bluuebunny/crossref_metadata_2025 huggingface dataset:
SUN-LB106 The Transcriptomic Evidences on Role of Abdominal Visceral vs. Subcutaneous Adipose Tissue in the Pathophysiology of Diabetes in Asian Indian Indicates the Involvement of Both
Authors: Mathur Sandeep Kumar , Kumar Anshul , tiwari Pradeep , Saxena aditya
Published: May 2020

Introduction: Asian Indians show “thin fat phenotype” characterized by higher visceral adipose tissue(VAT) and lower subcutaneous adipose tissue(SAT) mass and their higher cardio-metabolic risk has been attributed to this fat distribution. However, the underlying molecular pathology and role of these adipose depots in the pathogenesis of T2D in them remains unknown.Hypothesis: The comparison of transcription profiles of abdominal VAT and SAT and their correlation with diabetes related intermediate phenotypic traits could shed some light on their role in the pathophysiology of diabetes.MethodologySubjects: 19 diabetics (M: F ratio, 8:11) and 16 age and BMI matched controls (M: F ratio 5:11) undergoing abdominal surgery (non-malignant and non-infective conditions).Clinical Parameters: Anthropometry, Serum glucose, insulin, HOMA-R, HbA1c, lipid profile, FFA, adipocytokines. Abdominal VAT, SAT and liver fat were estimated by MRI.Adipose tissue biopsy: SAT and VAT samples were taken during surgery. Genome-wide gene expression profiling of these biopsies was performed using Affymetrix GeneChipPrimeView® arrays. The data was submitted to NCBI-GEO (Accession # GSE78721). Selected genes were validated by qPCR. Gene set enrichment analysis (GSEA) for functional and Weighted Gene Correlation Analysis (WGCNA) for statistical comparison was done.Results:Diabetics had higher waist circumference (p=0.05), HOMA-R (p=0.0002), Visceral fat content (p=0.02) and adipocyte size (p=0.02)GSEA: diabetics vs. controls: In VAT 16 gene sets were upregulated (FDR < 25%) enriching various immune system and inflammation-related pathways. In SAT too, various inflammatory genes were upregulated however they were statistically non-significant (FDR > 25%). Moreover, 12 out of 16 significantly enriched pathways in VAT were among the top 20 pathways in SAT. GSEA in diabetics: VAT vs SAT: None of the gene sets were found significant at FDR < 25% which substantiated our hypothesis that overall pathophysioloigcal alteration in both depots are similar. WGCNA for statistical comparison of VAT and SAT depots The correlation between measures of average gene expression and overall connectivity between both depots was significantly positive. Several modules of co-expressed genes in both VAT and SAT showed positive as well as negative correlation with various intermediate phenotypic traits of diabetes. In both depots they enriched several pathways otherwise known to be associated with pathological adipose tissue like inflammation, adipogenesis etc.

Conclusions

In Asian Indians, diabetes pathology inflicts similar molecular alternations in VAT and SAT, which are more intense in the former. The role of both adipose depots in the pathophysiology of diabetes is along similar lines and they enrich several molecular pathways which are otherwise known to be implicated in pathological adipose tissue.
SUN-LB34 A Case of BMAH With Aberrant Vasopressin Adrenal Receptors
Authors: Seedat Faheem , Mohamed Nazeer Ahmed , Lutchman Nereshni
Published: May 2020

We report on a 42 - year old woman was referred following an incidental finding of bilateral macronodular (nodules > 1cm) adrenal glands after a computed tomography scan for investigation of an unrelated urological problem. Clear features of Cushing’s syndrome were elicited on initial clincal evaluation and screening tests confirmed the diagnosis biochemically: midnight salivary cortisol 15.4nmol/L (0.2 - 3nmol/L), 24 hour urine free cortisol > 662.4nmol/L (8.3 - 118.7nmol/L per 24 hours) and an 8am serum cortisol measured 951nmol/L following 1mg dexamethasone suppression test (< 50nm/L). A serum adrenocorticotropic hormone (ACTH) measured 0.3pmol/L (1.6 - 13.9pmol/L) suggesting, in light of the CT findings, an adrenal source of the elevated cortisol. Screening for aberrant adrenal receptors to catecholamines, Gastric inhibitory peptide, ACTH, vasopressin and Gonadotropin releasing hormone was performed. A positive biochemical response to ACTH and vasopressin was noted as measured serum cortisol increased to 1600pmol/L (upper limit of the assay). Following a unilateral adrenalectomy, were pathological examination of the respected adrenal gland confirmed adrenal hyperplasia, the patient had both clinical and biochemical resolution of hypercortisolemia. 2 weeks following surgery her midnight salivary cortisol measured 2.1nmol/L (0.2 - 3nmol/L) and 24 hour urine free cortisol 218nmol/L (8.3 - 118.7nmol/L per 24 hours). Her 8am ACTH also increased to 2.9pmol/L (1.6 - 13.9pmol/L). Biochemical screening of her sister showed no evidence of Cushing’s syndrome. Bilateral macronodualr hyperplasia (BMAH) represents a rare cause of Cushing’s syndrome may be diagnosed incidentally and is often associated with an insidious onset. We use this case to highlight the complexities of provocative testing for aberrant adrenal receptors which occur with BMAH and the utilization of unilateral adrenalectomy to achieve clinical and biochemical remission of Cushing’s syndrome thus, removing the need for post - operative steroid replacement following bilateral adrenalectomy.
SAT-LB68 A Rare De Novo Mutation in LRP5 Gene in an Adolescent Female With Juvenile Onset Primary Osteoporosis
Authors: Shum Betty J , Cheung Clement C , Ryabets-Lienhard Anna
Published: May 2020

Background: Juvenile onset of primary osteoporosis is a rare skeletal disorder with a highly heterogenous clinical presentation and complex poorly understood genetic etiology. Low-density lipoprotein receptor-related protein 5 (LRP5), a Wnt-β-catenin pathway receptor involved in bone mineral density (BMD) regulation, has been reported in children with primary osteoporosis mainly due to missense and frame-shift mutations. To our knowledge, there is only one report of in-frame deletions in exon 21 possibly being implicated in pregnancy related osteoporosis (1). We report the first case of a rare heterozygous de novo in-frame deletion in exon 21 of LRP5 gene in a girl with juvenile onset primary osteoporosis.

