bluuebunny/crossref_metadata_2025 huggingface dataset:
SUN-LB12 Prenatal Trenbolone Exposure and External Genital Malformation: A Case Report
Authors: Chilukoti Padmaja , Farrell Ryan , Desai Riddhi , Omil-Lima Danly O , Hannick Jessica H , Gubitosi-Klug Rose Anne
Published: May 2020

Background Trenbolone is a synthetic anabolic steroid used for muscle growth in livestock. Human use is not FDA approved. The active metabolite, 17β trenbolone is 3 times more potent an androgen than testosterone propionate. Prenatal trenbolone exposure in rats results in female offspring with external genital malformations including an increased anogenital distance (AGD). We now report a case of prenatal trenbolone exposure in humans. Clinical Case A 10 hour old baby delivered vaginally at 37 6/7 weeks of gestation with a birth weight of 3615 grams was admitted to the NICU for concern of ambiguous genitalia. Baby was born to 30 year old G6P3 mother who was HIV positive and adequately treated with Triumeq. She had irregular cycles prior to conception and pregnancy recognized at 14 weeks. Unlike her previous pregnancies, during this pregnancy she had acne and mildly increased facial hair. Prenatal cell-free DNA screening was 46XX and ultrasound showed female genitalia. The 9 year old half-sister and 5 year old brother are healthy. No family history of early neonatal deaths. On arrival blood glucose was 55 mg/dL (45-90). On exam baby had no obvious facial dysmorphic features or midline defects. Hand creases were normal and no extremity edema was noted. Genitalia appeared symmetrical and, showed prominent soft tissue of clitoris without corpus enlargement. No gonads were palpable in the groin or labioscrotal folds. Significant posterior labioscrotal fusion was noted. Anogenital ratio was 0.8 (normal <0.5). A single orifice at the base of the clitoral hood was noted, consistent with likely urogenital sinus. Additional history provided by mother included her disclosure of use of 200 mg of IM trenbolone weekly for 5 weeks, for muscle building, prior to her knowledge of being pregnant. Multidisciplinary care included pediatric endocrinology, genetics, pediatric urology, and pediatric infectious disease. Labs at 24 hours of life: Sodium - 139 mmol/L (131-144), Potassium - 5.3 mmol/L (3.2-5.7), Serum glucose - 75 mg/dL (45-90), Random cortisol - 34.1 mcg/dL (1.0-10.0), 17 hydroxyprogesterone - 124 ng/dL (<460), CAH diagnostic panel - normal with exception of elevation in Progesterone - 3400 ng/dL (5-53), Newborn screening - normal, Chromosomal analysis - 46,XX and absent SRY, Ultrasound pelvis - normal Müllerian structures and bilateral intra-abdominal gonads present. Baby was hemodynamically stable, voided well, gained weight by discharge on DOL 4. Baby was stable on follow-up in endocrinology clinic on DOL 10. Surgical repair of anatomic malformation to be performed at 6 months of age by urology team. Conclusion To our knowledge, this is the first report of virilization of female offspring following human prenatal exposure to trenbolone. Women must be cautioned that trenbolone poses risks of external genital malformation to the developing fetus.
SAT-LB110 Sulfonylurea-Induced Hypoglycemia: To Use Octreotide or Not
Authors: Romeu Jose , Dodge Hannah , Mears Chad , Kozlow Erin , Patel Ravi , Vunnam Rama , Bhatt Dhirisha , Sahu Nitasa , Golamari Reshma , Jain Rohit
Published: May 2020

Background: Sulfonylurea poisoning can cause sustained hypoglycemia refractory to intravenous dextrose. Traditional treatment for sulfonylurea induced hypoglycemia includes intravenous dextrose and glucagon as well as diazoxide in refractory cases. Octreotide is recommended for sulfonylurea poisoning in adult and pediatric patients with laboratory evidence of hypoglycemia.

Clinical Case: An 89 year-old female with chronic kidney disease stage III, hypothyroidism, and diabetes mellitus type II, hypertension who presented with intractable nausea and diarrhea. Patient had been taking cefdinir for an UTI the prior week. On CT scan of the abdomen, colitis was demonstrated. Clostridium Difficile Assay was positive. She was incidentally found to have profound hypoglycemia with a blood glucose level of 30 mg/dL. Patient had hypoglycemia unawareness. Despite receiving 4 ampules of dextrose 50%, glucose level did not significantly improve. In the ED, patient was afebrile and hemodynamically stable. Her labs were significant for a hyponatremia of 125 mmol/L with an acute kidney injury [AKI] (Cr 1.94 mg/dL from 1.5 mg/dL). Patient was placed initially on a dextrose 5% normal saline infusion, but glucose levels continued to decline after brief response. Due to poor IV access, internal jugular central line was placed and patient was placed on D10NS infusion with good glycemic response. Patient had taken sulfonylurea despite not eating appropriately for 2 days. After 24 hours on D10 normal saline infusion, patient was able to maintain normal to slightly hyperglycemic levels with consistent carbohydrate diet. Her nausea and diarrhea had considerably improved after starting vancomycin 125 mg every 6 hours. Sulfonyurea was indefinitely discontinued.

Conclusion: Patients presenting with sulfonylurea induced hypoglycemia complicated by poor PO intake, AKI, and infection can be safely treated with supportive measures like proper hydration, and dextrose infusion medication is appropriately metabolized by body without the need for octreotide infusion.

