggests BMD by dual-energy radiographic absorptiometry (DXA) may overlook bone pathology in this region. Trabecular Bone Score (TBS), representative of bone microarchitecture, may be a more informative measurement of LS pathology in SCI. Our objective was to determine differences in BMD and TBS within the LS in humans with and without SCI. Correlation of fitness and body composition measures with TBS and BMD were also explored to determine their role in bone health after SCI.

Methods: Seven male participants with paraplegia (level T3 – T7) were recruited through The Miami Project to Cure Paralysis, and 6 males without SCI were recruited from local advertisement. DXA scans of the lumbar spine and whole body were performed using Hologic Discovery A densitometer. TBS score (unitless) was derived from L1-L4 scans using TBS iNsight software v3.0.2. A graded arm exercise test directly measured cardiorespiratory fitness (VO2peak) for all subjects. An independent samples t-test determined between-group differences in LS BMD and TBS. Pearson correlation analysis investigated within-group relations among LS BMD, TBS and VO2peak (ml/kg/min), weight (kg), total body fat (%), and visceral adipose tissue (estimated VAT mass(g)).

Results: In SCI, the mean duration of injury was 8.6 years. Mean LS BMD was not different (p=.47) between non-injured (1.10 ±0.11 g/cm2) and SCI (1.10 ±0.13 g/cm2) groups. However, mean TBS score was different (p=.053) between non-injured (1.55±0.09) and SCI (1.47±0.07) groups. In non-injured, VO2peak was correlated with LS BMD (r=.356) and TBS (r=.244). In SCI, VO2peak was correlated with LS BMD (r=.111) and TBS (r=.822). In non-injured, TBS was correlated with body mass (r=.244), total body fat (%) (r=.382), and visceral adipose tissue (r=.361). In SCI, negative correlations were observed; TBS was correlated with body mass (r= -.255), total body fat (%) (r= -.474), and visceral adipose tissue (r= -.513). LS BMD was positively correlated with body mass, total body fat (%) and visceral adipose tissue in both non-injured and SCI groups.

Conclusion: Men with and without SCI displayed similar BMD but differed in TBS at the LS. Correlations with measures of fitness and body composition were similar for LS BMD but discordant for TBS between non-injured and SCI groups. The data suggest changes in the relationships between cardiorespiratory fitness, metabolism and bone quality in SCI. TBS may capture alterations in bone microarchitecture at the spine after SCI that are undetected by conventional DXA.
MON-006 Progesterone Receptor Expression in Endometrial Biopsies After 12 Weeks of Exposure to A 4-µg E2 Softgel Vaginal Insert or Placebo
Authors: Simon James A , Liu James H , Archer David F , Komm Barry S , Bernick Brian , Mirkin Sebastian
Published: May 2020

The softgel, vaginal 17β-estradiol (E2) insert (TX-004HR) significantly improved the maturation index of the vaginal epithelium, dyspareunia and vaginal dryness in menopausal women with vulvar and vaginal atrophy (VVA) and moderate to severe dyspareunia, without histological changes to the endometrium (Constantine G et al, Menopause 2017;24:409-416). The 4-μg and 10-μg E2 doses were FDA approved as Imvexxy® (TherapeuticsMD, Boca Raton, FL), for the treatment of moderate to severe dyspareunia, a symptom of VVA, due to menopause. The progesterone receptor (PR) is an estrogen-regulated gene with expression that is very sensitive to E2 exposure (Xiao CW and Goff AK, J Reprod Fertil.1999;115:101-109). Endometrial PR expression in the biopsies of women using the softgel vaginal 4-µg E2 insert was used as a marker of E2 exposure to determine whether sufficient E2 applied with the vaginal insert reaches the endometrium to upregulate PR expression. Our hypothesis posits that there would be insufficient E2 from the 4-µg E2 insert to stimulate an increase in endometrial PR expression.

In this post hoc analysis of the REJOICE trial, endometrial biopsies from 25 women who had a normal baseline biopsy, an on-therapy biopsy after study day 70, and tissue readings from all pathologists were randomly selected from the 4-µg E2 vaginal insert and placebo groups. Endometrial tissue sections were stained to visualize PR expression using PgR1294 (Agilent; Santa Clara, CA). Cell staining was quantified using a trainable feature-recognition algorithm and mean expression levels between baseline and week 12 were analyzed by 2-sided t-tests.