Clinical Case: A 7.5 yo previously healthy European-African-American female born to non-consanguineous family, was noted to have left ankle and bilateral wrists fractures during sport activities occurring over the span of 1 y. On exam, she was of normal stature, had normal sclerae and vision, but was found to have hypermobile joints. Initial blood work revealed an elevated iPTH 72 pg/mL (9-59), normal Ca 9.6 mg/dL (8.9-10.4), and low 25OH-Vitamin D 17 ng/mL (30-100), which normalized with supplementation to 30.4 ng/mL. By 10.5 yo, she had sustained multiple sports related and pathologic fractures of long bones with progressive bone pain and functional ambulatory impairment. Radiographic evaluation showed osteopenia, multiple healed long bone fractures with presumed non-ossifying fibroma in the distal right femoral metaphysis, and subtle height loss of T4-5 vertebrae. CT bone densitometry at 12 yo showed low mean cancellous lumbar vertebral BMD of 190 mg/cm3 (ref. 285 ± 45) and normal cortical BMD of the femoral midshaft of 1977 mg/cm3 (ref. 2000 ± 60). Genetic testing for Osteogenesis Imperfecta returned negative for COL1A1 and COL1A2 mutations. Whole exome sequencing (WES) revealed a rare, de novo heterozygous mutation in exon 21 that involved deletion of nucleotides 4454 to 4465 resulting in an in-frame deletion of amino acid 1485 to 1488. This mutation is predicted to be deleterious by in silico analysis.

Conclusion: We present the first case of a young female with progressive pathologic fractures, functional ambulatory impairment, and low BMD in childhood, consistent with juvenile onset primary osteoporosis. WES revealed a rare de novo heterozygous in-frame deletion mutation in LRP5, providing a plausible biological mechanism for her clinical presentation, and further contributing to the increasing genetic heterogeneity of juvenile onset primary osteoporosis and LRP5-related bone disorders.

Reference: (1) Cook, F., Mumm, S., Whyte, M., Wenkert, D. Pregnancy-associated osteoporosis with a heterozygous deactivating LDL receptor-related protein 5 (LRP5) mutation and a homozygous methylenetetrahydrofolate reductase (MTHRF) polymorphism. JBMR. 2014;29 (4): 922-8.
MON-LB48 The Genomic Landscape of Sporadic Thyrotrophinomas
Authors: shen Angeline , Wang Paul , De Sousa Sunita M C , Torpy David J , Scott Hamish , King James , Colman Peter Grahame , Yates Christopher James
Published: May 2020

Background: Thyrotrophinoma (TSHoma) is rare and knowledge on the genomic landscape of this tumour type is very limited.

Aim: To perform whole-exome sequencing (WES) in a population of TSHomas to identify recurrent somatic genetic events

Method: WES was performed on paired tumour and germline DNA of 7 patients with TSHomas. Three tissue samples were formalin-fixed paraffin-embedded and 4 fresh frozen tumour samples. Fresh blood samples were also collected from each patient. The average of mean depth of coverage amongst all samples was 129X, and 97% of target bases were covered ≥20X.

Results:Four (57%) of the seven patients were male and median age at diagnosis was 52 years. (IQR 46, 60) Six patients (86%) had macroadenomas. Four patients (57%) had central thyrotoxicosis at diagnosis and three patients’ tumour stained positive for TSH on histology examination. Two patients (29%) had growth hormone co-secreting tumours. In total, 69 somatic variants were identified to be of potential interest, averaging 1.4 variants per million base-pair of DNA read. No variants were observed in more than one individual. According to the GTEx database, 9 of 69 genes (DRC3, HDAC5, KDM1A, POLR21, TCF25, THAP7, TTC13, UNC5D, UNC13A) were highly expressed in the pituitary (top 10%). Four of these genes appear to contribute to tumour development via epigenetic pathway. Specifically, three of these genes (HDAC5, KDM1A, THAP7) either interact with or form part of histone deacetylases whilst POLR21 encodes a subunit of RNA polymerase II which is responsible for mRNA synthesis. On the other hand, TCF25 gene is thought to act as transcriptional repressor and UNC5D plays a role in cell-cell adhesion.

Large scale copy number variations involving gain or loss of whole chromosome or chromosome (chr) arm were observed in six (86%) tumour samples. Chr 5, 9, 13 and 19 were most commonly affected by chromosomal gains. Deletion of chr 1p was seen in two cases and mutations in KDM1A (p.Glu161fs/c.482_491delAGGAAGAAAA) and ADGRB2 gene (p.Leu1565Gln/c.4694T>A) were found in each of the remaining single copy of chr 1p. ADGRB2 gene is thought to be involved in cell adhesion and angiogenesis inhibition. Copy neutral loss-of-heterozygosity were present in two (29%) of the tumour samples (chr 2 and 12q). However, no somatic mutation was found in these regions. Gene level copy number analysis identified a potential deletion in TTI2 gene which encodes for a regulator in DNA damaging response as well as telomere length regulation.

