bluuebunny/crossref_metadata_2025_split huggingface dataset:
OR19-07 Metformin Inhibits Activation of the Melanocortin Receptor 2 and 3 in Vitro, a Possible Mechanism for Its Anti-Androgenic and Weight Balancing Effects in Vivo
Authors: Flueck Christa E , Parween Shaheena 
Published: May 2020

Abstract
Metformin is recommended as one of the first-line drugs for the treatment of type 2 diabetes and the metabolic syndrome. In addition to its insulin sensitizing effects, it has been shown to attenuate androgen excess in women with polycystic ovary syndrome (PCOS) or congenital adrenal hyperplasia (CAH), as well as to ameliorate obesity. The mechanisms of metformin action seem manifold. Preclinical studies suggest that it inhibits the cellular stress response at the level of the mitochondrial OXPHOS system and through AMPK dependent and independent mechanisms. Recent studies have shown that metformin decreases ACTH secretion from pituitary and reduces ACTH-stimulated adrenal secretion. In this study we investigated the effect of metformin through its specific melanocortin receptor 2 (MC2R) on signaling targeting adrenal steroidogenesis. To assess this effect, we used mouse adrenal OS3 cells, which do not express the MC2R. Cells were transfected with the human melanocortin receptor 2 and stimulated by ACTH. Downstream cyclic AMP production was then assessed by a co-transfected cAMP-responsive vector producing luciferase that was measured by a dual luciferase assay. The amount of luciferase produced in this assay corresponds to the amount of receptor activation with varying amount of ACTH. The effect of metformin was then tested in this system. We found a significant inhibition of ACTH induced MC2R activation and signaling with 10 mM metformin. The ACTH concentration response curve (CRC) was half-log shifted indicating antagonism. This effect was dose dependent with an IC50 of 4.2 mM. Metformin did not affect cell viability and basal cAMP level under used conditions. We also tested the effect of metformin on homologous receptors (MCRs). No significant effect was found on MC1R and MC4R activity. However, a 2-log shift in ACTH EC50 was observed with MC3R. In conclusion, metformin seems to act on MC2R and MC3R signaling directly. The role of MC2R for steroidogenesis is well established. MC3R is involved in energy balance and seems to act as a rheostat when the metabolism is challenged. Our study may explain how metformin attenuates the excess response to ACTH and helps in weight loss and improving androgen excess in PCOS and CAH.
MON-473 Evaluating Conflicting Thyroid Function Tests in New Admissions: Discordance of TSH, FreeT4 and Clinical Status: A Clinical Challenge!
Authors: Patel Sabah , Krutilova Petra , Gilden Janice L , Barsano Charles P 
Published: May 2020

Abstract
Background: It is not uncommon to encounter patients whose thyroid function tests (TFTs) seem mutually inconsistent or inconsistent with a patient’s clinical status, At times, the simplest reconciliation of the findings invokes a rare disorder that we are hesitant to accept. In this case, a clinically euthyroid patient presents with elevated TSH and Free T4 (FT4) suggestive of a TSH-producing tumor or of Thyroid Hormone Resistance.
Clinical Case: A 72 yr-old man with cardiomyopathy on amiodarone is admitted to the Medical Service for treatment of anasarca. He had no symptoms or signs of thyroid dysfunction and was not taking L-T4, amphetamines or propranolol. Findings on exam included normal VS, runs of atrial tachycardia, and edema from feet to scrotum. Thyroid exam was normal. Serum creatinine was 2.24 mg/dl (NL: 0.67-1.17). Bili was 2.7 mg/dl (NL: 0.67-1.17); AST and ALT were normal, Chest x-ray revealed cardiomegaly with clear lung fields. Thyroid ultrasound revealed a normal size gland containing a few sub-centimetric nodules. On Day 2 The serum FT4, by analog assay, was elevated at 1.66 ng/dl (NL: 0.76-1.46) and TSH was elevated at 9.06 mIU/L (NL: 0.35-3.74), Anti-peroxidase and anti-thyroglobulin antibodies were negative. The Medical Service’ diagnosis was “amiodarone-induced thyroiditis.” The amiodarone was discontinued and diuresis was induced with bumetanide, Endocrinology consultation was requested On Day 4 the FT4 and TSH were still elevated at 1.62 and 10.1, respectively. FT4 by dialysis was not elevated at 1.62 ng/dl (NL: 0.9-2.2). The FT3 was 2.34 pg/ml (NL: 2.18-3.98). On Day 5 Anti-thyroxine antibodies and Thyroid Stimulating Immunoglobulins (TSI) were negative. Paired TSH samples with and without neutralization of Human Anti-Mouse Antibodies (HAMA) were identical: both elevated at 8.30 mIU/L (NL: 0.4-4.50). Serum Iodine was markedly elevated at 2288 mcg/L (NL: 52-109).