References:Glatstein M, Scolnik D, Bentur Y. Octreotide forthe treatment of sulfonylurea poisoning.Clin Toxicol (Phila). 2012 Nov;50(9):795-804. doi:10.3109/15563650.2012.734626. Epub 2012 Oct 10.
SUN-LB48 Increased Mortality in Acromegaly Is Mainly Due to Vascular and Respiratory Disease and Is Normalized by Control of Growth Hormone Hypersecretion
Authors: Orme Stephen Michael , McNally Richard , Peter James , plummer Zoe , Archer Natasha , Wass John A H , Trainer Peter James
Published: May 2020

Introduction: Epidemiological studies in acromegaly have shown increased mortality rates from vascular, respiratory and malignant diseases. We aimed to use a large national cohort of subjects with acromegaly to determine mortality rates due to the above disease categories and to determine whether suppressing post treatment growth hormone (GH) levels to < 1 ng/ml improved survival compared with GH levels of 1-2.5 ng/ml.Methods: We identified 1845 cases from the UK Acromegaly database diagnosed 1970-2016 (31,768 person-yrs.), determined population mortality rates (for the period in question, age and sex of the study population) based on historic data, and death certification data for the study population from NHS digital. We were then able to determine standardized mortality rates (SMR) for the above conditions and determine whether they were associated with with age at diagnosis, duration of disease, post treatment (last recorded random or mean of profile) and mean GH levels (day weighted average of all GH measurements). Data presented as SMR, 95% CI and P value.Results: Overall standardised mortality rate (SMR) was increased, Observed 556 vs. Expected 412.74, 1.35 (1.24 -1.46, P <0.001), with increased deaths from cardiovascular 1.38 (1.16-1.63, P<0.0001), cerebrovascular 1.49 (1.10-1.97, P <0.006) and respiratory disease 1.55 (1.22-1.93, P< 0.001), but not malignancy 0.94 (0.78-1.11, P=0.786).We found no increase in mortality from breast 0.62 (0.25-1.27, P=0.936), lung 0.87(0.58-1.26, P=0.789) or colon cancer 1.26(0.63-2.25, P= 0.265).There was no relationship between age at diagnosis and SMR, however, there was a declining relationship between duration of acromegaly and all-cause SMR <5 yrs. 6.02 (4.59-7.75) 5-10 yrs. 2.42 (1.9-3.03) >10yrs.1.13 (1.03-1.25) P <0.001.Lowering post-treatment GH levels lead to a significant reduction in all-cause SMR <2.5 ng/ml 1.15 (1.03-1.28) 2.5- 9.9 ng/ml 1.73 (1.47-2.02) ≥10 ng/ml 2.27 (1.72-2.95) P<0.001 and SMR in all disease categories. A similar relationship between mean GH levels and SMR was found for all disease categories and all-cause SMR < 2.5 ng/ml 1.00 (0.89-1.18) 2.5- 9.9 ng/ml 1.50 (1.33-1.69) ≥ 10 ng/ml 2.28 (1.85-2.79) P<0.001.Lowering post-treatment GH levels to less than 1 ng/ml appeared to have an additional beneficial effect for all-cause SMR, <1ng/ml 1.03 (0.89-1.18) 1-2.5 ng/ml 1.38 (1.16-1.62) P<0.001. A similar relationship was shown in cardiovascular, respiratory and malignant disease, but not cerebrovascular disease.Conclusion: Acromegaly is associated with an increased mortality from vascular, respiratory, but not malignant disease. The highest risk is within the first 5 years following diagnosis and the risk is abrogated by lowering GH levels to <1.0 ng/ml.On behalf of UK Acromegaly Register Study Group 2020
SAT-LB14 Anthropometry and Vertebral Abnormality in Children With Transfusion-Dependent Thalassemia in Phramongkutklao Hospital, Bangkok, Thailand
Authors: Lertvivatpong Nawachai , Phatarakijnirund Voraluck
Published: May 2020

Anthropometry and vertebral abnormality in Children with Transfusion-dependent Thalassemia in Phramongkutklao HospitalBackgrounds: Thalassemia is an untreatable inherited hematologic disorder, unless stem cell transplantation, characterized by anemia from decreased hemoglobin production. Growth failure is one of the most common endocrine dysfunction in children with transfusion-dependent thalassemia (TDT) Objective: To evaluate the prevalence and associated factors of anthropometry and vertebral abnormality in transfusion-dependent thalassemia (TDT) children in a single tertiary center. Method: A cross-sectional study was conducted in transfusion dependent thalassemia patients who had visited in pediatric hematology clinic during 1st January 2018 to 31st December 2019. Collaborators had examined by history taking, physical examinations, laboratory and radiology reviewed. Results: Eighty-one collaborators were enrolled. Mean age was 13.7 ± 6.4 years and 46 of them (56.8%) were male. Pre-transfusion Hb and serum ferritin were 8.0 ± 1.0 g/dL and 1,562 + 1,394 ng/mL, respectively. Twenty-one (25.9%) had short stature determined by predicted adult height (PAH) below target adult height (TAH), 27(33.3%) had decreased upper-lower segment ratio for and 21 (26%) had BMI z-score below -2SD for age. Delay puberty was found in 13.2% of patients. Radiological examinations revealed delayed bone age of 4.9% and osteopenia of 25.9% whereas no vertebral fracture was documented. In multivariate logistic regression analysis (backward Wald), Serum ALP (p=0.009), mean pre-transfusion hemoglobin <9 g/dL (p<0.001), osteopenia (p=0.05) and delay bone age (p=0.019) were associated with PAH below TAH. Duration of chelation (p=0.013) and osteopenia (p=0.015) were associated with decreased upper-lower segment ratio. Low serum calcium (p=0.009), high serum phosphate (p=0.04) and impaired fasting glucose (p=0.004) were associated with BMI z-score below -2SD for age. Conclusions: Anthropometry abnormalities, including short stature, abnormal upper-lower segment ratio and low BMI, are common in TDT children. However, no vertebral abnormality was found in this study. Routine screening program by multidisciplinary team approach should be applied in thalassemia children.Keywords: Thalassemia major, endocrinopathies, growth failure, short stature, body disproportion
SUN-LB130 Identification of IGSF1 Ligands
Authors: Smith Courtney L , Bayne Andrew N , Trempe Jean-François , Bernard Daniel J
Published: May 2020