ConclusionOverall, the rate of somatic variant mutations in TSHomas is low, consistent with the relative benign nature of this tumour type. No classical driver mutations were identified by this study however, chromosomal anomalies and epigenetics may play an important part in TSHoma development.
MON-LB77 Inhibitors of XIAP as Novel Therapeutic Agents in Thyroid Cancer
Authors: Chu Simon , Ibrahim Nalian , Chan Rainbow , Tran Trang , Nguyen Trang , Mond Michael , Fuller Peter J
Published: May 2020

Treatment options for radioiodine-refractory epithelial thyroid cancer (ETC) are limited to tyrosine kinase inhibitors (TKIs), which are associated with significant adverse effects and are not curative. The inhibitors of apoptosis (IAP) family have oncogenic properties and overexpression of X-linked IAP (XIAP) in papillary thyroid carcinoma (PTC) is associated with a poor prognosis. Our group has previously reported a synergistic interaction between SMAC mimetics (SM) (IAP antagonists with XIAP and cIAP1 specificity), and PPARgamma agonists in granulosa cell tumors (1). Such an approach has not been explored in ETC.

We hypothesize that SM may be efficacious alone or in combination with a secondary agent to inhibit proliferation, induce cell death and/or promote differentiation to resensitize cells to radioiodine.

Four ETC-derived cell lines (K1, Nthy-ori 3-1, TPC-1 and SW-1736) were examined for cIAP1, cIAP2 and XIAP expression by RT-PCR. The K-1 and TPC-1 cell lines (PTC origin, BRAFV600E and PI3KCA mutation positive) were chosen to investigate the effects of an SM in combination with either a PPARgamma agonist (rosiglitazone) or a broad-spectrum TKI (sorafenib). Cell proliferation was examined using xCELLigence Real-Time Cell Analysis. Viability was assessed using total cell counts at 24 and 48 hours.

In the four cell lines, we found abundant cIAP1 and XIAP expression and low cIAP2 expression. When an SM was used in combination with either rosiglitazone or sorafenib, we observed significant impairment of cell proliferation and viability with a clear morphological response. These effects appear SM-dependent, as SM treatment alone also showed significant effects on proliferation. However, these effects were enhanced when combined with sorafenib, which was ineffective alone. Markers of differentiation are currently being examined.

Our findings suggest a novel role for SM in treating or redifferentiating radioiodine-refractory ETC. Clinically, this may involve lower doses of individual agents than when used alone, thereby reducing adverse effects.

References1. Leung, D.T.H., et al., Combined PPARgamma Activation and XIAP Inhibition as a Potential Therapeutic Strategy for Ovarian Granulosa Cell Tumors. Mol Cancer Ther, 2019. 18(2): p. 364-375.
SAT-LB85 Use of Weekly Levothyroxine Regimen for Rapid Normalization of Thyroid Hormone Levels: A Case Report
Authors: Escudero Jose Renato Martinez , Kirupakaran Johnathan , Yau Alice , Rodriguez Giovanna , Bahtiyar Gul
Published: May 2020

Background: Hypothyroidism affects around 4.6% of the U.S. population1. Non-adherence with thyroid hormone replacement is one of the biggest challenges in treating hypothyroidism1. The half-life of T4 and T3 in hypothyroidism is about 7.5 and 1.4 days respectively2. A large dose once-weekly administration of levothyroxine (Lt4) is possible3, 4. Recent publications suggest that once-weekly Lt4 does not increase the risk of cardiovascular events and is well tolerated by most of patients4. Once weekly Lt4 produces similar results as daily Lt4 as evidenced by thyroid function tests3,4, and potentially improves patient compliance and satisfaction with the treatment4.

Clinical Course: A 29-year-old female with a history of Hashimoto’s hypothyroidism, polycystic ovarian syndrome, depression, presented with irregular menses. Her symptoms included depression, fatigue, increased appetite. Her TSH was grossly elevated at 217 uIU/mL (0.27-4.20 uIU/mL). However upon re-visit, after increasing Lt4 to 100 mcg daily her TSH increased to 280 uIU/mL. She admitted to non-adherence with her daily Lt4 prescription. Physical exam was notable for sinus bradycardia and slow mentation, otherwise unremarkable. Blood count, basic metabolic panel and hemoglobin A1C were within normal limits. Liver function tests showed mild transaminitis, ALT 46 U/L (10-45 U/L). Lt4 was started at 875 mcg per week. At five weeks, her TSH was 6.31 uIU/mL and at seven weeks, the patient was euthyroid with a TSH of 2.53 uIU/mL. Her periods have since normalized.

Conclusion: The current discourse on weekly dosing mainly focuses on its use for non-adherent patients. This case provides a clear time course also demonstrating rapid normalization of TSH using weekly dosing. Weekly Lt4 dosing as first-line therapy in noncompliant depressed patients with severe hypothyroidism should be considered. 1.Hepp, Z., Wyne, K., Manthena, S., Wang, S. and Gossain, V. (2018). Adherence to thyroid hormone replacement therapy: a retrospective, claims database analysis. Current Medical Research and Opinion, 34(9), pp.1673-1678.2.Colucci, P., Yue, C., Ducharme, M. and Benvenga, S. (2010). A Review of the Pharmacokinetics of Levothyroxine for the Treatment of Hypothyroidism. European Endocrinology, 9(1), p.40.3.Jayakumari, C., Nair, A., Puthiyaveettil Khadar, J., Das, D., Prasad, N., Jessy, S., Gopi, A. and Guruprasad, P. (2019). Efficacy and Safety of Once-Weekly Thyroxine for Thyroxine-Resistant Hypothyroidism. Journal of the Endocrine Society, 3(12), pp.2184-2193.4.Rajput, R. and Pathak, V. (2017). The Effect of Daily versus Weekly Levothyroxine Replacement on Thyroid Function Test in Hypothyroid Patients at a Tertiary Care Centre in Haryana. European Thyroid Journal, 6(5), pp.250-254.
SUN-LB39 ATAC-Seq Reveals Dynamic Changes in Chromatin Accessibility Following PKA Activation in NCI-H295R Adrenocortical Cells
Authors: LaPensee Christopher Ryan , Mohan Dipika , Lerario Antonio Marcondes , Hammer Gary D
Published: May 2020