The FT4 levels by analog assay therefore appear to have been falsely elevated (as indicated by the dialysis assay) though not by recognized factors such as thyroxine antibodies, amphetamines or propranolol. Continued observation is necessary to further assess the transience of the post-admission TFTs.
Conclusion: In patients admitted to Acute Medical or Psychiatric Services, most combinations of high or low TSH and FT4 have been reported as well other aberrations of “non-thyroidal illnesses.” In patients with conflicting TFTs at admission, especially those who are clinically euthyroid, it is generally better to allocate a few weeks for observation and monitoring than to immediately launch into searches for rare disorders. This is especially important when multiple potentially thyro-active clinical states exist, such as renal and hepatic compromise, amiodarone use, and highly elevated iodine levels.
SUN-482 A Very Rare Case of Thyroid Cancer
Authors: Lokshin Vladimir , Soni Lina , Luis Milay , Hope Lisel 
Published: May 2020

Abstract
Background: Cribriform-Morular variant of Papillary Thyroid Cancer (PTC-CMV) is an exceedingly rare subtype of thyroid cancer that predominantly affects younger females. As the name implies, it is a papillary thyroid carcinoma with predominantly cribriform and morular pattern of carcinoma cells on cytopathology. While completion thyroidectomy is usually recommended for larger and higher-risk Papillary Thyroid Cancer (PTC), surveillance may be acceptable with PTC-CMV, which tends to be a less aggressive malignancy. Clinical Case: A 46-year-old Guyanese woman presented with a three week history of an enlarging right-sided neck mass associated with a globus sensation while swallowing food. She denied any history of radiation exposure. Her exam findings were positive for a tender, right-sided neck mass. CT neck without contrast revealed a 4.1 x 4.0 x 5.9cm heterogeneous mass within the right thyroid lobe causing mild tracheal deviation to the left. Ultrasound of thyroid gland showed a solid heterogeneous hypoechoic 4.22 x 2.39 x 2.46cm right lobe nodule with no microcalcifications, border irregularity or taller-than-wider morphology. Fine Needle Aspiration of the nodule came back as Atypia of Undetermined Significance. The patient then underwent a core needle biopsy. The resultant pathology was negative for thyroid carcinoma or medullary thyroid carcinoma but was suggestive of a bronchial cleft cyst versus bronchogenic cyst with atypical glandular proliferation. She subsequently underwent a right hemithyroidectomy which revealed a final pathological diagnosis of a 3.5cm PTC-CMV. Such pathology warranted the patient to undergo a colonoscopy which was negative for Familial Adenomatous Polyposis (FAP). Given her negative GI workup and non-contributory family history for colonic polyposis or carcinoma the decision was made to continue surveillance rather than performing completion thyroidectomy as the disease was presumed to be sporadic. Discussion: PTC-CMV accounts for 0.2% of all PTC. It is associated with FAP in more than 50% of cases but can also occur sporadically. This subtype of PTC generally follows a less aggressive course. Review of current literature revealed several case series of CMV-PTC patients. In the largest one, 32 cases were observed over a 19 year period and only two out of twelve patients with FAP-associated PTC-CMV initially treated with hemithyroidectomy developed recurrence to the contralateral lobe. Interestingly, none of the remaining patients with the sporadic type developed recurrence suggesting that completion thyroidectomy may not be mandatory in this group. It is, therefore, critical to identify these patients and screen them with a colonoscopy to avoid the potentially unnecessary resection of the contralateral lobe and the consequent need for thyroid hormone replacement.