Acceptable PR expression results were available for 22 women in the 4-µg E2 group (three had insufficient tissue for analysis) and 25 women in the placebo group. For the 4-µg E2 group, mean ± SD (pmol/mg) PR expression was 0.455 ± 0.203 at baseline and 0.506 ± 0.226 at week 12. For the placebo group, mean PR expression was 0.579 ± 0.196 at baseline and 0.563 ± 0.213 at week 12. Mean PR expression levels at baseline and week 12 were not significantly different from each other within the 4-µg E2 (P=0.438) or placebo (P=0.783) group.

No meaningful difference in endometrial PR expression was observed with the vaginal 4-µg E2 insert at week 12. These data support our hypothesis and the assertion that low-dose, local vaginal E2 exposure with the insert placed in the lower part of the vagina, does not pose an endometrial safety issue in postmenopausal women.
SAT-288 Pituitary Developmental Defects Caused by Haploinsufficiency for the Transcription Factor SIX3 Are Worsened by POU1F1 Deficiency
Authors: Brinkmeier Michelle , Camper Sally Ann
Published: May 2020

Advances in genomic technologies are revolutionizing the practice of medicine by delivering molecular diagnoses that can be informative for prognosis and treatment of genetic disorders. Most of the known genetic causes of multiple pituitary hormone deficiency have been investigated as monogenic disorders. It can be challenging to predict clinical features from genetic data, as loss of function mutations in some genes can present with a spectrum of phenotypes ranging from craniofacial abnormalities, intellectual disability, and neurosensory and neuroendocrine defects to pituitary hormone deficiency with no other abnormalities. Although maternal exposures could be contributing factors, the contribution of rare, deleterious variation in other genes is a likely contributor. In humans, loss of function mutations in the transcription factor SIX3 cause variable, autosomal dominant holoprosencephaly with incomplete penetrance, and mouse models recapitulate some of the clinical features. Because Six3 and Pou1f1 gene expression patterns overlap in pituitary development, we hypothesized that doubly heterozygous mice (Six3+/-; Pou1f1+/dw) might have pituitary anomalies not present in singly heterozygous mice. We intercrossed Six3+/- and Pou1f1+/dw mice to produce doubly heterozygous animals. At e11.5, both Six3+/- and Six3+/-; Pou1f1+/dw exhibited abnormal morphology of the developing infundibulum and Rathke’s pouch, although ventral diencephalon expression of Tle4, Fgf10, and Nkx2.1 appeared normal. Both newborn Six3+/- and Six3+/-; Pou1f1+/dw littermates had abnormal pituitary gland morphology that resembled that of Aes-/-. AES is a co-repressor that interacts with SIX3. Specification of vasopressin neurons and anterior lobe hormone cell types appeared normal. Mice of all genotypes were born in expected Mendelian ratios (N=144, p=0.49), and there were no significant differences in body weight at 3 wks. A portion of the Six3+/- and doubly heterozygous mice developed hydrocephalus, exhibited failure to thrive, and died (6-9% of N=82, 85, respectively). At 6 wks, 25% (N=61) of the Six3+/-; Pou1f1+/dw animals exhibited striking pituitary dysmorphology in which the rostral aspect of the pituitary penetrated the palate. This was not observed in single heterozygotes. These results reveal that haploinsufficiency for Six3 affects Rathke’s pouch formation, resulting in pituitary gland dysmorphology in and around the stem cell niche. A significant portion of the Six3+/-; Pou1f1+/dw doubly heterozygous mice have a more pronounced pituitary phenotype than Six3+/-, supporting the possibility of digenic pituitary disease and highlighting phenotypic variability. Genetically engineered mice provide an excellent tool for assessing the possibility of gene-gene interactions that could enhance the severity of hypopituitarism and associated craniofacial development.
SUN-346 A Natural Antibody Against Oxidized Phospholipids Attenuates Age-Related Bone Loss and Prevents Age-Related Glucose Intolerance in Mice
Authors: Palmieri Michela , Teenamol Joseph , Gomez-acevedo Horacio , Witztum Joseph Lee , Manolagas Stavros C , Ambrogini Elena
Published: May 2020