The adrenal cortex is comprised of distinct concentric zones that produce hormones essential for life - the outermost zona glomerulosa (zG) produces aldosterone, and the innermost zona fasciculata (zF) produces cortisol. Adrenal zonation is maintained by a balance between paracrine (Wnt/β-catenin) and endocrine (ACTH/PKA) signaling. Wnt/β-catenin signaling is maintained in the outer cortex (zG, upper zF) by a gradient of Wnt ligands that diminish centripetally, and PKA signaling is maintained in the inner cortex (zF) by ACTH. Recent studies in vivo suggest that sustained PKA signaling promotes zF proliferation, enabling lineage conversion towards zF by inhibiting Wnt/β-catenin transcriptional programming. While these studies were crucial in elucidating mechanisms supporting adrenal zonation, it remains unclear if PKA-mediated repression of Wnt/β-catenin is carried out at the chromatin level or if it is secondary to ligand-dependent modulation of paracrine signaling as may happen in vivo. To address this question, we utilized the adrenocortical cell line (NCI-H295R), which harbors a mutation in CTNNB1 rendering Wnt/β-catenin signaling constitutively active. We stimulated PKA in NCI-H295R using forskolin, and assessed genome-wide chromatin accessibility by ATAC-seq and transcriptome changes by RNA-seq. Motif analysis of ATAC-seq from baseline NCI-H295R revealed that chromatin accessibility is dominated by transcription factors SF1 (master regulator of the adrenal cortex and steroidogenesis), AP1 (effector of PKA) and LEF1 (effector of Wnt/β-catenin). Following forskolin administration, we observed decreased accessibility in chromatin containing LEF1 binding motifs, and increased accessibility in chromatin bearing AP1 and SF1 motifs, suggesting that PKA activation drives AP1/SF1-dependent transcription and inhibits Wnt/β-catenin-dependent transcription at the chromatin level. Indeed, RNA-seq revealed that forskolin administration decreased the expression of zG and Wnt/β-catenin target genes, while simultaneously increasing expression of AP1/SF1 target genes. Collectively, these data demonstrate that PKA activation leads to profound chromatin remodeling that enables zF identity even in the setting of constitutive Wnt/β-catenin signaling. Ongoing studies are aimed at elucidating how chromatin modifiers and transcriptional machinery coordinate the dynamic regulation of differentiation programs required for adrenocortical homeostasis and zonation.
SUN-LB35 Using Chromogranin A to Unmask the Great Masquerader: A Case Reportof a Minimally Symptomatic Pheochromocytoma
Authors: Goukassian Ilona , Randle Reese , McClain Donald A
Published: May 2020

Introduction/Background: Pheochromocytomas are rare neoplasms, occurring in less than 0.2% of the population. The classic triad of symptoms includes hypertension, headaches and sweating. An increasing number of patients with pheochromocytomas that are diagnosed at a pre-symptomatic stage.Clinical Case A 69 yo male being worked up for hematuria and possible bladder cancer was referred to endocrinology due to a 3 cm x 3 cm right adrenal “incidentaloma.” The mass was noted to be heterogeneously enhancing on CT adrenal protocol, suggesting pheochromocytoma, adrenal carcinoma or metastasis. He endorsed no clinical symptoms of hormone excess and blood pressure was controlled HCTZ. He was found to have elevated serum metanephrines (184 pg/mL, nl <57) and noremetanephrine (608 pg/dL, nl <148) and total metanephrines (792 pg/dL, nl <205). Other hormonal determinations were normal including cortisol (9AM, 8.97 ug/dL, nl 3-22), DHEAS 66 mcg/dL (25-240), estradiol 23 pg/mL (<39), 17 OHD 60 ng/dL, ACTH 37 (6-50), free testosterone 43.6, total testosterone 396, androstenedione 63 (20-220). Further testing revealed 24 hour urine metanephrine and catecholeamines; urinary metanehrine 2025, noremetanephrine 1729, total 2442 and epinephrine 48, norepinephrine 336 and dopamine 112 which were 2-3 times the upper limit of normal. Because the patient consumed significant amount of caffeine (10 cups of coffee and cola daily), these studies were repeated after caffeine washout. Repeat serum testing revealed metanephrine at the upper limit of normal (metanephrine 47, noremetanphrine 146, respectively). Chromogranin A levels were elevated before (626 units) and after PPI discontinuation, (539 units, nl 25-140). Given the biochemical results and size of mass, he was referred him surgical resection. He was treated pre-operatively with doxazosin and underwent an uncomplicated right adrenalectomy via posterior right retroperitoneoscopic. Pathology was consistent with pheochromocytoma without capsular invasion. Immunohistochemical stains were characteristic of pheochromocytoma, positive for synaptophysin, chromogranin, and S100 but negative for Cytokeratin AE1/AE3 and calretinin. Conclusion: We present the case of a patient with a clinically asymptomatic pheochromocytoma. The diagnosis was supported by elevations in chromogranin and catecholamine metabolites, although the latter results were mixed and clouded by potential confounding factors such as heavy caffeine intake. The case demonstrates that with early detection, screening should include patients with no symptoms and otherwise low risk of disease. Decisions on surgical resection should be based on clinical suspicion, symptoms, imaging, tumor size and biochemical findings given the aggressive nature of these tumors and their malignant potential.
SUN-LB124 Novel Elisa Assays Demonstrate Specificity of Islet and Intestinal Processing of Proglucagon
Authors: D’Alessio David A , Kumar Ajay , Kalra Bhanu , Mistry Shivani , Tong Jenny
Published: May 2020

