bluuebunny/crossref_metadata_2025 huggingface dataset:
SUN-572 Estrogen Synergistically Interacts with Optic Atrophy Protein 1 to Promote Thrombosis
Authors: Souvenir Rhonda A , Renata Alambert , Campbell Robert , Hinton Antentor O , Rondina Matthew T , Abel Evan Dale
Published: May 2020

Thrombosis is a major concern in: premenopausal females on oral contraceptives, menopausal women undergoing hormone replacement therapy, post-menopausal women and transgender individuals receiving estrogen supplementation. The mechanisms linking estrogen exposure with increased thrombosis risk is incompletely understood. Analysis of platelet transcripts in the Framingham cohort identified Optic atrophy 1 (OPA1) expression as being highly predictive of female sex and correlating with increased risk of diabetes and cardiovascular disease. OPA1 regulates mitochondrial fusion, electron transport chain (ETC), complex assembly, cristae morphology and apoptosis. Thus, to determine the functional relationship between platelet OPA1 expression and platelet function in relation to sex steroids we generated mice with platelet specific deletion of OPA-1 protein (pOPA1KO). Male pOPA1KO exhibited structurally and functionally compromised mitochondria with a 50% reduction in mitochondrial DNA and respiration. Male pOPA1KO mice exhibited a prothrombotic phenotype they had: increased agonist-induced activation, shortened time to stable occlusion of the carotid artery as assessed in vivo by (rose Bengal) photochemical injury (~25 min knockout vs ~ 35 min control), and were more prone to develop a thrombus (14/15 knockouts vs. 4/8 controls) following permanent ligation of the inferior vena cava. In contrast, female pOPA1KO mice had normal mitochondrial structure, function and DNA. Both agonist-induced platelet activation and thrombus formation was unchanged in pOPA1KO females. Paradoxically, pOPA-1 KO female mice had increased time to stable occlusion of the carotid artery as assessed by photochemical injury (~75 min Knockout vs ~35 min control). Notably, when platelets from pOPA-1 KO or control males were transferred into females following depletion of endogenous platelets, the reconstituted male platelets acquired the phenotype of female pOPA-1 KO mice. Thus, the time to stable occlusion of the carotid artery following photochemical injury was increased. Similarly, reconstitution of male mice with female pOPA1KO platelets were no longer prothrombotic. Gonadectomized pOPA1KO males had an increased time to stable occlusion and gonadectomized female pOPA1KO no longer exhibited increased time to stable carotid artery occlusion. Eugonadal pOPA1KO male mice treated with estrogen exhibited the pOPA1KO female thrombotic phenotype, with increased time to stable occlusion relative to control males. Additionally, OPA-1 levels were positively correlated with increased platelet aggregation and increased estrogen levels in third trimester pregnant human females. Together, these findings reveal a synergistic interaction between platelet OPA1 levels and estrogen to promote thrombosis.
MON-254 Sympromic Hypogonadism: Co- Existence of Morsier and Klinefelter Syndromes
Authors: romero Fabiola , Arzamendia Sady , Ferreira Dahiana , de Souza Claudia Neves , Lopez Helen , Castellano Barbara , Valinotti Elizabeth , Ayala Alejandro
Published: May 2020

INTRODUCTION: Morsier Syndrome is a rare congenital malformation, characterized by hypoplasia / aplasia of the septum pellucidum and hypoplasia / aplasia of the optic nerves, in addition to pituitary and hypothalamic hormonal deficiencies. Klinefelter Syndrome is a sexual chromosomal genetic alteration, a frequent cause of male hypogonadism, The association of Morsier syndrome and Klinefelter is described below.

CLINICAL CASE

We report he case of a 12 year-old boy with psychomotor retardation and nystagumsho presented at 14 months of age with growth hormone deficiency (low weight and height,) and diabetes insipuidus with hypernatremia of of 159 mEq and low urinary density (less than 1,005).

MRI showed an absence of septum pellucidum, thick right frontal cortical dysplasia with asymmetric appearance of the grooves, small optic chiasma, hypoplastic pitutary gland (3 mm height), compatible with Morsier syndrome.

The physical examination draws attention to tall stature, and long lower limbs, facies with prominent forehead and hypertelorism, gynecomastia and small external genitalia for age.

Hormonal evaluation revealed hypergonadotropic hypogonadism with a 47 XXY karyoteype suggeting Klinefelter syndrome.

CONCLUSION:

We report the first case of Morsier syndrome, associated to Klinefelter syndrome. Both syndromes may present with hypogonadism. However, the diagnosis of klinefelter syndrome was made based on the phenotypic characteristics of this patient including hyeprgonadotroic hypogonadism and abnormal karyotype analysis.
SUN-LB104 Metabolic Inflexibility: Is It a Feature of Obesity or a Characteristic of Metabolically Unhealthy Youth?
Authors: Gebara Nour Y , Kim Joon Young , Bacha Fida , Lee SoJung , Arslanian Silva A
Published: May 2020

Obese individuals have metabolic inflexibility evidenced by diminished fasting fat oxidation and blunted increase in respiratory quotient (RQ) from fasting to insulin-stimulated state. Metabolically unhealthy obese (MUHO) adolescents, unlike their metabolically healthy obese (MHO) peers, have unfavorable metabolic characteristics despite having comparable adiposity. We investigated if metabolic inflexibility is a characteristic of obesity per se or is unique to MUHO compared with MHO youth.