Immunoglobulin superfamily, member 1 (IGSF1), is an X-linked, type 1 transmembrane glycoprotein that is highly expressed in the anterior pituitary gland and testes. Mutations in the IGSF1 gene cause congenital central hypothyroidism, variable hypoprolactinemia, growth hormone dysregulation, and macroorchidism. Igsf1 knockout mice exhibit reduced pituitary TRH receptor (Trhr1) expression with an associated impairment in TRH-stimulated TSH secretion. The mechanism through which IGSF1 loss leads to reductions in Trhr1 levels is unresolved, at least in part because IGSF1’s cellular functions are unknown. The mature form of the IGSF1 protein consists of seven extracellular Ig loops, a single transmembrane domain containing a positively charged arginine, and a short intracellular carboxy-tail devoid of known functional motifs. Recently, IGSF1 was argued to be a member of the leukocyte receptor cluster (LRC) family. LRC proteins act as cell surface receptors for soluble or membrane-bound proteins. We therefore hypothesized that IGSF1 is a cell surface receptor for a presently undescribed ligand that regulates Trhr1 expression in pituitary thyrotrope cells. To identify candidate IGSF1 ligands, we implemented a new ligand trapping method, Ecto-Fc MS. We fused the extracellular (Ecto) domain of IGSF1 to the fragment crystallizable (Fc) region of human IgG, creating an Ecto-Fc fusion protein. Secreted IGSF1-Fc was purified and used as a ligand trap for bait proteins extracted from rat testes. The protein complexes were affinity purified with protein A beads, trypsin digested into peptides, subjected to orthogonal high-pH fractionation, and identified by tandem LC-MS/MS. More than 700 proteins were enriched in IGSF1-Fc preparations compared to an Fc-only negative control. Several secreted ligands and plasma-membrane proteins were identified, many of which are also expressed in pituitary thyrotrope cells. Identifying the ligand or ligands will enable us to determine IGSF1 function, and may lead to the discovery of novel causes of central hypothyroidism and macroorchidism.
SUN-LB45 Identifying a Role for Lactogenic Hormones in Maternal Motivation
Authors: Swart Judith M , Ladyman Sharon Rachel , Grattan David Ross , Brown Rosemary Shanon Eileen
Published: May 2020

The onset of appropriate maternal behaviour is essential for the survival of dependent offspring in mammals. Lactogenic hormones, including prolactin and placental lactogen, play an important role in the regulation of this behaviour, mediated through prolactin receptor expression in the medial preoptic area (MPOA) of the hypothalamus1. However, it is unclear how lactogenic action in this region induces the display of maternal behaviour. It has been shown that activation of neuronal projections from the MPOA to the ventral tegmental area (VTA) is necessary for maternal behaviour2, with reward circuitry activated in order to motivate a mother to invest in time- and resource-costly care for her young. We aimed to investigate whether lactogenic hormones play a role in the activation of reward circuitry for maternal behaviour. First, we characterised specific aspects of motivation and reward behaviour in wildtype female C57BL/6 mice of different reproductive states, using three behavioural testing paradigms. We showed that virgin and pregnant mice develop a preference for contexts associated with the presence of foster pups in a conditioned place preference test (p<0.01, n=9 per group), an aspect of reward behaviour that was not observed in lactating females (p=0.14, n=8). However, in a novel T maze and when a climbable barrier was placed in the home cage, virgin and pregnant mice showed low motivation for pup retrieval compared to lactating mice (p<0.05, n≤6 per group). These data demonstrate that reproductive state differentially affects passive reward learning and active motivation for maternal care in wildtype mice. Moreover, we can differentiate between maternal and non-maternal states of pup-related reward behaviour with the use of the T maze and barrier climbing paradigms. Next, we tested mice with a conditional deletion of prolactin receptors in Gamma-Aminobutyric Acid (GABA) neurons (Prlr flox/VGat Cre) in the T maze during lactation. Knockout mice showed incomplete retrieval behaviour, and latencies for pup retrieval were significantly longer than in controls (p<0.01, n≤6 per group). The behavioural impairments observed in Prlr flox/VGat Cre knockout mice in the T maze imply that the action of lactogenic hormones on GABA neurons is required for full maternal motivation.

1.Brown RSE, et al. Prolactin action in the medial preoptic area is necessary for postpartum maternal nursing behavior. Proc Natl Acad Sci U S A114, 10779-10784 (2017). 2.Fang YY, Yamaguchi T, Song SC, Tritsch NX, Lin D. A Hypothalamic Midbrain Pathway Essential for Driving Maternal Behaviors. Neuron98, 192-207 e110 (2018).
SUN-LB8 Cross Sex Hormone Therapy and Breast Cancer in Transgender Male to Female
Authors: Eldin Randa Sharag , Zia Aleena , Pethe Gauri , Nabil Nur , Charkviani Mariam , Ibrahim Mohamed , Babiker Mohamed Abubakr Hassab Elrasoul
Published: May 2020