Circulating proglucagon peptides (PGP) are produced in islet α-cells, enteroendocrine L-cells. Release of PGP is thought to be tissue specific, e.g. α-cells make glucagon and L-cells make GLP-1 through predominant actions of proconvertases 2 and 1/3 (PC2 and PC1/3). However, this dichotomous model has recently been challenged. To address the contribution of the gut and pancreas to plasma PGP we developed 4 novel sandwich ELISA assays and applied them in studies with PGP stimulation from the islet (IV arginine) and intestine (meal). Monoclonal antibodies were raised in mice with genetic ablation of proglucagon transcription. Clones were screened and selected for affinity and specificity, and assays for glucagon, GLP-1, glicentin and oxyntomodulin developed. Eight healthy humans received 5 g arginine intravenously after a 12 hour fast and had blood sampled for 15 minutes; an additional 10 consumed a liquid mixed nutrient meal and prandial blood was taken for 180 minutes. None of the assays registered signal in plasma from proglucagon null mice, and specificity, background and cross-reactivity were acceptable in each. In response to IV arginine plasma glucagon increased 4-fold, and GLP-1 1.5-fold, with significant increases in 15-minute AUC; there was no significant change in either glicentin or oxyntomodulin. In response to meal ingestion there was no change in circulating glucagon, but oxyntomodulin, GLP-1 and glicentin increased 2, 3, and 4-fold respectively. These findings are generally compatible with PC1/3 dominant processing of PGP in the gut, but raise the possibility that α-cells produce both PC2 (glucagon) and PC1/3 (GLP-1) products.
MON-LB010 Cyclic Progesterone Therapy for Androgenic Polycystic Ovary Syndrome (PCOS) - A Systematic Review of the Literature
Authors: Shirin Sonia , Goshtasebi Azita , Kalidasan Dharani , Prior Jerilynn C
Published: May 2020

Women living with androgenic PCOS (WLWP) experience unpredictable oligomenorrhea1 and are at increased risk for endometrial cancer2. Oral micronized progesterone (OMP) given cyclically (14 days/cycle or 4 weeks, Cyclic OMP), in luteal phase doses3 (300 mg at bedtime) as a “luteal phase replacement” therapy would be likely to effectively treat both. In addition, evidence suggests PCOS is causally related to rapid pulsing of GnRH and LH 4; OMP normalizes LH pulsatility if androgen levels are not elevated 4. Previous searches did not find progesterone therapy for PCOS 5. Our research question: Does the peer-reviewed literature provide evidence for prescribing cyclic progesterone therapy in PCOS? Literature search methods used Medline (Ovid) and PubMed for published articles. Our search terms were: “polycystic ovary syndrome”, “androgenic PCOS”, and, “micronized progesterone.” We sought publications with eligible women participants having androgenic PCOS, drug exposures (cyclic

OMP, vaginal progesterone, and in varying doses and durations) and specific outcomes (biochemical or patient-reported data or both) in all languages. We excluded reviews and practice guidelines but searched bibliographies for missed citations. Results discovered 18 articles in combined Medline (n=6) and PubMed (12) searches. After excluding duplicates, articles on estradiol (E2) alone E2 with OMP therapy, five eligible articles remained. We read all in full detail.

Progesterone therapy was beneficial for WLWP as, even in sub-therapeutic doses (<300 mg at bedtime) and in cycles of too short durations (<14 days), it decreased luteinizing hormone (LH) 6,7 and total testosterone 7 levels. Vaginal progesterone (200 mg, b.i.d for 2 to 12 weeks) added to letrozole ovulation induction increased the pregnancy rate from 0 to 21% 8. Although present data suggest Cyclic OMP withdrawal predictively causes flow, we found no evidence it improved women’s cycle-related experiences nor decreased acne and hirsutism. Women-reported data on Cyclic OMP for improving androgenic PCOS cycle regularity, daily experiences and risks for endometrial cancer are needed.

Reference: 1Azziz R Nat Rev Dis Primers 2016;2:16057. 2Barry J Hum Reprod Update 2014; 20:748. 3Simon J Fertil Steril 1993;60:26. 4Blank S Hum Reprod Update 2006;12:351. 5Teede H Clin Endocrinol (Oxf) 2018;89:251. 6Livadas S Fertil Steril 2010;94:242. 7Bagis T J Clin Endocr Met 2002;87:4536. 8Montville C Fertil Steril. 2010;94:678.
OR18-05 Thyroid Hormone Use and Survival among Older Adults - Longitudinal Analysis of the Baltimore Longitudinal Study of Aging (BLSA)
Authors: Abbey Enoch Joseph , Simonsick Eleanor M , McGready John , Mammen Jennifer Sophie
Published: May 2020

Abstract: Introduction: Thyrotropin (TSH) levels on average are higher and vary more widely among older adults.1 Large meta-analyses and treatment trials for isolated elevated TSH in older adults did not demonstrate harm from no treatment or benefit from treatment in this population.2 Isolated, elevated TSH can result from adaptations to aging, rather than primary thyroid disease, suggesting that thyroid hormone treatment could actually cause harm.3

Objective:To determine if there is a survival effect from thyroid hormone treatment in adults aged 65+.

Methodology:Thyroid functional status and thyroid hormone exposure were analyzed for 1,258 participants of the BLSA aged 65+ through death or end of follow up. We analyzed exposures by visit and also compared survival between individuals with consistently elevated, euthyroid or low TSH both on and off of therapy.Incident rate ratios (IRR) were calculated using time-dependent Poisson regression models. Covariates included age, sex, race, walking index (measure of physical function), self-rated health (SF-12), body mass index (BMI), smoking and comorbidity score.

Results: Average follow-up was 9 years, with 169 deaths over the study period. The cohort comprised 49.5% women, with average age in the study being 78 years (SD ±8.2). Thyroid hormone use trended towards harm analyzed at each visit with an IRR=1.40 (95% CI 0.93–2.12) after adjusting for other covariates. Among ‘treated-to-target’versus euthyroid individuals, thyroid hormone use was associated with a significantly increased mortality rate with an IRR=1.80 (95% CI 1.09–2.96) in multivariable analysis.