Lipid peroxidation produces oxidized phospholipids (OxPL) such as oxidized phosphatidylcholine. These compounds react with amino groups of proteins and lipids to form adducts called oxidation specific epitopes (OSEs), which are proinflammatory moieties present on oxidized low density lipoproteins and on apoptotic cells and, unless removed, cause extensive cell damage. Natural antibodies (NAb) produced by B-1 lymphocytes, bind OxPL and prevent their inflammatory activity. E06 is a NAb that recognizes the phosphocholine moiety of OxPL. We previously showed that transgenic expression of a single chain (scFv) form of the antigen-binding domain of E06 IgM (E06-scFv) increases cancellous and cortical bone mass in both male and female mice by increasing bone formation. Age-related bone loss is characterized by a decline in osteoblast number and bone formation, associated with increased oxidative stress and lipid peroxidation. These findings, together with the evidence that serum anti-OxPL IgM titers decrease with age, suggest that increased OxPL formation and decreased anti-OxPL antibodies may contribute to age-related bone loss. Like humans, mice exhibit an age-dependent worsening in glucose tolerance, mainly due to alteration in body composition and increased fat tissue. Chronic low grade inflammation and oxidative stress are associated with development of diabetes mellitus and B-1 lymphocytes have been shown to be protective against obesity associated inflammation, glucose intolerance, and insulin resistance. We tested the hypothesis that overexpression of E06-scFv could attenuate age-related bone loss and glucose intolerance. Serial BMD measurements by DXA of both female and male C57BL/6 E06-scFv transgenic mice (and their WT littermates) up to 22 and 24 months, respectively, showed that E06-scFv attenuated age-related bone loss at the spine and femur in both sexes. As revealed by microCT analysis, this effect was due to the attenuation of the age-associated decline in cancellous bone in both sexes. Additionally, both male and female E06-scFv transgenic mice accumulated less fat mass than WT littermates during aging. Intraperitoneal glucose tolerance test, at 15 months of age, revealed that glucose tolerance was greater in both male and female E06-ScFv mice than in respective WT littermates and did not differ from the glucose tolerance of young mice, indicating that E06-scFv improves glucose metabolism. These data suggest that OxPL impair both age-related bone loss and age-related glucose intolerance. Therefore, targeting OxPL with a neutralizing antibody such as E06, represents a prototypic therapeutic intervention that may simultaneously ameliorate important age-associated diseases.
SAT-373 A Case of X Linked Hypophosphatemic Rickets Due to DE Novo Phex Gene Mutation
Authors: Badran Ahmed , Bargman Renee
Published: May 2020

Introduction

Rickets is a condition that can affect bones of infants and children. It is characterized by growth plate demineralization and can occur secondary to, most commonly, vitamin D deficiency or various problems with vitamin D, Calcium or Phosphate metabolism.

Hypophosphatemic rickets (HR) is a type of rickets that is inherited by X linked dominant pattern mainly however it can be also inherited by autosomal dominant and recessive patterns in rare cases. X linked dominant type (XLH) affects about 1 in 20,000 newborns. Each of the other hereditary forms of HR has been identified in only a few families.

Clinical features of XLH is similar to other types of rickets including metaphyseal widening, palpable rachitic rosaries, frontal prominence, malformation of the horizontal depression along the lower border of the chest, insufficient weight gain and leg bowing.

Case presentation:

A 10-month-old infant presented to endocrinology with vitamin D deficiency, low serum phosphorus and hyperparathyroidism. Physical examination showed macrocephaly with frontal bossing, widening of the wrists and rachitic rosaries. His lab results showed low 25 OH vitamin D (11 ng/ml) (N:20-50 ng/ml), low phosphorus (PO4) (3.3 mg/dl) (N:4-6.5 mg/dl), high PTH (113 pg/ml) (N: 20-65pg/ml), high alkaline phosphatase (ALP) (836 IU/L) (N: 135-518 IU/L) and normal calcium (Ca2+) (9.6 mg/dl) (N:9-11 mg/dl). Vitamin D treatment was started however his follow up lab results showed persistent hypophosphatemia for age (2.8mg/dl) and elevated ALP (600IU/l) despite normalization of vitamin D (38 ng/ml). Additional lab tests were done showing high PO4 excretion (19.5 mg/dl)(N:1:3.5 mg/dl), Ca/Cr ratio 0.005 (N <0.14), inappropriately normal FGF23 level (129 RU/ml) (N: >124 RU/mL). Genetic testing showed de novo mutation in PHEX gene (871C>T) which is consistent with XLH.

PHEX gene mutation is the most common mutation associated with XLH. Normally this gene can directly or indirectly regulate a protein called fibroblast growth factor 23 (produced from FGF23 gene). This protein normally inhibits renal reabsorption of phosphate into the bloodstream. Gene mutations increase the production or reduce the breakdown of fibroblast growth factor 23 leading to an overactivation of this protein and reduction of phosphate reabsorption by the kidneys, resulting in hypophosphatemia.

The patient was maintained on Burosomab (0.4 mg/kg biweekly); a recombinant human monoclonal antibody (IgG1) that binds to and inhibits the activity of fibroblast growth factor 23 (FGF23) and increases the phosphate reabsorption in the renal tubules.