Case Presentation: We are presenting a 53-year-old Male to Female transgender patient who has been receiving estradiol valerate injections every 14 days for 13 years and had no gender surgical reassignment procedures or breast implants. Her past medical history was significant for HIV on Highly Active Anti-retroviral therapy (HAART). No family history of breast cancer. She presented with severe bilateral left elbow, lower back and bilateral chest pain for 3 days. Chest CT done to exclude pulmonary embolism showed an incidental 4 cm right breast mass. Enlarged lymph nodes in the right axilla, scattered lytic lesions in the axial skeleton and the left humeral head were also noted. Breast exam was not performed until the significant findings were seen in CT chest and it showed a palpable hard-circumscribed subareolar right breast mass without skin changes. Ultrasound guided biopsy of the breast mass confirmed invasive ductal carcinoma of the breast. The patient had no previous mammogram testing. Oncology work-up was positive for estrogen and progesterone receptors but negative for human epidermal growth factor-2 receptor. The patient opted to return home in another state to seek treatment and further oncological workup but subsequently lost follow up. Discussion: Male to female breast cancer was first recognized in 1968. However, risk factors for this condition remain unclear. In our patient, long-term use of Cross-sex Hormone Therapy (CHT) represented a major risk factor for breast cancer. In a Dutch study, the risk of breast cancer increased during a relatively short duration of CHT and the cancer characteristics reassembled female pattern. As theoretically implicated, increased estrogen exposure in males may have a role in the proliferation of neoplastic breast epithelium. There are growing evidence to support increasing rates of breast cancer in HIV-positive population, making it a potential risk factor as well. Loss of CXCR-4 protective effect promoted by HIV virus may explain the increase in the breast cancer incidence after the introduction of HAART. In general, routine screening for breast cancer in MTF transgender population remains controversial. The Endocrine Society Clinical Practice guidelines suggest that MTF transsexual individuals who have no known increased risk of breast cancer should follow screening guidelines for biological women. While the Canadian Cancer Society recommends screening mammography every two years for MTF individuals taking CHT for more than 5 years and those between the ages of 50 and 69 years.

Conclusion:Breast cancer in MTF transgender patients is associated with receiving CHT and represents diagnostic and treatment challenge. More research is need to comment on routine breast cancer screening in this population. However, physicians should remember performing a regular breast exam in MTF individuals looking for a possible mass.
MON-LB72 Multicentric Carpotarsal Osteolysis Syndrome (MCTO) Has a Generalized High Turnover Bone Phenotype, High S RANKL and Responds to Denosumab
Authors: Regev Ravit , Laxer Ronal , Whitney-Mahoney Kristi , Elia Yesmino , Noone Damien , Shammas Amer , Reza Vali , Sochett Etienne B
Published: May 2020

Background:MCTO is a rare disorder, caused by mutations in the MABF gene, a negative regulator of RANKL. Manifestations include carpal tarsal osteolysis and subsequent renal failure in some. Pathophysiology is poorly understood, and no effective treatment is available. Clinical case:A 5y old boy presented (2011) with R wrist pain and diffuse swelling. MRI showed pan-carpal synovitis with joint effusion. He did not respond to different anti-inflammatory medications. Plain films showed central loss of the proximal row of carpal bones. His mother was followed as an adolescent with presumed juvenile rheumatoid arthritis. Genetic testing confirmed MAFB gene mutation (c.206C>T,p.Ser69Leu) in both patient and mother.At 7y, skeletal survey showed diffuse osteopenia and mild height loss in T1. DXA (L1-4) Z-score was -0.7. Calcium phosphate metabolism indices were within reference ranges. Bone Specific Alk Pi was modestly increased and C-telopeptide markedly increased.He received Denosumab (0.5-0.75 mg/Kg) 4-monthly for two years and experienced less pain and increased daily activities with improved R wrist function. Osteolysis stabilized and none was noted in the L wrist or ankles. BMD Z-score was -0.2. A year following treatment (2016) he received two more injections of Denosumab following pain and movement restriction of R elbow, R knee and L ankle. In 2019 (13y) he fell and radiology showed, R knee osteopenia, R wrist almost complete destruction of the carpal bones. Neither ankle nor L wrist showed osteolysis. R upper limb musculature was wasted when compared with the left. Shoulder and elbow strength were preserved. BMD Z-score was -1.2. Serum calcium, 25(OH)Vitamin D and PTH were normal. Bone specific alkaline phosphatase and C-Telopeptide were elevated. Serum creatinine was normal, eGFR 150 ml/min/1.73m2, ACR (6.6 [normal< 3.5] mg/mmol)) with no hypercalciuria or nephrocalcinosis. He was normotensive.High resolution peripheral quantitative computerized tomography (HRpQCT) of the L distal radius and distal tibia compared with 7 age-matched healthy males showed reduced total volumetric BMD (186.4;198.2-306.4), normal trabecular volumetric BMD and markedly reduced cortical volumetric BMD (320.4;636.5-792.5). Cortical thickness was below the expected range. HRpQCT measurements of the R wrist and tibia were similar. sRANKL, 6 weeks after Denosumab were markedly increased in both undiluted (35.4 pmol/L) and averaged diluted samples (83.73 pmol/L) when compared with healthy age-matched children (0.21-0.41pmol/L).

Conclusions/Clinical Lessons:MCTO (MAFB, mutation c.206C>T,p.Ser69Leu), has a generalized high turnover skeletal phenotype (osteoporosis), likely driven by very high levels of sRANKL. Denosumab is a targeted treatment for the osteoporosis, which may help stabilize the osteolysis.
SAT-LB46 Depression as an Atypical Presentation of Cushing’s Disease
Authors: Pahwa Dhivya , Shanik Michael Howard
Published: May 2020

Introduction: Cushing’s disease is an abnormal secretion of ACTH from the pituitary that causes an increase in cortisol production from the adrenal glands. Resultant manifestations from this excess in cortisol include multiple metabolic as well as psychiatric disturbances which can lead to significant morbidity and mortality.