Conclusion: Thyroid hormone replacement among older adults,even when treated-to-target, is associated with a significantly increased mortality risk compared to euthyroid individuals with no history of thyroid hormone exposure. This suggests that treating isolated elevated TSH when changes are aging adaptations rather than primary thyroid disease could adversely affect health by altering key homeostatic adaptation. We recommend clinicians consider the underlying physiology of aging and employ age specific reference ranges when deciding on treatment for elevated TSH in older adults.4References 1. Surks et al., J Clin Endo. Met. 2007;92(12):4575–4582. 2. Stott et al., NEJM. 2017;376(26):2534–2544. 3. Mammen et al., Thyroid. 2017;27(11):1370–1377. 4. Surks et al., J Clin Endo. Met. 2010:95(2):496-502Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.
MON-296 Craniopharyngiomas Presenting as Incidentalomas: Results of Kraniopharyngeom 2007
Authors: Boekhoff Svenja , Bison Brigitte , Eveslage Maria , Sowithayasakul Panjarat , Muller Hermann Lothar
Published: May 2020

Objective: Childhood-onset craniopharyngiomas (CP) are diagnosed due to clinical symptoms (symCP) or incidentally (incCP). We investigated clinical manifestations and outcome in incCPs and symCPs.

Design and methods: IncCP were discovered in 4 (3m/1f) and symCP in 214 CP (101m/113f) recruited 2007–2014 in KRANIOPHARYNGEOM 2007. Age, sex, height, body mass index (BMI), tumor size, degree of resection, pre- and postsurgical hypothalamic involvement/lesions, pituitary function and outcome were compared between both subgroups.

Results: Reasons for imaging in incCP were cerebral palsy, head trauma, nasal obstruction, and tethered-cord syndrome, whereas headache (44%) visual impairment (25%), and growth retardation (17%) lead to imaging in symCP. Tumor size at diagnosis was smaller in incCP (median tumour size 3.26 cm2; range: 0.56–5.13 cm2) when compared with symCP (median tumour size 12.16 cm2; range: 0.004–79.54 cm2). Age, gender, BMI, height, hydrocephalus, tumor location, and hypothalamic involvement at diagnosis of incCP were within the range of these parameters in symCP. Complete resections were achieved more frequently (3/4 patients) in incCP when compared with symCP (20%). Surgical hypothalamic lesions were distributed similar in incCP and symCP. Irradiation was performed only in symCP (33%). No noticeable differences were observed concerning survival rates, endocrine deficiencies, BMI, height, functional capacity and quality of life of the 4 incCP cases when compared with the symCP cohort.

Conclusions: IncCP are rare (1.8%) and characterized by lack of endocrine deficiencies, resulting in normal height and BMI, no hydrocephalus, and smaller tumor size at diagnosis when compared with symCPs. Outcome of the observed incCP is similar with symCP.
SUN-904 Ga68 Dotatate Detects Ectopic ACTH Secreting Atypical Carcinoid Tumor
Authors: Simons Zachary Brent , Wangsiricharoen Sintawat , Gelwan Elise , Lilja Solnes Bjork , Santhanam Prasanna
Published: May 2020

Title Ga68 DOTATATE detects Ectopic ACTH secreting Atypical Carcinoid tumor Introduction Ga-68 DOTATATE PET/CT has been shown to have a significant impact in localizing Ectopic ACTH secreting tumors especially those that are not identified on conventional imaging (CT, MRI). We present a person with a tumor that was reported benign (on biopsy) elsewhere but was found to be the source of the Cushings syndrome and was localized on Ga-68 DOTATATE PET/CT, pathology confirming atypical carcinoid tumor after surgical excision. Discussion She was a 63-year-old who presented with a severe proximal myopathy, high urinary free cortisol- 911.6 (µg/day) (<45), elevated ACTH 104(<63), and negative Inferior Petrosal Sinus Sampling. The CT scan demonstrated a small nodule at the right lung base. Axial Ga-68 DOTATATE PET images demonstrated radiotracer activity in the lesion, SUV max of 7.15. Fused Coronal Images showed a 1.9 cm radiotracer avid nodule, that was detected in the medial segment of the right middle lobe. The patient underwent a pulmonary wedge resection. H and E stain of the tumor -Immunohistochemical stains demonstrated that the tumor was strongly positive for synaptophysin and INSM-1 (markers of neuroendocrine differentiation) and the mitotic count was up to 2–3 mitoses per 10 high-power fields, supporting diagnosis as an atypical carcinoid tumor. The patient had significant improvement of symptoms post excision. Somatostatin Receptor (SSR) based tracer Ga-68 DOTATATE PET/CT has a reported sensitivity for detection of 50 % in occult neuroendocrine tumors (NET), with an overall sensitivity of 64 % in a systematic review. It has been shown in retrospective reviews to help with clinical management both at initial diagnosis as well as follow up of Ectopic Cushings in approximately 65% of the cases. SSR analogue tracers like DOTATATE have been noted to be slightly better than FDG PET/CT at localizing ACTH producing bronchial carcinoids while small-cell lung cancers and other aggressive tumors are better visualized on FDG PET. The favorable aspect of Ga-68 DOTATATE includes great tumor to background ratio and the half-life of Gallium 68 that is suitable for transport and delivery. Metastatic NET in conjunction with ectopic Cushing syndrome can be also be treated with peptide receptor radionuclide therapy using either 90Y-DOTATOC and 177Lu-DOTATATE (both SSR based) resulting in improved clinical outcomes.
MON-291 Postoperative Quality of Life in Children and Adolescents with Craniopharyngioma - Results of the Prospective Multicenter Trial Kraniopharyngeom 2007
Authors: Eveslage Maria , Calaminus Gabriele , Warmuth-Metz Monika , Kortmann Rolf-Dieter , Pohl Fabian , Timmermann Beate , Schuhmann Martin U , Flitsch Joerg , Faldum Andreas , Muller Hermann Lothar
Published: May 2020

Background: Craniopharyngioma is an embryonic tumor of low-grade malignancy. Children and adolescents with this diagnosis are analyzed concerning quality of life (QoL) and (progression-free) survival within the project KRANIOPHARYNGEOM 2007.