Conclusion:

XLH due to PHEX gene mutation should be considered in rachitic children who have persistently low phosphate levels despite treating vitamin D deficiency.
SUN-665 Peripheral CB1R Blocker Improves Metabolism in Diet Induced Obese Mice Independent of Hepatic FGF21
Authors: Liu Jie , Godlewski Grzegorz , Liu Ziyi , Cinar Resat , Xiong Keming , Kunos George
Published: May 2020

Obesity is associated with an overactive endocannabinoid system, and selective blockade of CB1R in peripheral tissues, including the liver, reverses HFD-induced metabolic abnormalities by restoring normal lipid and glucose homeostasis. Fibroblast growth factor-21 (FGF21) has emerged as a major endocrine regulator derived from the liver that reduces adiposity and hepatic steatosis and improves glucose tolerance and insulin sensitivity, with changes similar to those induced by CB1R blockade. Here we investigated whether FGF21 mediate the metabolic effects of CB1R blockade in DIO mice.

In C57BL/6J wild-type mice, HFD caused a robust increase in hepatic Fgf21 mRNA and serum FGF21 levels, which were reversed by chronic CB1R blockade to levels observed in STD or vehicle-treated hepatocyte-specific CB1R-/- (LCB1-/-) mice, indicating activation of CB1R in the liver is largely involved in HFD-induced “FGF21-resistant” state. In contrast, the expression of the FGF21 receptor Fgfr1 and co-receptor β-klotho (Klb) were dramatically reduced by HFD in both epididymal fat and brain tissue in wild-type mice, and these effects were reversed by peripheral CB1R antagonist JD5037 treatment.

To address whether FGF21 mediated the metabolic effects of CB1R blockade, we repeated JD5037 treatment in liver-specific FGF21-/- (FGF21-LKO) mice. Surprisingly, JD5037 treatment was almost equally effective in both HFD-fed wild-type and in FGF21-LKO mice in reducing body weight and hepatic steatosis, attenuating hyperinsulinemia and hyperleptinemia. The current data suggest that peripheral CB1R blockade in obese mice improves insulin sensitivity and energy expenditure independently of hepatic FGF21.
SUN-514 Thyrotoxic Periodic Paralysis in Adolescence Patient a Case Report and Literature Review
Authors: He Luke , Lawrence Veronica , Moore Wayne V , Yan Yun
Published: May 2020

BACKGROUND: Thyrotoxic periodic paralysis (TPP) is an uncommon disorder characterized by acute flaccid paralysis due to hypokalemia. It is diagnosed primarily in Asian adult males and is rare in children and adolescents. Here we report an adolescent male patient of Vietnamese descent who presented to the emergency department with an episode of syncope, muscle weakness, and shortness of breath one day after the initiation of methimazole treatment for Graves’ disease. The laboratory revealed significant hypokalemia. In this report we also included and summarized the reported cases of TPP in adolescent patients since 1997.

Clinical Case: A 17-year-old Vietnamese American male who was recently diagnosed with Graves’ disease presented to the emergency department after an episode of syncope, muscle weakness, and difficulty breathing. Two months previously, he began having episodes of tachycardia. He was diagnosed with hyperthyroidism with a TSH of 0.007 mIU/mL and free T 4 > 7 ng/dL (0.8-1.9). He was subsequently evaluated by Cardiology and started on atenolol. He was then seen by Endocrinology 5 days after and started on methimazole 15 mg twice daily. On the next morning after starting methimazole, he reported feeling weak and passed out. His father had found him on the floor, weak and unable to move, approximately 30 minutes after his father “heard a thud upstairs”. The patient recalled that his legs gave out and he “hitting his face on a table”. In the emergency department, he was tachycardic at 116 bpm, widened pulse blood pressure of 131/50 mmHg with normal respiratory rate 24 BR/min. He had diffused and significant muscle weakness on his all extremities including grip strength.

His potassium was 1.6 mmol/L (3.5 - 5.2) and magnesium 1.6 mmol/L (1.6-2.3). The rest of his chemistry panel was unremarkable. He had EKG changes consistent with hypokalemia with U waves, also revealing atrial rhythm with first degree AV block, intraventricular conduction delay, and QTc prolongation at 588 (<450). His chest x-ray was normal. Normal saline was administered, and potassium replacement was given with 40 mEq of KCl followed by D5 NS with 40 meq/L KCl at maintenance. He continued taking atenolol and methimazole. He was also given an IV dose of magnesium. His muscle strength returned completely and potassium level returned to normal range at 4.6 mmol/L after 24 hours of treatment.