Case: The patient is a 29 year old woman who presented with fatigue, decreased energy, poor memory and insomnia for 3 months. She noted irregular menses for 4 months. She was referred from her primary doctor for elevated salivary cortisol and DHEA levels. Evaluation revealed BP: 104/76, HR 78, RR 12, BMI 22.7. She was a thin woman without striae, moon face, buffalo hump or bruising. 24 hour urine free cortisol was 90.3 mcg/24hr. One mg dexamethasone suppression test resulted in an AM cortisol of 17.6 ug/dL and ACTH 25 pg/mL. An 8 mg dexamethasone suppression test showed a cortisol level of 1.2 ug/dL with an ACTH <5 pg/mL. The combined results were suggestive of Cushing’s disease. The patient went for MRI of the pituitary which showed a 4 mm hypoenhancing region on the right side of the gland suspicious for a microadenoma. The patient was followed closely and continued to report fatigue and insomnia. Inferior petrosal sinus sampling was performed. Venous blood sampling of ACTH from the periphery at 0 min, 5 min and 15 min were: <5 pg/mL, <5 pg/mL, and <5 pg/mL respectively. On the right at 0 min, 1 min, 5 min, 15 min ACTH levels were: 12 pg/mL, 14 pg/mL, 16 pg/mL, 14 pg/mL. On the left at 5 min and 15 min ACTH measured 8 pg/mL and 7 pg/mL. These findings confirmed the suspicion of a right-sided ACTH-secreting pituitary adenoma. She was referred to a neurosurgeon to evaluate for resection of the adenoma. Due to the ongoing symptoms, the neurosurgical removal of the lesion was expedited and scheduled within several weeks. While awaiting removal the patient sadly took her own life.

Conclusion: Aside from the more commonly associated metabolic manifestations of elevated cortisol levels, psychiatric symptoms can be the initial complaint of patients with Cushing’s disease. Symptoms can include fatigue, depressive symptoms, insomnia, and sleep dysregulation. Currently the Endocrine Society Guideline for Cushing’s syndrome does not have any specific recommendations regarding depression screening. Psychiatric complications are a known manifestation of Cushing’s disease. Close follow up and urgent psychiatric referral with the onset of signs of depression or anxiety should be included as part of Cushing’s disease evaluation. Symptoms of mental health disturbances may be subtle and thus all patients with Cushing’s disease should be screened and monitored for underlying psychiatric illnesses.

Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5152600/pdf/JMedLife-09-12.pdf
SUN-LB50 Increased In Vivo Pulsatile LH Secretion and Hypothalamic Kisspeptin, NKB, and Dynorphin RNA Levels in a PCOS-Like Mouse Model
Authors: Esparza Lourdes , Schafer Danielle , Ho Bryan , Thackray Varykina G , Kauffman Alexander S
Published: May 2020

Polycystic ovary syndrome (PCOS) is a reproductive disorder in women characterized by hyperandrogenemia, anovulation, cystic ovaries, and LH hyper-pulsatility, but the mechanisms causing the pathophysiology remain incompletely understood. We recently reported a novel mouse model that recapitulates the majority of PCOS phenotypes in adulthood. Females given constant, long-term letrozole to reduce aromatase activity demonstrate PCOS-like phenotypes, including polycystic ovaries, anovulation, elevated circulating testosterone, and increased LH. In vivo LH pulsatile secretion, which is greatly elevated in PCOS women, was not previously studied, nor were possible changes in reproductive neurons known to control GnRH/LH secretion. Here, we used recent technical advances in the field to examine in vivo LH pulse dynamics of freely-moving LET female mice versus control and ovariectomized (OVX) mice. We also studied whether hypothalamic gene expression of several important reproductive regulators, kisspeptin, neurokinin B (NKB), and dynorphin, is altered in LET females. Compared to controls, LET females exhibited very rapid, elevated in vivo LH pulsatility, with increased pulse frequency, amplitude, and basal levels, similar to PCOS women. LET mice also had markedly elevated Kiss1, Tac2, and Pdyn expression along with increased Kiss1 neuron activation in the hypothalamic arcuate nucleus. Although elevated, most hyperactive LH pulse parameters and increased arcuate mRNA measures of LET mice were significantly lower than in OVX littermates. Our findings demonstrate that LET mice, like PCOS women, have markedly elevated LH pulsatility which likely drives increased ovarian androgen secretion. Increased arcuate kisspeptin and NKB levels may be fundamental contributors to the enhanced stimulation of LH pulse secretion in this PCOS-like condition, and perhaps, in some PCOS women.
SUN-LB22 PLK1 as a New Treatment Target for Adrenocortical Carcinoma
Authors: Smith Gabrielle , Liang Raimunde , Chortis Vasileios , Khan Sana , Lippert Juliane , Hantel Constanze , Altieri Barbara , Fassnacht Martin , Foster Paul Alexander , Ronchi Cristina Lucia
Published: May 2020

Background: Adrenocortical carcinoma (ACC) is an aggressive malignancy with limited medical treatment options. We previously identified polo-like kinase 1 (PLK1) as one of most overexpressed genes in ACC; thus PLK1 represents a potential treatment target for this cancer type. Some PLK1 inhibitors are under evaluation in clinical trials for other solid organ malignancies, and seem to be more effective in TP53 mutated tumours. The aim of this study was to evaluate PLK1 protein levels in a large series of ACC and assess the in vitroefficacy of PLK1 inhibitors in two different ACC cell lines. Methods: 104 formalin-fixed paraffin-embedded ACC tissue samples with available genetic data were investigated. Nuclear PLK1 protein expression was evaluated by immunohistochemistry and a semi-quantitative H-score was calculated. PLK1 expression levels were correlated to clinical and histological parameters. Efficacy of PLK1-specific inhibitor Volasertib (0-200 nM) was tested in the standard NCI-H295R ACCcell line, which presents PLK-1 overexpression and a large TP53 deletion, and in the newly established MUC1 cell line, which bears a frameshift mutation in TP53. Cell proliferation was analysed using DNA fluorescence and cell apoptosis by Caspase Glo 3/7 assay. Results: Nuclear PLK1 expression was classified as high in 59% of ACC samples, with a significant difference noted between TP53-mutated (n=24) and wild-type (n=80) cases (87.5 vs 51%, p<0.01). PLK1 levels did not correlate with either progression-free or overall survival. H295R cells showed a significant time- and dose-dependent reduction of cell proliferation compared to vehicle control after 72h of Volasertib treatment (p<0.005 per trend, p=0.01 by 200nM by non-parametric two-way ANOVA). A less pronounced and non-significant trend towards inhibited proliferation was observed in MUC1 cells. Cell apoptosis was significantly higher in the H295R cells treated with 175nM and 200nM Volasertib when compared to control (p<0.05), while there was no significant difference in MUC1 cells. Conclusion:In this pilot study, we propose PLK1 inhibitors as promising candidates for treatment of a subset of ACC patients that may be pre-selected according to the tumour molecular pattern. We plan to extend functional experiments to further PLK1 inhibitors, including additional ACC cell lines with a different molecular profile.
MON-LB83 The Initial Dose of 131I as a Potential Independent Predictor for Residual/Relapsed Disease in Pediatric Differentiated Thyroid Cancer
Authors: Bustamante Escobar Carmen L , Bao Yong
Published: May 2020