Obese youth (n=188; age 14.1 ± 0.1 yrs [SE]; BMI 33.6 ± 0.4 kg/m2) were divided into 137 MUHO (age 14.1 ± 0.2 yrs; BMI 35.4 ± 0.5 kg/m2) and 51 MHO (age 13.9 ± 0.3 yrs; BMI 29.0 ± 0.7 kg/m2) based on cut points for in vivo insulin sensitivity (IS) [MHO within 1.5 SD and MUHO <1.5 SDs of 72 normal-weight (NW) adolescents’ IS values]. RQ (by indirect calorimetry) at fasting and during a hyperinsulinemic (80mu/m2/min)-euglycemic clamp was measured, and ∆RQ calculated. Body composition (by DEXA), visceral adipose tissue (VAT) (by CT and MRI), hepatic IS (HIS) (calculated from fasting hepatic glucose production by [6,6-2H2]glucose and fasting insulin), adipose IS (ATIS) (calculated from whole body lipolysis by [2H5]glycerol and fasting insulin), and peripheral IS were assessed.

MUHO vs. MHO youth had blunted ∆RQ (0.088 ± 0.004 vs. 0.107 ± 0.007, p=0.035), but MHO was not different from NW (0.098 ± 0.004, p=0.893). Further, MUHO vs. MHO youth had lower HIS (15.3 ± 0.7 vs. 24.3 ± 1.6 (mg/kg/min·uU/mL)-1, p<0.0001) and lower ATIS (9.8 ± 0.5 vs. 22.3 ± 3.1 (umol/kg/min·uU/mL)-1, p<0.0001), but HIS and ATIS were not different between MHO and NW youth (24.3 ± 1.6 vs. 20.8 ± 1.2 (mg/kg/min·uU/mL)-1, and 22.3 ± 3.1 vs. 22.0 ± 1.4 (umol/kg/min·uU/mL)-1, p=ns for both). ∆RQ correlated with HIS (r=0.535), ATIS (r=0.288) and VAT (r=-0.309) (p<0.0001 for all), but not with BMI, BMI Z-scores or % body fat. The differences between MUHO and MHO youth in ∆RQ, HIS and ATIS remained significant after adjusting for % body fat, race, pubertal status and VAT.

The present study reveals that metabolic inflexibility is not a feature of obesity, rather it is a characteristic of MUHO youth who have significantly lower ∆RQ compared with MHO youth, with no difference between MHO and NW youth. Moreover, MUHO compared with MHO youth have worse metabolic profile, represented in lower HIS and ATIS.
SUN-LB100 GDF15 May Be Regulated by Cortisol After Sleeve Bariatric Surgery GDF15 May Be Regulated by Cortisol After Sleeve Bariatric Surgery
Authors: Dias Jenny Pena , Carlson Olga , Brown Todd Tarquin , Clark Jeanne , Schweitzer Micheal , Egan Josephine Mary , Lee Clare
Published: May 2020

Context: Weight regain (WR) occurs frequently after surgical weight loss. Yet, factors contributing to WR remain poorly understood. Growth/differentiation factor 15 (GDF15), a stress-responsive hormone, has emerged as a potential therapeutic target in obesity treatment. Increase in GDF15 was reported in response to diet-induced weight loss in preclinical and human studies. After a meal tolerance test (MTT), macronutrients stimulate postprandial increases in circulating cortisol. In addition, individuals with obesity display lower cortisol levels with a flat and blunted diurnal cortisol rhythm compared to lean subjects, thereby exhibiting dysregulated hypothalamic-pituitary-adrenal axis (HPA). Hormonal changes after bariatric surgery are key contributors to understanding WR: GDF15 responses to MTT are unknown.

Objective: To compare meal-stimulated GDF15 and cortisol response in adults with versus without WR after sleeve gastrectomy (SG). We hypothesized that MTT (stress-stimulus) will decrease cortisol and GFDF15 in SG patients who experience WR≤10% versus without WR≤10%.

Design: Cross-sectional study of adults without diabetes, who underwent SG 3.9±0.8 years ago.

Methods: Plasma GDF15, insulin, glucose and serum cortisol were measured at 0, 15, 30, 45, 60, 90, 120, 240 minutes after MTT; Outcome: WR≤10% and was calculated as 100x(weight-nadir/(preoperative weight-nadir)). Analysis: t-test, ANOVA, linear mixed model repeated measures by SAS.

Results: N=21, 85% female with mean age 43±10 years. The groups (WR and without-WR) were significantly different with respect to BMI (WR:38.6±7.6 vs without-WR:30.3±3.5, p=0.02) and in overall insulin secretion (WR AUC 6289±3432 vs without-WR AUC 3025±2089, p=0.04) despite similar time since surgery. We observed a reduced cortisol and GDF15 response among the WR group after SG versus without WR. The GDF15 response to MTT between the groups differed after 60 mins where a steady increase in secretion was observed in both groups; however more pronounced in the without-WR group p<0.05. The serum cortisol increased differently from 0 to 60 minutes ~7 ug/dL,p=0.05) and ~3 ug/dL in the both groups respectively, afterwards the curve decline rate was also different between the groups with a faster decline in the without-WR group. The WR group displayed a flat cortisol response vs without-WR group. In addition, among the all subjects after adjustment for cortisol, demographics, time, group, insulin, glucose, time*group, one unit increase in serum cortisol was associated with an increase in GDF15 (4.70;95%CI: 0.69-8.71ng/L).