Methods: The prospective, multi-center project consists of a randomized, unblinded substudy with adaptive design and an observational study. The randomized substudy for incompletely resected patients compares direct postsurgical radiation with radiation at progression. Endpoint is self-assessment of QoL measured by PEDQOL. In explorative analyses, the influence of additional factors was analyzed using linear mixed models.

Results: In the interim analysis of the randomized substudy according to the intention-to-treat approach only marginal differences concerning QoL between the two treatment groups were observed (n=24). The explorative analyses (n=131) show that ant-/ and posterior preoperative hypothalamic involvement and postoperative hypothalamic lesions are associated with decreased QoL. After complete resection, the QoL is lower than with incomplete resection. Radiation, which is often performed due to progression after incomplete resection, is associated with reduced quality of life.

Conclusion: In order to achieve best QoL for children and adolescents with craniopharyngioma, hypothalamus-sparing therapeutic approaches are recommended. Based on the current data, it is not possible to recommend the optimal time for radiotherapy after incomplete resection with regard to QoL.
SAT-362 A Bone to Pick with FGF23
Authors: Soliman Peter , Kamel Dina , Lopresti Jonathan S
Published: May 2020

A 48 yo M with a past medical history of bilateral femoral neck stress fractures at age 44 status post closed reduction percutaneous pinning (CRPP) presented to the emergency room with bilateral lower extremity pain after a ground level fall. Plain films were notable for a right intertrochanteric fracture and left hip nonunion. The patient underwent removal of right CRPP hardware and revision fixation with a short TFN-Advanced Femoral Nailing System (TFNA) and fixation of the left femoral neck nonunion. Given his injuries following a ground level fall, endocrinology was consulted for recommendations. Labs during his hospital course were notable for hypophosphatemia as well as normal levels of alkaline phosphatase, serum calcium, and PTH. Serum protein electrophoresis and urine protein electrophoresis were within normal limits. A 24-hour urine calcium and phosphorous were done and the patient was found to have a low calculated renal phosphate threshold (TmP04/GFR), concerning for hypophosphatemic osteomalacia. An FGF23 level was drawn and was elevated, suggestive of an FGF23-induced hypophosphatemic osteomalacia. A low vitamin D 1,25-OH was also found consistent with this process, given interference of alpha-hydroxylation of vitamin D 25-OH from FGF23. The patient therefore underwent a PET scan to rule out a mesenchymal tumor-induced osteomalacia but his PET scan was largely unremarkable. Given that there were no issues with bone development or fractures during childhood, the suspicion for X-linked hypophosphatemia or autosomal recessive hypophosphatemia was low. The patient was believed to have either a small mesenchymal tumor not seen on PET scan or an autosomal dominant hypophosphatemia, which can manifest clinically during adulthood, and so was treated with daily Calcitriol and phosphate with subsequent correction of his serum phosphorous. Such a delayed presentation of hereditary hypophosphatemic osteomalacia, however, has been reported only in women either soon after puberty, during pregnancy, or after delivery (1). This case thus represents a possible autosomal dominant hypophosphatemia in a male patient or a rare case of tumor-induced hypophosphatemic osteomalacia.

Reference: (1) Drezner MK, Whyte MP. Heritable renal phosphate wasting disorders. Genetics of bone biology and skeletal disease, 2nd ed. 2018; 761–782.
SUN-503 Thyroid Storm Followed by ATD Induced Agranulocytosis in Late Pregnancy: A Management Dilemma
Authors: Aljehani Faisal , Mushref Malek , Sora Nicoleta Dorinela , Javid Mahsa , Karanchi Harsha
Published: May 2020

Background:

Management of Graves’ disease (GD) in pregnancy presents challenges. Thionamide Antithyroid drugs are the treatment for GD hyperthyroidism with goal of achieving mild but persistent hyperthyroidism and avoiding over-treatment in pregnancy. ATD Induced Agranulocytosis is a rare but serous side effect and presents management dilemmas.

Clinical Case:

A 37-year-old woman with history of Graves’ disease was admitted to our hospital at gestational age of 34 weeks with fever, palpitations and diarrhea. Burch-Wartofsky Point Scale was 35 concerning for impending thyroid storm. She had been diagnosed with hyperthyroidism 6 weeks into her pregnancy, initially treated with PTU which was then changed to methimazole in 2nd trimester. A work up for infection and PE was negative. Non-compliance was suspected, methimazole was resumed, and hydrocortisone and propranolol were added. After 2 days, her vital signs and free hormone levels normalized. Her methimazole dose was decreased and she was discharged home in a stable condition.

Five days after her discharge, she presented with sore throat, fever and chills. She had an absolute neutrophil count (ANC) of 0 and a positive rapid strep test. ATD Induced Agranulocytosis was suspected. Her labs showed elevated fT3 of 4.5(nl 1.7–3.7), normal fT4 and suppressed TSH with <0.01(nl 0.3–4.9). A CT scan of the neck showed no evidence of retropharyngeal or thyroid abscess. Methimazole was stopped and she was started on glucocorticoids (initially betamethasone for fetal lung maturity, then switched to prednisone) and cholestyramine. She was also started on Cefepime and G-CSF for her neutropenia. A thyroid ultrasound showed enlarged and hypervascular gland. TSI was 157%(nl. <122%), and thyroglobulin 155 ng/ml (nl. <33 ng/ml). After 4 days, her ANC started to recover. Simultaneously, she started to show worsening thyrotoxicosis but remined hemodynamically stable. A decision to induce labor was then made and was successfully done on the 6th day of her admission. Post-delivery, PTU was started at low dose along with SSKI to prepare her for total thyroidectomy which was done on day 3 post-delivery. Post-thyroidectomy, she had an uncomplicated course and was discharged on levothyroxine. Her child did well with no evidence of thyroid disease.