Introduction: In the guidelines for management of pediatric Differentiated Thyroid Cancer (DTC) 131I therapy is recommended for treatment of iodine-avid persistent locoregional disease that cannot be resected as well as iodine-avid distant metastases. To date, no consensus has been reached regarding the 131I dose for treatment of DTC in children. We report our institutional experience and highlight the initial dose of 131I as a potential independent predictor of residual/relapsed disease.

Methods: We performed a retrospective analysis of all pediatric patients diagnosed with DTC between 2010 and 2018. The cohort included all patients up to 21 years of age, with minimal length of follow-up of 24 months. The risk stratiﬁcation was done following the American Thyroid Association guidelines for pediatric DTC. We defined residual/relapsed disease as detectable thyroglobulin and positive anatomical lesions in imaging studies during the follow-up period. The log-rank test was used to evaluate disease-free survival. The P value was set at < 0.05.

Results: Among 59 eligible patients, females were 69.5% (n=41) and males were 30.5% (n=18). The mean age at diagnosis was 16 years (9-21 years). All patients were alive at follow-up (median, 42 months; range 24 to 144 months). Fifty-eight patients had classic papillary thyroid cancer (PTC) and only 1 patient had follicular thyroid cancer. Among the patient with PTC, 39.6% (23/58) had follicular-variant PTC, 8.6% (5/52) had diffuse-sclerosing PTC and 17.2% (10/58) had other variants. Nineteen (32%), 30 (51%), and 10 (17%) had low-risk, intermediate-risk, and high-risk disease, respectively.

Within the Low-risk group, 68% (13/19) received 131I. The mean initial dose was 60.9 mCi [26-150 mCi]. Eighty four percent (11/13) received ≤100 mCi and 27% (3/11) had residual/relapsed disease. Fifteen percent (2/13) received >100 mCi and none had residual/relapsed disease. Sixteen percent (1/6) of patients without 131I therapy had residual/relapsed disease. (P=0.48)

Within the Intermediate-risk group, all 30 patients received 131I. The mean initial dose was 97.5 mCi [27.3-215 mCi]. Sixty percent (18/30) received ≤100 mCi and 38.8% (7/18) had residual/relapsed disease. Forty percent (12/30) received >100 mCi and 16.6 % (2/12) had residual/relapsed disease. (P=0.15)

Within the High-risk group all 10 patients received 131I. The mean initial dose was 159.9 mCi [129.3-384 mCi]. Fifty percent (5/10) received ≤150 mCi and 60% (3/5) had residual/relapsed disease. Fifty percent (5/5) received >150 mCi and 20% (1/5) had residual/relapsed disease. (P=0.2)

Conclusion: There are no statistical differences of disease-free rate between the initial dose of 131I among all risk categories. However, the use of more than 100 mCi in the intermediate-risk category and more than 150 mCi in the high-risk category may be recommended.
SAT-LB121 Development of a Machine-Learning Method for Predicting New Onset of Diabetes Mellitus: A Retrospective Analysis of 509,153 Annual Specific Health Checkup Records
Authors: Nomura Akihiro , Yamamoto Sho , Hayakawa Yuta , Taniguchi Kouki , Higashitani Takuya , Aono Daisuke , Kometani Mitsuhiro , Yoneda Takashi
Published: May 2020

Diabetes mellitus (DM) is a chronic disorder, characterized by impaired glucose metabolism. It is linked to increased risks of several diseases such as atrial fibrillation, cancer, and cardiovascular diseases. Therefore, DM prevention is essential. However, the traditional regression-based DM-onset prediction methods are incapable of investigating future DM for generally healthy individuals without DM. Employing gradient-boosting decision trees, we developed a machine learning-based prediction model to identify the DM signatures, prior to the onset of DM. We employed the nationwide annual specific health checkup records, collected during the years 2008 to 2018, from Kanazawa city, Ishikawa, Japan. The data included the physical examinations, blood and urine tests, and participant questionnaires. Individuals without DM (at baseline), who underwent more than two annual health checkups during the said period, were included. The new cases of DM onset were recorded when the participants were diagnosed with DM in the annual check-ups. The dataset was divided into three subsets in a 6:2:2 ratio to constitute the training, tuning (internal validation), and testing datasets. Employing the testing dataset, the ability of our trained prediction model to calculate the area under the curve (AUC), precision, recall, F1 score, and overall accuracy was evaluated. Using a 1,000-iteration bootstrap method, every performance test resulted in a two-sided 95% confidence interval (CI). We included 509,153 annual health checkup records of 139,225 participants. Among them, 65,505 participants without DM were included, which constituted36,303 participants in the training dataset and 13,101 participants in each of the tuning and testing datasets. We identified a total of 4,696 new DM-onset patients (7.2%) in the study period. Our trained model predicted the future incidence of DM with the AUC, precision, recall, F1 score, and overall accuracy of 0.71 (0.69-0.72 with 95% CI), 75.3% (71.6-78.8), 42.2% (39.3-45.2), 54.1% (51.2-56.7), and 94.9% (94.5-95.2), respectively. In conclusion, the machine learning-based prediction model satisfactorily identified the DM onset prior to the actual incidence.
SAT-474 Amiodarone-Induced Thyrotoxicosis After Weight Loss Following Sleeve Gastrectomy
Authors: Osafehinti Deborah , Rakhlin Luba , Park Patricia , Resta Christine A
Published: May 2020