Conclusion: TPP is a rare cause of acute paralysis and can lead to cardiac arrhythmia and death without accurate diagnosis and prompt treatment. Our case should raise awareness of this disorder among pediatricians, emergency department physicians and endocrinologists. Acute paralysis with hypokalemia should also prompt the physician to consider evaluating thyroid function as a differential diagnosis in young Asian men.
OR16-05 Single-Cell Sequencing Identifies Novel Regulators of Thyrotrope Populations and POU1F1-Independent Thyroid-Stimulating Hormone Expression
Authors: Cheung Leonard , Daly Alexandre , Brinkmeier Michelle , Camper Sally Ann
Published: May 2020

We implemented single-cell RNA sequencing (scRNAseq) technology as a discovery tool to identify factors enriched in differentiated thyrotropes. Thyroid-stimulating hormone (TSH) is produced in the pars distalis of the anterior pituitary (AP) and primarily acts on the thyroid gland to regulate metabolism through T3/T4. However, TSH is also produced by cells in the pars tuberalis (PT), which is comprised of a thin layer of cells that extends rostrally from the pars distalis along the pituitary stalk to the median eminence in the hypothalamus. TSH produced by PT thyrotropes acts on hypothalamic tanycytes to regulate seasonal reproduction. PT thyrotropes likely descend from rostral tip thyrotropes that arise at e12.5 of mouse development, which transcribe the TSH beta subunit (Tshb) without detectable expression of the transcription factor POU1F1. POU1F1 is required for Tshb transcription in thyrotropes of the adenohypophysis, and it acts synergistically with GATA2 to drive cell fate. The molecular mechanisms driving Tshb expression independently of Pou1f1 in PT thyrotropes are unclear.

Thyrotropes are the least abundant endocrine cell-type in the pituitary gland. We used genetic labeling and fluorescence-activated cell sorting (FACS) to enrich for thyrotropes for single-cell sequencing. We performed scRNAseq on 7-day-old GFP-positive pituitary cells from Tshb-Cre; R26-LSL-eYFP and intact whole pituitaries, recovering more than 15,000 cells altogether. We observe two distinct populations of cells expressing Tshb. The larger thyrotrope population has approximately twenty fold higher levels of Tshb and five fold higher Cga transcripts than the smaller population, and they are also distinguished by expression of Pou1f1, TSH-releasing hormone receptor (Trhr), and deiodinase 2 (Dio2), consistent with expectations for AP thyrotropes. The smaller thyrotrope population does not express Pou1f1, but those cells are characterized by expression of TSH receptor (Tshr) and melatonin receptor 1A (Mtnr1a), consistent with expectations for PT thyrotropes. They express mildly increased levels of Eya3 and Six1, although these genes are expressed in other cell-types including AP thyrotropes, stem cells, and gonadotropes. They have two-fold higher levels of Gata2 transcripts and uniquely express the transcription factor Sox14. SOX14 is a SoxB2 family transcription factor that counteracts the transcriptional activity of SoxB1 family members, such as Sox2. In conclusion, our scRNAseq has identified novel markers of PT thyrotropes and unveils novel insights into the similarities and differences in the development and function of pituitary thyrotrope subpopulations.
SUN-712 Familial 46, XY Complete Female External Sex Development with a Non-Mosaic Inherited SRY Gene Variation
Authors: Vaiani Elisa , Chen Yen-Shan , Ramirez Pablo , Baquedano Maria Sonia , Malosetti Maria del carmen , Racca Joseph , Touzon Maria Sol , Marino Roxana , Costanzo Mariana , Bailez Marcela , Berensztein Esperanza , Galuzzo Laura , Weiss Michael Aaron , Belgorosky Alicia
Published: May 2020

Context: SRY, an architectural transcription factor containing a SOX-related high-mobility group (HMG) box, initiates testis formation in the mammalian bipotential gonadal ridge. Inherited human SRY mutations can be associated with differences in sexual differentiation (DSD) with variable phenotypes in a family.

Objective: To describe the clinical, histopathological and molecular features of a novel inherited SRY allele (pMet64Val; consensus box position 9) observed within an extensive pedigree: two 46, XY sisters with primary amenorrhea (16 and 14 years of age; probands P1 and P2), their normal father and brother, and an affected paternal XY grandaunt.

Design, Setting, Participants and Outcome Measurements: Following DNA sequencing to identify the SRY mutation, hormonal studies of the probands and histopathological examination of their gonads were performed. Functional consequences of p.Met64Val (and other mutations at this site) were also investigated.

Results: Breast development in P1 and P2was Tanner II and IV, respectively. Müllerian structures and gonads resembling ovaries were found in each sister. Histopathology revealed gonadal dysgenesis, gonadoblastoma and dysgerminoma. AMH/MIS, P450 SCC, and P450 aromatase were expressed in gonadoblastoma tissues. Variant p.Met64Val impaired Sox9 transcriptional activation associated with attenuated occupancy of the testis-specific enhancersEnh13 and TESCO.