SUN-032 Digenic Inheritance of PCSK1 and CHD7 Mutations in PAX4 Homozygous Diabetic Male with Normosmic Hypogonadotropic Hypogonadism
Authors: Cho Yun Kyung , Kim Sang-Wook 
Published: May 2020

Abstract
Background: Normosmic congenital hypogonadotropic hypogonadism denotes Kallmann syndrome not associated with anosmia or hyposmia. Over the past few years, the availability of next-generation sequencing has started to unravel the complex molecular basis of congenital hypogonadotrophic hypogonadism including digenic or oligogenic pathogenecity in addition to classic monogenic causality (1).
Clinical Case: A 22-year-old male patient was referred to the endocrine clinic in 2018 with recent -onset hyperglycemia. His weight was 82.2 kg with a height of 180 cm (BMI of 25.3 kg/m2). Physical examination revealed small testes, micropenis, and no axillary and pubic terminal hair. His smell sense was intact. His hormonal test reveals low testosterone (0.10 ng/mL) and low free testosterone (0.65 pg/mL) levels with inappropriately low gonadotrophins levels. Secretion of LH and FSH increased 2-fold after GnRH stimulation. His bone age was 13-years 6-months old, and brain magnetic resonance imaging showed the presence of olfactory bulbs, and unremarkable findings except for small size of the pituitary gland. There were no signs associated with CHARGE syndrome (coloboma ocular, heart defects, atresia or stenosis of the choanae, retardation of growth and/or development, genitourinary anomalies, and ear abnormalities). Biochemical investigation demonstrated high serum glucose level and high HbA1c (13.8%). To identify variants to cause the phenotype of the proband, we adopted trio-based whole exome sequencing (WES) and candidate gene approach. Candidate genes was listed from the orphanet (https://www.orpha.net). WES of the proband revealed the presence of heterozygote missense mutations of the CHD7 gene (c.6107C&gt;T, p.Pro2036Leu, rs369543203) and PCSK1 gene (c.239G&gt;A, p.Arg80Gln, rs1799904). The missense variants were predicted to have a damaging effect on the encoded protein, by SIFT and PolyPhen-2 analyses. Genetic analyses of his family revealed that his father had the same heterozygote missense mutations of the CHD7 gene, but wild type of PCSK1. Proband’s mother had the same heterozygote missense mutations of PCSK1, but wild type of CHD7. Furthermore, the proband had homozygote missense mutation of PAX4 (c.575G&gt;A, p.Arg192His, rs2233580) known as maturity-onset diabetes of the young (MODY) 9 gene. Both parents have the same but heterozygous mutation of PAX4 p.Arg192His, and pre-diabetic range of hyperglycemia.
Conclusion: This is the first case demonstrating digenic inheritance of mutations in PCSK1 and CHD7 as a potential cause of normosmic hypogonadotrophic hypogonadism, interestingly in PAX4 homozygous diabetic male.
Reference: (1) Maione L, et al. Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing. Eur J Endocrinol. 2018;178(3):R55-R80.
SUN-744 Phosphorylation Site S122 in Estrogen Receptor α Has a Tissue-Dependent Role in Female Mice
Authors: Gustafsson Karin L , Farman Helen H , Henning Petra , Lionikaite Vikte , Movérare-Skrtic Sofia , Sjogren Klara , Andersson Annica , Islander Ulrika , Bernardi Angelina I , Chambon Pierre , Ohlsson Claes , Lagerquist Marie K 
Published: May 2020

Abstract
Estrogen treatment increases bone mass and reduces fat mass but is associated with adverse effects in postmenopausal women. Knowledge regarding tissue-specific estrogen signaling is important to aid the development of new tissue-specific treatments. We hypothesized that the posttranslational modification phosphorylation in estrogen receptor alpha (ERα) may modulate ERα transcriptional activity in a tissue-dependent manner. Phosphorylation of site S122 in ERα has been shown in vitro to affect ERα activity, but the tissue-specific role in vivo is unknown. We herein developed and phenotyped a novel mouse model with a point mutation at the phosphorylation site 122 in ERα (S122A). Female S122A mice had increased fat mass and serum insulin levels but unchanged serum sex steroid levels, uterus weight, bone mass, thymus weight, and lymphocyte maturation compared to WT mice. In conclusion, phosphorylation of ERα S122 has a tissue-dependent role with an impact specifically on fat mass in female mice. This study is the first to demonstrate in vivo that phosphorylation of a transactivation domain in a nuclear steroid receptor modulates its activity in a tissue-dependent manner.