AMIODARONE-INDUCED THYROTOXICOSIS AFTER WEIGHT LOSS FOLLOWING SLEEVE GASTRECTOMY

INTRODUCTION:

Bariatric surgeries have shown major health benefits improvement in co-morbidities such as HTN and DM. We are less familiar with how these surgeries affect the pharmacokinetics of drugs.1,2

CLINICAL CASE:

Our patient is a 65-year-old man with a fib/v tach and no prior thyroid history. He was on amiodarone 200 mg daily since September 2016. He had sleeve gastrectomy in March 2019 at weight 380 lbs. By June 2019, weight was 278 lbs.

In June 2019, he had palpitations, diarrhea, and heat intolerance for one month. Labs showed: TSH <0.01 (0.4 – 4.5 MCIU/L), FT4 6.5 (0.8 – 1.8 NG/DL), and TT3 309 (76 – 181 NG/DL). Other labs: TPO antibodies <1 IU/mL (<9 IU/mL) TSI <89 (<140% baseline). Thyroid sonogram was heterogeneous without nodule

He started Methimazole (MMI) 20mg BID and Prednisone 40mg daily. In the next seven weeks, symptoms and TFTs improved. FT4 was 3.1 NG/DL, TT3 was 85 NG/DL, but TSH remained <0.01 MCIU/L. Because of the rapid improvement, he was felt to have type 2 AIT (destructive thyroiditis). MMI was quickly tapered. Prednisone was tapered to 30mg daily.

At week 8, he was hospitalized for septic shock from diverticulitis and perianal abscess. He also had leukopenia attributed to MMI and sepsis. MMI was stopped. Amiodarone was stopped by cardiology. TFTs during hospitalization improved on only steroids: TSH was 0.01 MCIU/ML, FT4 was 2.34 NG/DL, and TT3 was 0.56 NG/ML. He was discharged on Prednisone 30mg daily with plans to taper off steroids.

CONCLUSION:

Our patient is the second reported case of AIT after bariatric surgery-induced weight loss. Amiodarone is a highly lipophilic drug that accumulates in adipose tissue. Rapid weight loss may result in the release of large amounts of amiodarone into the circulation with resultant thyrotoxicosis. As clinicians, we should be aware that patients who undergo bariatric surgery are at risk for complications that are not only directly related to the operation but also related to rapid weight loss that affects how the body handles drugs.

REFERENCES

1.

Bourron O, Ciangura C, Bouillot J-L, Massias L, Poitou C, Oppert J-M. Amiodarone-induced hyperthyroidism during massive weight loss following gastric bypass. Obes Surg. 2007;17(11):1525–1528. http://www.ncbi.nlm.nih.gov/pubmed/18219784. Accessed September 21, 2019.

2.

Geraldo M de SP, Fonseca FLA, Gouveia MR de FV, Feder D. The use of drugs in patients who have undergone bariatric surgery. Int J Gen Med. 2014;7:219–224. doi:10.2147/IJGM.S55332
SUN-LB87 De-Novo Graves Ophthalmopathy After Total Thyroidectomy With Exacerbation Following Rifampicin Therapy for Latent Tuberculosis: A Call for Attention to Disease Modifying Interventions
Authors: Shaklai Sigal , Marcus-Perlman Yonit , Klein Ainat , Stern Naftali , Greenman Yona
Published: May 2020

Introduction Factors influencing development and course of ophthalmopathy, the most common extrathyroidal manifestation of Graves’ disease, remain poorly defined. Clinical Case A 46 year old healthy, non-smoking, medical secretary, presented with Graves’ disease. Laboratory investigation showed thyrotoxicosis with high thyroid stimulation immunoglobulin (TSI) levels (1608 %, normal <140%). At presentation there was no evidence of thyroid eye disease on clinical exam and orbital MRI. Treatment with Methimazol and PTU induced severe pruritus and she underwent total thyroidectomy. One month after surgery she presented with retroorbital pain, eyelid edema and chemosis, as well as bilateral limitation in abduction; a clinical activity score (CAS) of 3/7. She received IV pulse methylprednisolone 4.5 gr with minor improvement. MRI showed bilateral thickening of all rectus muscles with orbital fat infiltration. TSI increased concomitantly to 3600%. Three months later, she underwent standard retrobulbar radiotherapy (20 Gy), again with only minor improvement. She continued treatment with oral prednisone 20mg with small fluctuations in disease activity in the following months during which TSI remained high (3145%) and latent tuberculosis was detected (elevated interferon-gamma release assay). Therefore, rifampicin 600mg/d was started. A month later the ophthalmopathy worsened (a CAS score of 5/7 without optic neuropathy). Laboratory tests showed new perturbation in thyroid function tests (TSH increased from 5 to 15 mIU/l, normal: 0.5-5; FT4 decreased from 16 to 11 pmol/l, normal: 10-20) and TSI increased to 3879%. Euthyrox dose was increased by 50% from 800 to 1200 microgram/week. It was postulated that prednisone was also being rapidly metabolized by rifampicin mediated induction of the CYP450, and therefore the dose was increased from 20 to 40 mg/d. Six weeks later, normalization of thyroid function tests was followed by improvement in the ophthalmopathy (CAS-3). Conclusion (Clinical lesson) A) De-novo severe Graves’ ophthalmopathy after thyroidectomy requiring multiple forms of treatment is rare but close surveillance is advisable, perhaps particularly in the presence of high TSI. A plausible mechanism may be transient increase in antigenic exposure/dissemination during surgery. B) Rifampicin, through induction of cytochrome P450-mediated metabolism of levothyroxine, steroids and mycophenolate (the latter not used in our patient) can lead to disease flare-up. Tight clinical and laboratory monitoring of thyroid function tests with individualized dose escalation might be needed. In the future, pharmacogenomics may serve to personalize treatment protocols.
SUN-LB114 Remission of Type 2 Diabetes (DMT2) in Hypogonadal Men Under Long-Term Testosterone Therapy
Authors: Mskhalaya George , Tishova Yuliya , Skiba Olga , Mskhalaia Maria , Kalinchenko Svetlana
Published: May 2020