Conclusion: We suggest that GDF15 is regulated by cortisol in subjects with weight regain, elevated insulin secretion and blunted meal-induced cortisol response, indicative of HPA dysregulation. Further investigation is needed to examine the role of GDF15 and cortisol in WR after bariatric surgery.
SAT-LB58 Molecular Investigation of Recessive Inheritance by Exome Sequencing of Patients With Congenital Hypopituitarism
Authors: Pereira Ferreira Nathalia Garcia Bianchi , Madeira Joao Luiz do Oliveira , Kertsz Renata , Gergics Peter , Benedetti Anna Flavia Figueredo , Biscotto Isabela Peixoto , Fang Qing , Ma Qianyi , Ozel Bilge Ayse , Li Jun , Camper Sally Ann , Jorge Alexander Augusto Lima , Mendonca Berenice Bilharinho , Arnhold Ivo J , Carvalho Luciani Renata Silveira
Published: May 2020

Background: Growth hormone deficiency (GHD) occurs in ~ 1/8000 individuals, and 14% of the patients have mutations in five major candidate genes. However, over 30 genes have been implicated in hypopituitarism. WES (Whole Exome Sequencing) is a promising approach for molecular diagnosis of patients with GHD because it offers the opportunity to screen for all known genes in addition to novel disease gene discovery. Methods: WES was performed for 13 unrelated patients with congenital hypopituitarism born from consanguineous parents. The variants were filtered assuming autosomal recessive inheritance, rare variants in population databases, in silico analysis predicted as deleterious and pituitary and/or hypothalamus gene expression. To determine whether variants in CDH2 that were predicted to be deleterious were functionally significant, L1 fibroblast lines that have no endogenous CDH2 protein were stably transfected with either human wild type or variant CDH2, the transfected cells were labelled with lipophilic dyes, and cell adhesion properties were assessed. Results: Homozygous pathogenic or likely pathogenic allelic variants were found in 2 of the 13 patients. First, a female patient with GH, TSH, ACTH and LH/ FSH deficiencies presenting ectopic posterior pituitary lobe, non-visualized stalk, and hypoplastic anterior pituitary lobe had two homozygous rare variants predicted as deleterious: PLA2G4A p.Asn703Lys and CDH2 c.865G>A (p.Val289Ile). Only CDH2 is known to be expressed in the pituitary, and Pla2g4a null mice have a pleiotropic phenotype without obvious hypopituitarism. The CDH2 variant is rare and classified as deleterious. Sanger sequencing of CDH2 in four family members of the affected proband revealed that the unaffected parents and two unaffected siblings were heterozygous carriers. The effect of the CDH2 variant on cell aggregation was assessed in cell culture. Large cell aggregates formed in cells transfected with wild type CDH2, but cell aggregates were small or absent in cells that were either non-transfected or transfected with the CDH2 variant. Second, a patient with isolated GHD and no MRI abnormalities was identified with a rare, likely deleterious, homozygous GH1 c.171delT (p. Phe 57Leufs*43) variant. He had a sister who died at the age of 5 and had features of GHD. Conclusion: In a cohort of congenital hypopituitarism from consanguineous parents we had 15% molecular diagnosis using WES. We identified a variant in a known gene, GH1 c.171delT and a variant in a novel gene, CDH2 p.Val289I.
SAT-LB97 MiRNA-99a and mTOR2 Mediate Enhanced Endothelial Mineralocorticoid Receptor Signaling-Induced Activation of Sodium Channel and Endothelium Stiffness
Authors: Jia Guanghong , Aroor Annayya R , Habibi Javad , Yang Yan , DeMarco Vincent G , Hill Michael A , Whaley-Connell Adam T , Jaisser Frederic , Jaffe Iris Zamir , Sowers James R
Published: May 2020

In diet induced obesity enhanced endothelial cell (EC) mineralocorticoid receptor (MR) (ECMR) and downstream sodium channel (EnNaC) activity increases oxidative stress and inflammation, thereby promoting vascular stiffness and associated impaired endothelial mediated relaxation. For example, consumption of a Western diet (WD) containing excess fat (46%) and fructose (17.5%) for 16 weeks elevated plasma aldosterone levels and increased vascular MR expression in conjunction with increased endothelial and vascular stiffness in female mice. EC specific deletion of either the ECMR or EnNaC significantly attenuated this diet induced endothelial/vascular stiffness. Emerging information suggests that abnormal expression of miR-99a may be involved in these processes. To this point, we recently observed that aldosterone (10-7 mol/L) causes a reduction in miR-99a that was prevented by the MR antagonist, spironolactone (10µM) in in vitro ECs. By using RNA sequencing, we also demonstrated that ECMR activation reduced arterial miR-99a expression in diet induced obesity. Since the mammalian target of rapamycin (mTOR2)/SGK1 signaling pathway is involved in aldosterone activation of ENaC we then explored the effects of miR-99a on mTOR2 expression. Indeed, miR-99a reduced mTOR2. We further observed that inhibition of mTOR2 with PP242 inhibited EnNaC activity as determined by patch clamping of ECs. Collectively these data suggest that consumption of a WD induced ECMR activation and increased EnNaC activity and endothelial stiffness, in part, by reducing the tonic inhibitory effects exerted by miR-99a on mTOR2 mediated EnNaC activation.
SUN-LB94 Impact of the Gut Microbiome and Renin-Angiotensin-Aldosterone System in Hypertensive Patients With Low-Salt Intake
Authors: Taniguchi Kouki , Nagase Satoshi , Karashima Shigehiro , Kometani Mitsuhiro , Aono Daisuke , Higashitani Takuya , Yoshikura Syohei , Takeda Yoshiyu , Nambo Hidetaka , Yoneda Takashi , Okamoto Shigefumi
Published: May 2020

Salt intake is one of most important environmental factors responsible for triggering the onset of hypertension. Renin-angiotensin-aldosterone system (RAAS) plays a key role in adjusting sodium homeostasis and blood pressure. Recently, the potential role of the gut microbiome (GM) in altering the health of the host has drawn considerable attention. We investigated the impact of intestinal microflora and RAAS in hypertensive patients with low-salt or high-salt intake using an observational study.

A total of 239 participants were enrolled and their GMs and clinical backgrounds examined, including the renin-angiotensin-aldosterone system and inflammatory cytokine levels. On the basis of enterotypes—determined by cluster analysis—and salt intake, the participants were classified into four groups, low salt/GM enterotype 1, low salt/GM enterotype 2, high salt/GM enterotype 1, and high salt/GM enterotype 2.