Conclusion: The partial biological activity of p.Met64Val SRY, maintained at the threshold of SRY function, rationalizes opposing paternal and proband phenotypes (the “the father-daughter paradox”).Sex steroids biosynthesis by gonadoblastoma may delay genetic diagnosis and recognition of gonadal tumors. Quantitative assessment of inherited SRY alleles highlights the tenuous transcriptional threshold of developmental decision-making in the bipotential gonadal ridge.
SAT-003 Prolactin Is Expressed in Uterine Leiomyomas and May Promote Their Growth
Authors: DiMauro Alessandra R , Dahal Ankit , Okeke Ifunanya , Lerman Irina , Amitrano Andrea , Seger Christina , Kumar Divya , Bhagavath Bala , Taya Manisha , Hammes Stephen R
Published: May 2020

Uterine leiomyomas, commonly referred to as fibroids, are benign, estrogen sensitive smooth muscle tumors that occur in the myometrium of the uterine wall. Leiomyomas are common, as it is estimated that 60% of reproductive-aged women are affected, and 80% of women develop leiomyomas during their lifetime. In fact, uterine leiomyomas are the leading cause of abnormal menstrual bleeding or menstrual pain, as well as the number one reason for hysterectomy. Novel treatment options are necessary as current treatments are limited to anti-estrogen therapy or hysterectomy. Estrogen is known to have an effect on the etiology of leiomyomas, but little is known about the proliferative roles of other hormones in leiomyomas. One hormone of interest is prolactin (PRL) which is primarily secreted from the pituitary to regulate lactation, but has been linked to proliferation in breast cancer, perhaps via local prolactin production in breast tissue. With this background, we examined local PRL production and its effects on leiomyomas. RNA isolation and quantitative PCR of human leiomyoma samples (n=20) relative to adjacent myometrium in the same patients confirmed significant expression of both PRL (p= 0.0028) and dopamine receptor D2, a known regulator of PRL production in the pituitary (p<0.0001), with no difference in prolactin receptor expression. Using both immunohistochemistry and immunofluorescence of human leiomyomas samples, we find increased prolactin expression in leiomyomas when compared to adjacent myometrium or control uteri. These results suggest that leiomyomas contain cells producing PRL, which in turn may promote signaling in smooth muscle leiomyoma cells to regulate proliferation. Accordingly, we find that PRL robustly activates STAT5 and MAPK signaling in the rat leiomyoma cell line ELT3. Functional assays were also conducted to evaluate the ability of PRL to induce migration, invasion and proliferation of ELT3 cells. Together, our findings suggest that local prolactin production in leiomyomas may promote their growth, migration, invasion and proliferation. It is possible that this local production is mediated by the dopamine receptor D2. Thus, anti-PRL therapy or dopamine receptor D2 modulation may prove useful in treating this prevalent and often debilitating disease.
SAT-043 Utility of Ultrasensitive Inhibin B Measurement for the Management of Men with Non-Obstructive Azoospermia
Authors: Barbotin Anne-Laure , Kumar Ajay , Kalra Bhanu , Savjani Gopal , Mitchell Valarie , Pigny Pascal
Published: May 2020

Inhibin B measurement by conventional assay(s) may be useful in the assessment of spermatogenesis in infertile male patients, especially in cases of azoospermia. Indeed, numerous previous studies have shown that Inhibin B could be helpful to predict a positive testicular sperm extraction (TESE). However, an undetectable Inhibin B concentration (<10pg/mL) does not predict a TESE failure in all cases. These findings explained that most medical centers have precluded the use of Inhibin B assay in the pre-operative hormonal assessment of azoospermic men. Recently, an ultrasensitive Inhibin B assay has been developed allowing the measurement of concentrations below 10pg/mL. The current study aims to assess the clinical relevance of this new assay in men with azoospermia with undetectable Inhibin B levels by conventional assay(s).

Methods: This retrospective study included 71 non-obstructive azoospermic men who had undetectable Inhibin B levels (i.e. <10pg/mL by Gen II ELISA from Beckman Coulter, USA) and who underwent a TESE procedure between 2013 and 2019 in the Lille University Hospital. Serum LH, FSH and testosterone levels were systematically measured by routine immunoassays. Cryopreserved serum samples were used to perform ultrasensitive Inhibin B assay (Ultrasensitive Inhibin B, AL-195, Ansh Labs, USA). Additional hormonal assays including Inhibin A, Activin B and Activin A were performed on available subset of samples.