Objective: The increasing prevalence of DMT2 and obesity represents a growing clinical and health-care cost problem. These two pathologies simultaneously increase the risk of hypertension, myocardial infarction, stroke or venous thromboembolism. An existing but undetected testosterone deficiency will substantially hamper weight loss or render it impossible. In such cases, returning the testosterone level to normal range is therefore the necessary pre-condition to fight obesity and thus the related comorbidities. Materials and methods: 35 obese (waist circumference (WC) > 94 cm) men aged 48 [33;57] with diagnosed DMT2 (IDF 2019 criteria), hypogonadism (ISSAM 2015 criteria) and vitamin D deficiency (Endocrine Society Guidelines 2014 criteria) were treated with testosterone undecanoate (1000 mg 4 mL injected i.m. every three months following an initial 6-week interval), cholecalciferol 5. 000-10.000 IU per day. 29 patients received 1000-2000 mg per day, 1 patient received liraglutide 1,8 mg a day + metformin 1500 mg a day, 1 patient received Sitagliptin 100 mg and metformin 1000 mg a day. 4 patients did not use anti-diabetic treatment ever. The duration of follow up was 36 months. Waist circumference (WC, cm), glucose (mmol/L), HbA1c (%), total testosterone (nmol/L) and vitamin D (25(OH)D3, ng/mL) were assessed at baseline and after 36 months of follow up. Statistical research was made using a software package statistics (StatSoft Inc. U.S., version 6.0). Quantitative data are presented as medians and quartile range. When comparing the quantitative data of two groups Wilcoxon test was used. Values were considered statistically significant if p <0.05. Results: All patients had no DMT2 diagnostic criteria after 24 months of treatment. WC changed from 107 [102;116] to 94 [88.5;97.5], HbA1c from 7,2 [6.9;7,7] to 5,7 [5.25;5.8], TT from 7.37 [6.2;9.18] to 24.65 [22.3;25.9], 25(OH)D3 from 20.2 [11.7;26.2] to 72 [65;88] at baseline and after 24 months of follow up, respectively. All changes were statistically significant. Anti-diabetic therapy was cancelled in all patients after 20,5 [15;24] months of follow up. All patients remained under further follow up for the period up to 36 months, no cases of DMT2 recurrence were registered.Conclusion: We conclude that correction of testosterone and vitamin D deficiency may work as a necessary stimulus for consequential facilitation of weight reduction and associated recovery, particularly in terms of a complete remission of diabetes. Long term data is needed.
SAT-LB111 Improving Classification of Diabetes Etiology in Electronic Resources Using Phenotype Algorithms and Polygenic Risk Scores
Authors: Sulieman Lina , He Jing , Carroll Robert , Bastarache Lisa , Ramirez Andrea
Published: May 2020

Electronic Health Records (EHR) contain rich data to identify and study diabetes. Many phenotype algorithms have been developed to identify research subjects with type 2 diabetes (T2D), but very few accurately identify type 1 diabetes (T1D) cases or more rare forms of monogenic and atypical metabolic presentations. Polygenetic risk scores (PRS) quantify risk of a disease using common genomic variants well for both T1D and T2D. In this study, we apply validated phenotyping algorithms to EHRs linked to a genomic biobank to understand the independent contribution of PRS to classification of diabetes etiology and generate additional novel markers to distinguish subtypes of diabetes in EHR data. Using a de-identified mirror of medical center’s electronic health record, we applied published algorithms for T1D and T2D to identify cases, and used natural language processing and chart review strategies to identify cases of maturity onset diabetes of the young (MODY) and other more rare presentations. This novel approach included additional data types such as medication sequencing, ratio and temporality of insulin and non-insulin agents, clinical genetic testing, and ratios of diagnostic codes. Chart review was performed to validate etiology. To calculate PRS, we used genome wide genotyping from our BioBank, the de-identified biobank linking EHR to genomic data using coefficients of 65 published T1D SNPS and 76,996 T2D SNPS using PLINK in Caucasian subjects. In the dataset, we identified 82,238 cases of T2D but only 130 cases of T1D using the most cited published algorithms. Adding novel structured elements and natural language processing identified an additional 138 cases of T1D and distinguished 354 cases as MODY. Among over 90,000 subjects with genotyping data available, we included 72,624 Caucasian subjects since PRS coefficients were generated in Caucasian cohorts. Among those subjects, 248, 6,488, and 21 subjects were identified as T1D, T2D, and MODY subjects respectively in our final PRS cohort. The T1D PRS did significantly discriminate well between cases and controls (Mann-Whitney p-value is 3.4 e-17). The PRS for T2D did not significantly discriminate between cases and controls using published algorithms. The atypical case count was too low to calculate PRS discrimination. Calculation of the PRS score was limited by quality inclusion of variants available, and discrimination may improve in larger data sets. Additionally, blinded physician case review is ongoing to validate the novel classification scheme and provide a gold standard for machine learning approaches that can be applied in validation sets.