The prevalence of hypertension was significantly lower in the low-salt intake (low salt/GM enterotype 1 = 47% vs low salt/GM enterotype 2 = 27%, p = 0.04) groups. No significant difference in the prevalence of hypertension was observed for the two GM enterotype groups with high-salt intake (GM enterotype 1 = 50%, GM enterotype 2 = 47%; p = 0.83). Plasma aldosterone concentration was significantly different among the four groups (p < 0.01). Furthermore, the relative abundance of Blautia, Bifidobacterium, Escherichia-Shigella, Lachnoclostridium, and Clostridium sensu stricto was also significantly different among these enterotypes. This suggested in certain individuals (with specific gut bacteria composition) changing dietary habits—to low salt—would be ineffective for regulating hypertension through RAAS. Our findings provide a new strategy for controlling blood pressure and preventing the development of hypertension through restoring GM homeostasis.
SAT-LB122 Characterization and Functional Rescue of a Nephrogenic Diabetes Insipidus Causing S127F Substitution in V2 Vasopressin Receptor
Authors: Hunyady Laszlo
Published: May 2020

Laura Szalai1, András Sziráki1, László Sándor Erdélyi1, András Balla1,2, László Hunyady1,2

1Department of Physiology, Semmelweis University, and 2MTA-SE Laboratory of Molecular Physiology, Budapest, Hungary

The concentrating function of the kidney is important to maintain the water homeostasis of the body. It is regulated by the arginine-vasopressin system through the type 2 vasopressin receptor (V2R). Loss-of-function mutations of V2R in kidney can lead to nephrogenic diabetes insipidus (NDI) which results several symptoms such as polyuria, polydipsia, and hyposthenuria.

In this study, we functionally characterized and investigated the potential rescue of a missense mutation (S127F) of the V2R. We monitored the cellular localization of the S127F mutant V2 receptor using HA-tagged receptors in confocal microscopy experiments. The S127F V2 receptor was detected only in the endoplasmic reticulum but not in the plasma membrane. Flow cytometry measurements revealed that only limited amount mutant receptor can be found on the cell surface compared to the wild type V2R. We also determined the cAMP signaling capability of the mutant receptor with BRET measurements. The S127F receptor was not able to increase the intracellular cAMP levels in response to vasopressin stimulation. Certain ER retention mutations can be rescued by pharmacological chaperones, which cause misfolded mutant receptors to present in the plasma membrane. We examined the effect of tolvaptan (a V2R antagonist) on the S127F V2 receptor. HEK293 cells were transiently transfected with the plasmid of the mutant receptor and after one day the cells were incubated for 18 hours with tolvaptan. After the pretreatment, the cells were exposed to vasopressin, and we were able to detect significant cAMP signal generation of the mutant receptor. We also checked whether the result after tolvaptan pretreatment was due to restored plasma membrane location of the receptor. We were able to demonstrate significant increase of the mutant receptors in the plasma membrane using flow cytometry. We also investigated the effect of MCF14 compound (a cell permeable high-affinity agonist for the V2R) on the mutant receptor and we found that the MCF14 was also capable to restore the cAMP signaling function of the receptor.

This work was supported by the National Research, Development and Innovation Fund (NKFI K116954 and NVKP_16-1-2016-0039).
SAT-LB135 A Novel Cytoplasmic Membrane Estrogen-Mediated Biogenic Signaling Pathway
Authors: Pestell Richard G
Published: May 2020

The estrogen receptor α (ERα) is known to convey both genomic and extra-genomic activities. The extra-nuclear estrogen signaling pathway is thought to involve a membrane-associated estrogen receptor (ERα), which activates PI3-kinase and Akt signaling. Maximal activation of Akt requires S473 phosphorylation. The essential G1-cyclin, CCND1, is a collaborative nuclear oncogene that is frequently overexpressed in cancer. D-type cyclins bind and activate CDK4/6, contributing to G1-S cell-cycle progression. Herein, cyclin D1 was shown to be located in the cytoplasmic membrane of patients with inflammatory breast cancer, human diploid fibroblasts and cancer cell lines (breast, prostate). The extra-nuclear vs. nuclear E2-induced signaling pathways can be distinguished using 17β-estradiol linked to a dendrimer conjugate (EDC), which excludes estradiol from the nucleus. In contrast with the nuclear-localized form of cyclin D1 (cyclin D1NL), the cytoplasmic membrane-localized form of cyclin D1 (cyclin D1CML) was sufficient to induce phosphorylation of the serine threonine kinase Akt (Ser473) and augmented extra-nuclear localized 17β-estradiol dendrimer conjugate (EDC)-mediated phosphorylation of Akt (Ser473). Cyclin D1CML was sufficient to induce G1-S cell-cycle progression, cellular proliferation, colony formation. In contrast with cyclin D1NL, the cyclin D1CML induced transwell migration and the velocity of cellular migration. Together these studies suggest distinct subcellular compartments of cell cycle proteins may convey distinct functions. The major adjuvant therapy for the ~70% of ERα expressing human breast cancer involves anti-estrogen therapy and the ERα/PI3K/Akt complex pathway is hyperactivated in aggressive breast tumors. The non-genomic actions of E2/ERα, mediated via cyclin D1CML may provide an important additional target. References. 1. 2. Casimiro MC et al Mol Endocrinol. 2013;27(9):1415-28. Di Sante, G, Expert Rev Anticancer Ther. 2019 Jun 20:1-19.
SUN-LB13 Idiopathic Infantile Hypercalcemia Secondary to CYP24A1 Mutation: A Rare Case Without Exogenous Vitamin D Supplementation
Authors: Tell Shoshana , Finn Erin , Ohman-Hanson Rebecca Anne , Ma Nina
Published: May 2020