Results: The TESE was successful, allowing sperm cryopreservation in 32.5 % (25/71) of the cases. No significant statistical difference was found in FSH, LH, or testosterone levels between patients with positive or negative TESE. By contrast, men with positive TESE had more than twice higher serum ultrasensitive Inhibin B levels (median 5.03pg/mL [1.93-8.5] vs. 2.19pg/mL [0.2-4.72], p=0.006). An ultrasensitive Inhibin B serum level >3.67 pg/mL (determined by ROC analysis) was associated with increased odds ratio (OR= 4.82; 95% CI: 1.647-12.93) for positive TESE. Inhibin A, Activin B and Activin A serum concentrations did not differ significantly between the two groups.

Conclusion: FSH measurement which is routinely performed in men with azoospermia was not predictive of successful TESE whereas, Inhibin B was found to be a valuable marker in predicting TESE success in this population using ultrasensitive Inhibin B assay.
MON-454 Lower Extremity Leiomyosarcoma Metastatic to a Benign Thyroid Nodule
Authors: Gupta Suruchi K , Gavrila-Filip Alina
Published: May 2020

Background: Metastases to the thyroid gland from non-thyroidal malignancies have been reported in 1.4-3% of patients undergoing thyroid surgery for malignant thyroid tumors, but only 4% of these are due to sarcomas1. Metastases in a pre-existing thyroid nodule are even more rare. We present a patient with a lower extremity leiomyosarcoma that metastasized to a pre-existing benign thyroid nodule.

Clinical Case: A 70-year-old woman was referred to the Thyroid Nodule Clinic for a 5 cm thyroid nodule replacing most of the right thyroid lobe. Twenty years earlier the patient had a left thyroid lobectomy for a benign nodule. One year before presentation, she was diagnosed with a high grade lower extremity leiomyosarcoma with lung metastases and started on treatment. A large right thyroid nodule pressing on the trachea was incidentally found on an initial chest CT performed for sarcoma staging. On PET-CT, the nodule was not FDG-avid. On ultrasound, the thyroid nodule was solid and heterogeneous, iso- to hyperechoic with smooth margins, inspissated colloid and grade 3 vascularity. Fine needle aspiration (FNA) of the nodule showed benign cytology (Bethesda II). The patient did not have local compressive symptoms and decided not to undergo surgical removal of the nodule.

The thyroid nodule was initially stable on periodic follow-up CT scans and thyroid ultrasounds. However, a thyroid ultrasound performed 2.5 years later showed a change in the nodule echogenicity without change in size. The nodule had become hypoechoic, heterogeneous and well-defined with grade 2 vascularity. FNA revealed a poorly differentiated malignant spindle cell neoplasm, similar to biopsies of other metastatic sites, supporting a diagnosis of metastatic high grade sarcoma. The patient underwent a right thyroidectomy; pathology revealed a 4.1 cm metastatic sarcoma with multifocal angioinvasion with tumor present at the surgical margin. Follow-up neck ultrasounds showed no evidence of local recurrence, while the patient was receiving chemotherapy for pulmonary metastases. The patient died 3 years later due to a massive pulmonary embolism.

Conclusion: To our knowledge, this is the first report of a lower extremity leiomyosarcoma metastatic to a benign thyroid nodule. Although metastasis of an extra-thyroidal malignancy to a pre-existing benign thyroid nodule is very rare, patients with thyroid nodules and a history of malignancy should have regular surveillance of the nodule by ultrasound, and any changes in the nodule features concerning for malignancy should be evaluated with FNA of the nodule.

1. Chung, A. Y., Tran, T. B., Brumund, K. T., Weisman, R. A., & Bouvet, M. (2012). Metastases to the thyroid: a review of the literature from the last decade. Thyroid, 22(3), 258-268.
OR20-04 Modeling Uterine Disorders Utilizing Adult Uterine Stem Cells
Authors: Chowdhury Indrajit , Banerjee Saswati , Xu Wei , Driss Adel , Amin Radhika , Delsarte L Rachel , Keck Katherine , Sidell Neil , Taylor Robert N , Nezhat Ceana , Ali Mohamed , Yang Qiwei , Al-Hendy Ayman , Thompson Winston E
Published: May 2020