Conclusion:

We present a unique case of thyrotoxicosis in late pregnancy complicated by ATD Induced Agranulocytosis. Given the high risk of thyroid surgery during pregnancy, our multi-disciplinary team approach opted for labor induction, followed by preparation for thyroidectomy and subsequent surgery. Individualization of management approach using a multi-disciplinary team with emphasis on maternal and fetal well-being is of paramount importance with such challenging presentations.
SAT-078 Griscelli Syndrome and Late Endocrine Effects After Stem Cell Transplant
Authors: Mencher Shana , Patel Anisha D , Tamborlane William V
Published: May 2020

BACKGROUND: This a unique case of late-onset endocrinopathies after stem cell transplant in a girl with Griscelli syndrome. Griscelli syndrome is a rare disorder characterized by partial albinism, silver hair and immune failure with alteration in genes necessary for melanin transport, which is curative by stem cell transplant. Although late endocrinopathies are quite common in other disorders after stem cell transplant, these complications have not been reported in Griscelli syndrome.

CLINICAL CASE: A 7-year old female who received a stem cell transplant as a toddler and subsequently developed graft-versus-host-disease (GvHD) at 2 years of age presented for evaluation of growth failure. Patient had severe short stature along with mild hyperthyroxinemia with subsequent diagnosis of Graves’ disease which was treated with methimazole. Although hypothyroidism is more commonly seen after stem cell transplant, rare cases of hyperthyroidism have been reported. Despite normal GH and IGF-1 levels, GH therapy was commenced due to persistent growth failure. She showed a robust increase in growth parameter from -6 to -2 SD below the mean. She started spontaneous puberty, however, biochemical evaluation showed hypergonadotropic hypogonadism with undetectable anti-mullerian hormone (AMH) which is consistent with low ovarian reserve most likely related to total body irradiation prior to stem cell transplant.

CONCLUSION: Our patient demonstrates that growth failure, thyroid disease and ovarian dysfunction can be complications of stem cell transplants in young children with Griscelli syndrome. This can be a result of the underlying disease leading to transplant, conditioning regimen prior to transplant or complications thereafter. GvHD may also be a risk factor for future autoimmune endocrine complications in this syndrome and in other syndromes treated with stem cell transplant.

REFERENCES: (1) Griscelli C, Prunieras M. Pigment dilution and immunodeficiency: a new syndrome. Int J Dermatol. 1978;10:788–91.

(2) Sağ E, Gönç N, Alikaşifoğlu A, et al. Hyperthyroidism after allogeneic hematopoietic stem cell transplantation: A Report of Four Cases. J Clin Res Pediatr Endocrinol. 2015;4:349–54.
SUN-921 Indolent Presentation of Medullary Thyroid Cancer in a Patient with MEN Type 2B Due to a Germline RET M918T Mutationo
Authors: Kim Stephanie , Hsiao Victoria C , Seib Carolyn , Gosnell Jessica Erin , Liu Chienying
Published: May 2020

Background: MEN type 2B is rare and most commonly due to a germline methionine-to-threonine substitution at codon 918 (M918T) of the RET proto-oncogene. Medullary thyroid cancer (MTC) occurs in 100% of the patients affected with the mutation. This mutation is considered the highest risk and is typically associated with aggressive disease and worse overall survival. We describe a case of a late diagnosis of MEN 2B in a patient and his son, both with a relatively indolent presentation of MTC. Clinical Case: A 39-year-old man presented to an outside institution with difficult to control hypertension, headaches and anxiety and was found to have bilateral pheochromocytomas (left, 5.8 x 5.5 x 3.8 cm and right, 9 x 5.2 x 7.3 cm). Upon presentation to our institution, he was noted to have classic phenotypic features of MEN 2B with a marfanoid habitus and multiple mucosal neuromas. Genetic testing confirmed RET M918T mutation. His family history was negative for similar features in his parents and siblings. However, one of his three children, age 12, had similar phenotypic features and was found to have the same mutation. The patient subsequently underwent a successful bilateral adrenalectomy and pathology confirmed pheochromocytomas. Thyroid ultrasound showed multiple nodules with calcifications but no lateral nodal metastases. Calcitonin and carcinoembryonic antigen (CEA) levels were elevated (170 pg/mL, normal ≤10, and 180.4 ug/L, normal <3.8, respectively). He underwent a total thyroidectomy and bilateral central node dissection, with pathology confirming bilateral MTC (2.7 cm and 1.0 cm), metastatic in 4 of 10 positive lymph nodes (largest focus 2 mm). Whole body PET/CT post-operatively did not show metastatic disease. The patient’s son also had multiple thyroid nodules on ultrasound without lateral nodal metastases and elevated calcitonin and CEA levels (3015 pg/ml, normal ≤10, and 433 ng/mL, normal <2.5, respectively). MRI of the abdomen and pelvis was negative for pheochromocytomas. He underwent total thyroidectomy and bilateral central neck dissection, with pathology showing bilateral MTC (2.7 cm and 1.0 cm) with 0 of 14 positive lymph nodes. For both the patient and his son, calcitonin and CEA levels normalized following thyroidectomy and surveillance over a year later reveals no evidence of disease. Conclusion: Early diagnosis of MEN type 2B is important as MTC develops early in life and is the leading cause of death in these patients. When diagnosed early, prophylactic thyroidectomy in childhood is indicated and can improve long-term survival. There are salient phenotypic features associated with this disease which were unfortunately not recognized early in this patient and his son. Fortunately, their MTC presentations appear to be relatively indolent despite their late diagnoses, and they will continue to be closely monitored for recurrent disease.