Background: Mutations in CYP24A1, which encodes 24-hydroxylase, the key enzyme for Vitamin D breakdown, cause symptomatic hypercalcemia and nephrocalcinosis in infants on Vitamin D supplementation. New, symptomatic diagnoses of idiopathic infantile hypercalcemia without exogenous supplementation are rare. Previous case reports describe a seasonal effect with worsening hypercalcemia and hypercalciuria during summertime, attributed to increased sun exposure and endogenous Vitamin D production. Clinical Case: A 10-month-old female presented to endocrine care with hypercalcemia and nephrocalcinosis, detected on renal ultrasound (US) due to history of UTI. Her first renal US and serum calcium (Ca) at 3mo of age were normal. Subsequent renal US at 6mo and 9mo of age demonstrated nephrocalcinosis, prompting nephrology and endocrine evaluation. History was significant for failure to thrive. She was born in the fall, with worsening hypercalcemia and nephrocalcinosis during the summer. Diet consisted of standard infant formula and age appropriate solid foods with no added Vitamin D supplementation (~300 IU/day in her formula). She had no family history of nephrocalcinosis, nephrolithiasis, bone disease, or disorders of Ca regulation. Initial labs were notable for Ca corrected for albumin 11.5 (7.8-11.1 mg/dL), PTH <4 (8.7-77.1 pg/mL), 25-OH-Vitamin D 81 (30-96 ng/mL), 1,25-OH-Vitamin D 23.1 (26.1-95 pg/mL), Urine Ca/creatinine ratio of 0.9 mg/mg (<0.81), normal chromosomal microarray, and normal thyroid function tests. She was started on reduced mineral formula PM 60/40. One week later, repeat Ca level increased to Ca corrected 14.2 (7.8-11.1 mg/dL). She was admitted for IV fluids and pamidronate, and was transitioned to a low Ca and Vitamin D formula (Calcilo), with improvement in Ca levels. Testing revealed an increased ratio of 25-OH-Vitamin D to 24,25-OH-Vitamin D of 192 (normal <25), and genetic testing showed 2 pathogenic missense mutations in CYP24A1 genes: c.1226T>C p.(Leu409Ser) and c.1186C>T p.(Arg396Trp). The Leu409Ser mutation has shown a small amount of 24-hydroxylase activity in previous in vitro analysis. She has continued a low Ca diet with stable Ca corrected of 10.7-10.8 (8.7-9.8 mg/dL) and significantly improved weight gain. Conclusion: This is one of the few documented cases of symptomatic idiopathic infantile hypercalcemia secondary to CYP24A1 mutation in an infant without exogeneous Vitamin D supplementation. Her nephrocalcinosis and hypercalcemia worsened over the summer, suggesting increased sun exposure may have been a contributing factor. This case demonstrates that 1,25-OH-Vitamin D levels may be normal or low in this condition, particularly for individuals with the Leu409Ser mutation who may retain partial 24-hydroxylase function.
SUN-LB18 Serum 25-Hydroxyvitamin D Is Not Associated With the Type of Central Precocious Puberty in Girls
Authors: Xu Liya , Li Pin , Guo Sheng , Yuan Dandan
Published: May 2020

[Objective] To evaluate the clinical value of serum 25-hydroxyvitamin D (25OHD) in girls with different types of central precocious puberty (CPP), in order to provide basis for the clinical diagnosis and treatment.

[Methods] 340 CPP girls diagnosed in our hospital from January 2016 to January 2018 were enrolled and retrospectively studied. According to the progression of Tanner stage ≥1 during 6 months, bone age(BA) levels were higher than chronological age of more than 1 year. 226 patients were included in the rapidly progressive CPP group (RP-CPP), while 114 patients were included in the slowly progressive CPP group (SP-CPP) as a control. We analyzed the correlation between serum 25OHD levels and the different puberty characteristics (BA, disease course, body mass index (BMI), bone mineral density (BMD), serum LH peak to FSH peak ratio (LHP/FSHP), insulin-like growth factor 1(IGF1)) of two groups. According to sunshine duration, the sampling season was divided into two groups (December to May, June to November), then we compare the correlation between different serum 25OHD levels and season of sampling as well as the different puberty characteristics respectively.

[Results] (1) The mean serum 25OHD levels of CPP girls were 15.89±6.87ng/ml. The 25OHD levels of 68 (20.0%), 95 (27.9%) and 167 (49.1%) patients were <10, 10-15 and 16-29 ng/mL, respectively. Only 10 (2.9%) patients had normal 25OHD (>30 ng/mL). (2) No significant difference in serum 25OHD levels between RP-CPP group and SP-CPP group (F =0.809, p=0.369) was found. There is no correlation of BMD and disease course between the two groups (p>0.1). Bone age, BMI, LHP/FSHP and IGF1 levels in RP-CPP group were higher than SP-CPP group (P<0.05). Logistic regression analysis showed that BMI, LHP/FSHP and IGF1 were the independent risk factors for CPP (OR 2.690, 1.005, 3.288, respectively). (3) There were significant differences among different serum 25OHD levels as for season, disease course and IGF1 (p<0.05). The correlation with the season was the highest (r=0.402, p<0.001).

[Conclusions] (1) Vitamin D levels are generally insufficient in CPP girls and are not related to different types of CPP. (2) The higher BMI, IGF1, LHP/FSHP levels are, the easier CPP girls will transfer to RP-CPP, but not associated with vitamin D levels. (3) CPP girls suffer from vitamin D deficiency in seasons of winter and spring easilier.
MON-LB78 Thyroid Nodules > 4cm: High-Risk for Malignancy or Not?
Authors: Fishel Heather , Rao Ambika
Published: May 2020

Background: Thyroid nodules are very common in adults. One percent of men and 5% of women have nodules on exam, and 19-68% of adults have thyroid nodules on ultrasound. Majority (85-90%) of them are benign. Most concerning is the diagnosis of thyroid cancer. These nodules can be stratified into risk groups based on ultrasonographical criteria. There are 5 internationally endorsed sonographic classification systems (ATA, ACR, European Thyroid Association and Korean Society of Thyroid Radiology). After classification, decision to perform FNA biopsy is made based on size of the nodules. Some of the other parameters that have been considered to increase risk of cancer are BMI, TSH level, radiation exposure to the neck before puberty and family history of thyroid cancer. Cytogenetic testing of the FNA specimen may also help determine the need for excision.