Endometriosis and uterine fibroids (leiomyomas) are benign gynecological disorders affecting 5-15% of women of reproductive age. They cause a wide range of symptoms including mild to severe pelvic pain and infertility. Due to a paucity of proper study models, hormonal and cellular mechanisms driving the pathology of endometriosis and fibroid development and growth remain unclear. Therefore, in the current study, we established 3D spheroid/organoid cultures from human uterine epithelial and Stro-1+/CD44+ myometrial stem cells and also from cells isolated from normal proliferative phase endometrium. Uterine organoid cultures were derived from endometrial epithelial and myometrial cells isolated from women who were not receiving exogenous hormones at the time of laparoscopy or hysterectomy. They were embedded in Matrigel, and grown in culture media. To determine whether spheroids/organoids were responsive to steroid hormones, the cultures were treated in presence or absence of estradiol (E2), progesterone (P4) or the combination (E2+P4) in serum free culture media. Time-dependent spheroid/organoid-growth curves and morphological analyses were used to define growth characteristics of endometrial and myometrial organoids. Subsequently, immunohistochemical colocalization of steroid hormone receptors (estrogen receptor alpha (ER-α) and progesterone receptor (PR-A\B), alpha smooth muscle actin (α-SMA; myometrial cell marker), vimentin (stromal cell marker) and E-cadherin (endometrial epithelial cell marker) was assessed. Epithelial organoids expressed only E-cadherin in the absence of hormonal treatment. Myometrial organoids expressed α-SMA and vimentin. No expression of E-cadherin was observed in myometrial organoids. However, we observed the expression of ER-α and PR-A\B when organoids were treated with E2+P4 in a time-dependent manner. Stro-1+/CD44+ myometrial stem cells differentiated into α-SMA and fibroblast/stromal cells and response to sex hormones. These findings suggest human uterine organoid cultures retained their characteristic cellular responses to E2+P4 and could be maintained long-term in ex vivo culture. Thus, the current 3D uterine organoid systems show high expansion capacity with retention of phenotypical and functional properties, which can be used for uterine pathophysiological studies, drug discoveries and drug repositioning.
MON-664 Are Hospitals Doing Enough in Caring for Patients with Diabetes?Results of a Landmark Survey: Current State of Inpatient Diabetes Care and Glycemic Management
Authors: Rhinehart Andrew S , Mabrey Melanie , Garrett Valerie
Published: May 2020

BACKGROUND

On average, 1 of every 3 hospitalized patients — the majority with diabetes — requires insulin to control blood glucose during their stay. Although widely prescribed and absolutely necessary, insulin is inherently dangerous: 50% of all medication errors involve insulin, including 1/3 of all fatal medication errors. Results of a nationwide survey indicate that prioritization of glycemic control is lacking, which hinders high reliability and increases risk of morbidity and mortality.

METHODS

Healthcare professionals who serve in roles involving diabetes care and glycemic management were invited to participate in an online survey. To qualify, an initial question that read: “Where do you work?” had to be answered “hospital or health system with focus on inpatients” (those who answered “physician’s office or clinic with focus on outpatients” were disqualified). There were a total of 619 respondents from 408 U.S. hospitals.

KEY RESULTS

• The consensus among respondents is that fear of hypoglycemia has a strong influence on the prescribing of insulin (i.e., causes non-prescribing or lack of intensification following hyperglycemia). On a scale of 1 to 5, with 1 being ‘very little if any influence’ and 5 being ‘considerable influence,’ the average weighted score was 3.45.

• About 70% of respondents are of the opinion glycemic control is ‘extremely important’ or ‘very important’ to nurses and physicians, whereas about 48% believe this to be true of senior clinical executives and 25% believe this to be true of non-clinical senior executives.

• Only 24% of respondents maintain their hospital uses primarily basal bolus for subcutaneous insulin therapy. Close to 34% maintain their hospital uses primarily sliding scale and 42% maintain their hospital uses sliding scale and basal bolus equally as often. The top three barriers to full adoption of basal bolus insulin are: (1) inadequate prescriber knowledge about basal-bolus-correction regimens, (2) beliefs that sliding scale is acceptable practice and not harmful, and (3) difficulties coordinating glucose monitoring, insulin administration and meal delivery.

• Slightly more than 2/3 of respondents work at a hospital that routinely tracks and reports the rate of hypoglycemia (on a monthly or quarterly basis). Of those, 54% use a threshold of 60 and/or 70 mg/dL exclusively, which encompasses all episodes of hypoglycemia without accounting for severity; only 24% use thresholds of 60 and/or 70 mg/dL as well as thresholds of 40, 50 and/or 54 mg/dL, allowing episodes of greater severity to be isolated for analysis and quality improvement.

CONCLUSION

Results of the survey indicate better care, specifically better glycemic control, is needed for hospitalized patients with diabetes. With the shift from volume to value and a stronger focus on quality and safety, this data should be catalyst for making glycemic control a strategic imperative.