SAT-661 The Lesser Evil: Pembrolizumab Induced Remission of Metastatic Melanoma with Autoimmune Diabetes, Hypothyroidism, and Colitis
Authors: Harris Asaf , Andres Kayla , Kawji Mohammad 
Published: May 2020

Abstract
Background: Immune checkpoint inhibitors (ICI) are a new class of immunotherapy agents that empower the innate immune system to destroy cancer cells by overcoming checkpoints against autoimmunity and self-tolerance. ICI use against certain cancers has yielded impressive results. Pembrolizumab, an ICI approved by the FDA in 2014 for treatment of metastatic melanoma, is a monoclonal antibody which binds the programmed cell death protein 1 (PD1) receptor, blocking it’s activation. Recent case reports have demonstrated a link between pembrolizumab and severe immunotherapy related adverse events including the incidence of autoimmune disorders.
Clinical Case: A 68-year-old male with hypertension and a past medical history of cutaneous melanoma treated fifteen years earlier with tumor resection was started on pembrolizumab after identification of new metastases to the lung and bones. After 3 cycles of therapy he began to experience dizziness, lightheadedness, and vision changes with diarrhea. Outpatient labs demonstrated hyperkalemia with hyponatremia. He was directed to the emergency department by his oncologist for presumed adrenal insufficiency, where he received one dose of IV dexamethasone (4 mg). Repeat labs demonstrated severe diabetic ketoacidosis with elevated blood glucose 981 (70-99 mg/dL), pH 7.19 (7.32-7.42), anion gap of 37 (4-15 mmol/L), and betahydroxybutyrate &gt; 9.00 (0.00-0.40 mmol/L). Following endocrinology consultation steroids were discontinued in favor of iv insulin and fluid resuscitation, with admission to the medical intensive care unit. Further lab testing demonstrated low C-peptide levels and positive IA-2 and GAD-65 antibodies, confirming autoimmune diabetes. Endoscopic biopsy was also consistent with autoimmune colitis, and TSH one month after discharge was 123.70 (0.30-5.00 mcIU/mL) with free T4 &lt; 0.1 (0.6-1.6 ng/dL).
Despite early discontinuation of anti-PD1 therapy the melanoma has remained in remission for three years, suggesting a sustained immune response. He continues to require insulin and thyroid hormone replacement, though the autoimmune colitis has resolved.
Conclusion: This case demonstrates the overall benefit of immune checkpoint inhibitor therapy in the treatment of metastatic melanoma, while highlighting a potentially lethal therapy complication with the concurrent onset of multiple autoimmune processes affecting separate organ systems. Increased awareness of the potential for DKA in patients not previously diagnosed with diabetes is needed to avoid delays in care and improve outcomes. This case also suggests a potential benefit to integrating routine blood glucose monitoring in immune checkpoint inhibitor treatment protocols, the utility of which should be further investigated.
MON-302 The Prevalence of Acromegaly in the Sleep Apnoea Clinic
Authors: Lynch Julie Marie , Kyriakakis Nikolaos , Elliott Mark , Baldwin Lisa , James Anneli , Seejore Khyatisha , Ghosh Dipansu , Watts Sue , Sathyapalan Thozhukat , Murray Robert Douglas 
Published: May 2020

Abstract
Introduction: The prevalence of acromegaly in the general population ranges 4-14/100,000. 45-80% of acromegaly patients have obstructive sleep apnoea (OSA). The OSA population might represent a target group for earlier detection of acromegaly, thereby reducing associated long-term morbidity.
Methods: Patients attending the sleep service (11/2014-04/2018) were recruited in a prospective multicentre cohort study. All had serum IGF-1 measurement and completed a screening questionnaire for five key symptoms associated with acromegaly. Those with raised age-specific IGF-1 underwent further biochemical assessment to investigate for acromegaly.
Results: 1080 participants (73% male, mean age 55.6±12.0yrs) with confirmed OSA were recruited across two sites. Forty-three patients (4%) reported at least 4/5 acromegaly-related symptoms. There was no correlation between serum IGF-1 and symptom score. Sixty-one patients (5.7%) had elevated IGF-1 level on initial assessment. Fifty-one had repeat IGF-1 testing, while one had growth hormone measurement of &lt;1µg/L. Nine patients were lost to follow-up, including one death.