Study Design: We retrospectively studied a group of veterans referred for endocrine consultation for thyroid nodules that had undergone FNA based on ACR and ATA ultrasonographical classification (total of 127 nodules). On reviewing these charts over the past 4 years, we noted that approximately 39% (49/127) of the nodules were <2cm, 35% (44/127) were 2-4cm and 26% (34/127) were >4cm in size. We examined patient demographics and characteristics of nodules >4cm, since it is frequently a dilemma whether to clinical monitor these nodules or refer them for surgical excision.

Results: Seventeen percent of patients were females. Majority were between 60-65 years of age, had a BMI 30-35 and TSH of <2. Based on review of ultrasound images and ACR and ATA classification, 55% of the nodules (19/24) had a score of 4-6 points on the TIRAD’s scale and based on ATA classification, 52% (18/34) were in the high-risk category. The ultrasound-guided FNA results showed that 65% were benign-Bethesda II (22/34), 12% were Bethesda III (4/34) and IV, 3% Bethesda V (1/34) and 15% Bethesda I (5/34). Eighteen percent of the nodules were referred for surgical excision (6/34); 3% were malignant (1/34), and the rest were benign (27/34).

Discussion: It is unclear if the risk of thyroid cancer in nodules >4cm is any different from that of smaller nodules and if there should be different criteria used in nodules >4cm for risk stratification. Other questions to address are how these nodules should be monitored for growth and what criteria should be used to determine need for surgical intervention, other than FNA results or compression symptoms. Recent studies looking at growth of thyroid nodules over time do not indicate clear predictors for malignancy. Further studies are needed.
SAT-278 Vaginal Cabergoline: A Simple Solution to a Challenging Problem
Authors: Abuaisha Munder , Gibbs Otto , Bier Rachel
Published: May 2020

Introduction: Prolactinomas is a common endocrine disorder that can be associated with significant morbidity. Generally, prolactinomas are more responsive to pharmacologic treatment than any other types of pituitary adenoma. Dopamine agonists (DA), including cabergoline and bromocriptine, are the first line of treatment in all sizes of prolactinomas and they decrease both the secretion and size of these adenomas. However, treatment remains challenging for patients who are intolerance to those medications. Case: We report a 32-year-old Hispanic woman who presented with secondary amenorrhea, she was found to have hyperprolactinemia of 1496 mcg/L. MRI of the brain showed a pituitary adenoma measuring 2.7 cm with sella turcica invasion and mass effect on the optic chiasma. She failed the lowest doses of oral cabergoline and bromocriptine and underwent TSS and gamma knife radiosurgery. Given her persistent symptoms (marked depression, insomnia, fatigue, short-term memory loss, and lack of concentration along with constipation) and elevation of prolactin, she was started on low dose vaginal cabergoline leading to a marked improvement of her symptoms and a steady decrease in serum prolactin. Discussion: Despite the availability of DA as a first-line treatment of Prolactinoma, treatment remains challenging, given the commonly reported side effects for all DA. Cabergoline is oftentimes the treatment of choice due to efficacy and favorable side-effect profile. However, intolerance to those medications can lead to discontinuation of therapy and increase morbidity. Other strategies, including transsphenoidal surgery (TSS) or radiation therapy, have been considered for the minority of patients whose adenomas are resistant to DA or who cannot tolerate these drugs. Interestingly, tolerance to DA can be improved by administering the drug intravaginally, which can have similar efficacy to the oral route and a more favorable side-effect profile. However, only a few studies assessed the effectiveness and tolerance of vaginal DAs in hyperprolactinemic patients intolerant to oral medications, little evidence supports the use of intravaginal DA to improve drug tolerance, and further studies are necessary to determine the safety and efficacy of vaginal cabergoline.
SAT-LB116 Extreme Insulin Resistance: The Diagnostic Challenges When Cost Is a Limitation
Authors: Cavalcante Parr Nadia Carenina Nunes , Leong Jaclyn , Fazel Maryam , Te Charisse , Pendergrass Merri Lou
Published: May 2020

Introduction: Insulin resistance occurs most commonly in association with obesity but may result from multiple causes, e.g. medications, lipodystrophy, or antibodies to insulin or insulin receptors. We review a case of an unusual presentation of insulin resistance. We highlight challenges of diagnostic testing and treatment when there are cost limitations. Clinical Case:A 41 year old Hispanic male with T2DM and a history of well-controlled BPD on quetiapine only presents for management of diabetes. His current treatment is metformin and a TDD of 170 U human insulin; A1C is 12.2%. He was diagnosed at age 32 via routine lab tests. At diagnosis BW was 96.4 kg, BMI 29, BP 100/70, CHOL 152, TG 247, HDL 35, LDL 68. Physical exam was unremarkable without acanthosis or lipodystrophy. Anti-GAD, anti-islet cell antibodies, insulin and C-peptide levels were ordered, but not obtained due to cost. He was managed with lifestyle modification for 2 years with maintenance of A1C <7%. At age 35 he developed symptomatic hyperglycemia with A1C 9.4% and was started on metformin and glyburide. At age 36 A1C was >11%, with no change in BW. Glargine 5 U was added, and glyburide was changed to glipizide. Glargine was increased to 40 U without changes in glycemia. At age 37 glipizide was stopped, and he could not afford glargine. He was switched to 70/30 human insulin. Insulin dosages were progressively increased to 220 U a day with no change in glycemia. Liraglutide was tried but not continued due to cost, and quetiapine was switched to trazodone without improvement in A1C. LFTs, CBC, HIV, Hepatitis C and B have been negative. The patient has had multiple visits for education with documented adequate disease understanding and performance of injections. Nonadherence was suspected; for its evaluation, the patient was observed in clinic self-injecting 30 U of regular insulin (brought from home); fasting was confirmed for 3hrs post-injection. BG was 327mg/dL pre-injection and 326mg/dL 3hrs post-injection. Insulin antibodies were requested but not obtained due to cost. Insulin receptor antibodies are not commercially available in the US. Potential empiric strategies, e.g. the NIH protocol for insulin type B resistance (rituximab + dexamethasone + cyclophosphamide) was considered but cost is a limitation. We discussed steroids or methotrexate for possible antibody mediated insulin resistance versus a trial of thiazolidinedione, which has been reported to decrease severe insulin resistance in patients with lipodystrophy. The patient opted to initially try a thiazolidinedione. Conclusion:Although poor adherence has not been excluded, the patient appears to have no response to high doses of injected human insulin, suggesting extreme insulin resistance. Cost limitations preclude optimal diagnostic evaluation. Empiric treatment with low cost options potentially may provide diagnostic information as well as efficacious treatment.
MON-LB034 A Severe Case of Pheochromocytoma Presenting as Classic Takotsubo’s Cardiomyopathy With Rapid Resolution
Authors: Sarma Shohinee , Hernandez Karen Ester Gomez
Published: May 2020

Background: Inverted Takotsubo’s cardiomyopathy requiring extra-corporeal membrane support (ECMO) with pheochromocytoma is well described. Classic Takotsubo’s cardiomyopathy, however, is rarely described in this setting.

Clinical Case: A 50-year old woman with no previous comorbidities presented with pulmonary edema and cardiogenic shock. She required rapid escalation of vasopressor, inotrope, and intra-aortic balloon pump then ECMO with consideration of cardiac transplant. Initial echocardiogram showed an ejection fraction of 17%. Coronary angiography showed apical ballooning in keeping with classic Takotsubo’s cardiomyopathy. Abdominal ultrasound for transplant screening showed a 4.6 cm abdominal mass. Computed tomography confirmed a 4.6 cm mass with classic radiologic features of pheochromocytoma. Plasma free normetaphrine and metanephrine were elevated at 2.34 nmol/L and 0.25 nmol/L. A 24-hour urine collection included urine volume of 3500 ml, urine creatinine 7.2 mmol/day, elevated urine norepinephrine 1199 nmol/day, elevated urine epinephrine 888 nmol/day, and normal urine dopamine 335 nmol/day. Parathyroid hormone and calcitonin were normal at 0.4 pmol/L and 4.8 pmol/L, respectively. Plasma aldosterone was normal at 87 pmol/L and plasma renin normal at 3.5 ng/L. Doxazosin 1 mg daily was initiated and she had clinical improvement next day and came off ECMO. Her ejection fraction improved to 55% subsequent week. She had retroperitoneoscopic adrenalectomy two weeks later with full recovery.

Conclusion: Classic Takotsubo’s cardiomyopathy is a possible presentation of pheochromocytoma with rapid resolution with alpha blockade.
MON-LB74 The Problem of Measuring 1,25(OH)2 Vitamin D in Patients With High Levels of 25(OH) Vitamin D
Authors: Vieira Jose Gilberto , Okai Guilherme , Ferrer Cláudia , Cardozo Karina
Published: May 2020

Recently, the use of Vitamin D in high doses for treatment of several conditions, mainly autoimmune in nature, has been advocated with dubious results. Hypercalcemia is an important side effect of this intervention. Here we describe our findings in samples that presented 25(OH)D in excess of 150 ng/mL (375 nmol/L) and had 1,25(OH)2D also measured.

Material and Methods: we used serum samples from our diagnostic routine, received for measurement of 25(OH)D and 1,25(OH)2D according to medical requisition. A first group (group A) included 213 samples collected up to November 2018, used Diasorin’s chemiluminescent assays for 25OHD and 1,25(OH)2D, and a second group (group B), comprising 88 samples, used the same 25(OH)D assay and LC-MS/MS method for 1,25(OH)2D.

1,25(OH)2D measurement in the group A used a chemiluminescent competitive assay (Liason XL, Diasorin). The 1,25(OH)2D LC-MS/MS assay includes a previous sample prep, extraction, derivatization and chromatrography. APCI+ is followed by SRM (Selected Reaction Monitoring) and CAD (Collision Activated Dissociation) fragmentation. Precision studies showed, between run CVs of 6.8% to 7.4% and within run of 2.9% to 5.5%.

In vitro investigations testing standards and spiked samples with 25(OH)D3, 25(OH)D2, 3-epimer-25(OH)D3 and 24R,25(OH)2D3 were also used to verify possible analytical interferences in the 1,25(OH)2D LC-MS/MS.

Results: in group A, 25(OH)D median was 371 ng/mL (928 nmol/L), range 154 ng/mL to 856 ng/mL; 1,25(OH)2D median of 350 pg/mL (875 pmol/L), range 41 pg/mL to 1280 pg/mL. Correlation (Spearman) between 25(OH)D and 1,25(OH)2 was r= 0.8649 (P<0.001). In group B, 25(OH)D showed a median of 349 ng/mL (872 nmol/L), range 171 to 756 ng/mL; 1,25(OH)2D median of 54 pg/mL (135 pmol/L), range 24 pg/mL to 108 pg/mL. Correlation between 25(OH)D and 1,25(OH)2 was r= 0.185 (P= 0.08).

In group A 189 samples had calcium measurement (median 9.7 mg/dL, range of 8.7 to 13.6 mg/dL), 182 creatinine (median of 0.8 mg/dL range of 0.3 to 1.8 mg/dL) and 179 PTH (median 19 pg/mL, range 5 to 68 pg/mL). In group B 75 cases had measurements of calcium (median 9.7, range 8.6 to 16.6 mg/dL), 75 of creatinine (median 0.8, range 0.3 to 2.5 mg/dL) and 75 of PTH (median 20, range 9 to 49 pg/mL).