Of the repeat IGF-1 tests, results were normal in 24 cases and no further investigation was undertaken. Repeat IGF-1 results were unavailable in 3 cases. In the remaining 24 patients with persistently raised IGF-1, 11 had GH &lt;1µg/L, suggesting that acromegaly was unlikely. The remainder (n=13), as well as the 3 individuals with unavailable IGF-1 results, had an oral glucose tolerance test. One patient (BMI of 23.7kg/m2) was diagnosed with acromegaly, was diagnosed with severe OSA and reported 4/5 acromegaly-related symptoms during screening.
Conclusion: Our study identified a single case of acromegaly within the OSA population that may represent a higher prevalence than in the background population, however is based on a single case. As a consequence of the significant number of patients with elevated serum IGF-1 measurements requiring further investigation, IGF-I is not currently a cost-effective screening tool for early detection of acromegaly in OSA patients.
Funding: Ipsen UK
SAT-377 Case Series of Ectopic Parathyroid Gland
Authors: Rajoo Subashini , Kuan Yueh Chien , Tong Chin Voon 
Published: May 2020

Abstract
The prevalence of mediastinal parathyroid adenoma is unknown. Embryological origin and more extensive aberrant migration of the parathyroid glands result in ectopic glands found in the mediastinum. We report herein 4 cases of ectopic parathyroid adenoma causing primary hyperparathyroidism from three public hospitals in MalaysiaCase 1.A 70 year old lady with underlying diabetes mellitus, hypertension, chronic immune thrombocytopenic purpura and liver cirrhosis presented with incidental asymptomatic hypercalcemia during an admission for pneumonia. Her blood results revealed high corrected calcium of 2.93 mmol/L (2.02-2.60) and a low phosphate of 0.66 (0.81-1.45) mmol/L with an unsuppressed intact parathyroid hormone (iPTH) of 14.56 pmol/L (1.6-6.9). She had an equivocal urinary calcium excretion ratio of 0.01. Her bone mineral density confirmed severe osteoporosis at distal radius and neck of femur with a Tscore of -3.6 and -3.1 respectively. A hyperfunctioning ectopic parathyroid gland was seen in the Technetium Sestamibi scan which corelates with a mediastinal lymphadenopathy on CECT. The largest node measured 1.6 x 1.2 cm. Parathyroid gland was confirmed on HPE of the video-assisted-thoracoscopic surgical (VATS) excision of the mediastinal mass. Intraoperative iPTH (ioPTH) serially reduced from 8.87 to 1.94 to 1.03 pmol/L and she maintained a serum calcium levels of 2.4 mmol/L post surgery. She did not require any calcium or vitamin D supplementation. Case 2. A 36 year old male presented with generalized body weakness secondary to hypokalemia. His calcium was 3.07 mmol/l, phosphate 0.64 mmol/l and iPTH 11.53 pmol/L. Increase Technetium uptake seen at mediastinum. Post operatively, calcium normalized and remained stable 1 year later. Case 3.47 year old female presented with acute gallstone pancreatitis complicated with a pancreatic pseudocyst. She was found to have hypercalcemia of 2.77 mmol/L, phosphate 0.70 mmol/l and iPTH 21.87 pmol/L. Sestamibi scan revealed hyperfunctiong parathyroid tissue posterior to the left thyroid lobe and in the mediastinum. She is awaiting surgery. Case 4.Another asymptomatic 47 year old male who has history of post Radioactive-iodine hypothyroidism had an incidental finding of serum calcium of 2.69-2.84 mmol/L, phosphate 0.71-0.91 mmol/L and iPTH 9.89 pmol/L with urinary calcium excretion ratio of 0.019. His Sestamibi scan showed uptake at the superior mediastinum. Ectopic parathyroid gland is rarely encountered. With the advent of Technetium-Sestamibi scintigraphy, ectopic parathyroid adenoma can be localized easily. However, surgery poses a challenge due the location of the adenoma which may occasionally be near large vascular structures in the mediastinum. The availability of intraoperative PTH aids the decision for surgical exploration and completion.