The in vitro tests showed a slight interference from 25(OH)D3, 3-epimer-25(OH)D3 and 24R,25(OH)2D3 molecules in the LC-MS/MS method.

Conclusion: our results confirm data already published showing interference of high levels of 25(OH)D in 1,25(OH)2D measured by immunoassay and, in a milder way, by LC-MS/MS (1). V. Care should be taken in the interpretation of 1,25(OH)2D values in samples with high 25(OH)D values.

1. Hawkes CP, Schnellbacher S, Singh RJ, Levine MA. 25-Hydroxyvitamin D can interfere with a common assay for 1,25-dihydroxyvitamin D in vitamin D intoxication. J Clin Endocrinol Metab. 2015; 100:2883-2889.
SAT-LB92 Sex Hormones Therapy Differentially Modulates HDL Function in Transgender Individuals
Authors: Ruscica Massimiliano , Adorni Maria Pia , Zimetti Francesca , Greco Maria Francesca , Sirtori Cesare , Den Heijer Martin , van Valzen Daan M
Published: May 2020

Background/aim: The main proposed atheroprotective function of high-density lipoproteins (HDL) lays on their role to promote macrophage cholesterol efflux. An insightful way to learn more about the effects of sex hormones on HDL function is to study changes during hormone therapy. The present study was aimed at evaluating the effects of exogenous sex hormones administration on HDL cholesterol efflux capacity (CEC) within transgender individuals. CEC estimates the ability of HDL to remove cholesterol from cells, i.e. the initial step in reverse cholesterol transport.

Subjects/Methods: Transmen were treated with testosterone gel, a mix of testosterone esters once every three weeks) or testosterone undecanoate once every twelve weeks, whereas transwomen were treated with either oral estradiol valerate or a transdermal application of estradiol (patches). Cyproterone acetate was prescribed as a testosterone-blocking agent to all transwomen. HDL function was evaluated by a radioisotopic technique. Hormone levels, lipids and HDL function were evaluated after one year of follow-up.

Results: In transmen (n= 15), testosterone markedly increased (+ 97%; p < 0.0001), whereas luteinizing hormone (LH) decreased significantly (- 64%; p = 0.049). Total cholesterol and low-density lipoprotein cholesterol (LDL-C) were not affected by testosterone treatment, whilst triglycerides (TG) were raised (+ 11.76%; p = 0.0078) and HDL-C reduced (- 19.6%, p=0.0103). Concerning HDL CEC, only the aqueous diffusion process was lowered (- 9.8%; p = 0.0032), an effect directly correlated with HDL-C changes (r = 0.6242, p = 0.0002). Total-, ATP-binding cassette transporter (ABCA1)-, and ABCG1-mediated CEC were not affected by testosterone treatment. In transwomen (n= 15), estradiol levels were raised (+200%, p=0.013) whereas LH and testosterone significantly reduced, i.e. - 97% for both. Relative to lipids, estradiol supplementation reduced total cholesterol (- 10.7%, p=0.0017), HDL-C (- 14.3%, p = 0.0024) and LDL-C (- 10.9%, p = 0.0058). Total HDL CEC decreased (- 11%, p=0.0001) with a specific decrement in CEC mediated by the ATP-binding cassette transporter (ABCA1) (-24%, p = 0.0003) and aqueous diffusion (-4.7%, p = 0.0014). This last was associated to a reduction in HDL-C (r = 0.4084, p = 0.0251). Conversely, the drop in ABCA1 and total CEC did not associate to reductions in HDL-C levels.

Conclusions: In transmen, testosterone supplementation was associated with a reduction in aqueous diffusion-mediated CEC, an effect potentially dependent to HDL-C changes. In transwomen, estrogen significantly decreased HDL function (CEC), independent of HDL-C levels changes.
SAT-LB64 Teriparatide and Its Bone Healing Power
Authors: Joseph Aneeta J , Penabad Jesus L , Pinero-Pilona Antonio
Published: May 2020

Introduction:

Teriparatide, a parathyroid hormone analog, is an important anabolic agent approved by the U.S. Food and Drug Administration to increase bone mineral density in osteoporotic patients. Parathyroid hormone (PTH) regulates calcium, phosphate, and active vitamin-D metabolites.The amino terminal peptide fragments of PTH has been known to increase bone mass and are being used in clinical practice for osteoporosis management (1).

Current literature shows the efficacy of teriparatide in increasing bone density of lumbar spine and femoral neck, and decreasing the risk of vertebral and non-vertebral fractures both in postmenopausal women and men. It is also known to prevent fractures in patients with osteoporosis and promote healing of fractures (2).

Case Description:

A 79-year-old Hispanic female with history of osteopenia and major lumbar spine wedge compression fractures presented to our clinic for consultation. She was on ibandronate for the past four months and was having symptoms of pill esophagitis. Her last bone mineral density done on August 2017 revealed T-score of -2.5 at the lumbar spine, -1.5 at the left femoral neck, and 3.3% bone loss on the left femoral head. Rather than being started on teriparatide, zoledronic acid, or denosumab, she continued ibandronate along with calcium and vitamin D. Two months after the initial consultation, she sustained a traumatic fracture of the posterior arch and body of C2 bilaterally following a motor vehicle accident. There were discussions about starting anabolic treatment, as serial imaging did not show any significant improvement in the healing process despite the use of a collar. Two months after sustaining C2 fracture, she was started on teriparatide. Repeat cervical spine x-ray three months later showed complete healing of the C2 fracture.

Discussion:

There are a limited number of cases reported in regards to teriparatide induced healing of non-osteoporotic fractures (3). Our case is one of the very few reported to have shown complete radiographic and clinical healing of a traumatic, non-osteoporotic fracture after use of teriparatide for 12 weeks.