bluuebunny/crossref_metadata_2025 huggingface dataset:
SAT-161 Adrenal Incidentalomas: Pattern of Referral According to Clinical Specialty
Authors: Hanna Fahmy W F , Hancock Sarah , George Cherian , Issa Basil George , Lea Simon , Powner Gillian , Waldron Julian , Golash Anurag , Fryer Anthony
Published: May 2020

Whilst the estimated prevalence of adrenal incidentaloma is 0.5-2% following abdominal CT scan (1), little is known about subsequent endocrine referral patterns according to clinical specialty. We therefore examined the range of specialties that were responsible for requesting CT and MRI scans that led to reporting potential adrenal lesions. We also explored the referral pattern to endocrinology following identification. We extracted data from all radiology reports for all CT and MRI scans from Jan 2018-Oct 2019. We utilised a key phrase search strategy (eg adrenal adenoma/lesion/mass/nodule/incidentaloma, incidental adrenal, indeterminate adrenal). Where possible we excluded false hits (eg no adrenal lesion). These were lined to the referral patterns as identified by a referral logged or an attendance (new or follow-up) to endocrine clinic 3 months post index scan. These data were stratified by requesting specialty. Preliminary data showed that, out of 127878 scans, 2021 patients were identified to have a potential adrenal incidentaloma. These requests came from a total of 45 different clinical specialities (medical and surgical). The top 12 specialties accounted from 82.8% of these referrals. Medical specialties (renal, gastroenterology, respiratory, general medicine, acute medicine and geriatric medicine) accounted for 50.2%. The remaining 32.6% were via surgical specialities. The overall referral pattern in these cases was 8.5% with no difference between medical (8.6%) and surgical (8.4%) specialties. In conclusion, adrenal incidentalomas are potentially identifiable across a wide range of specialties. Currently, despite a dedicated adrenal multidisciplinary team and nationally-acknowledged quality improvement programme for the management of adrenal incidentalomas (2), the majority of cases are overlooked and not referred for endocrine review as suggested in current guidelines. We expect the findings in our centre to be reproducible elsewhere. We are considering innovative approaches to improve the process and cope with the additional workload cost-effectively. 1. Barzon L, Sonino N, Fallo F, Palu G, Boscaro M. Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol. 2003;149:273-285. Hanna FWF, Issa BG, Lea SC, George C, Golash A, Firn M, Ogunmekan S, Maddock E, Sim J, Xydopoulos G, Fordham R, Fryer AA. Adrenal lesions found incidentally: how to improve clinical and cost-effectiveness. BMJ Open Quality. 2019;In press.
SAT-168 Adrenal Incidentalomas: Impact of Patient Age on Referral Rates for Endocrine Evaluation
Authors: Fryer Anthony , Hancock Sarah , George Cherian , Issa Basil George , Lea Simon , Powner Gillian , Waldron Julian , Golash Anurag , Hanna Fahmy W F
Published: May 2020

It is estimated that the prevalence of adrenal incidentaloma increases with age: ~3% of those aged 50 years, rising to 10% in those >70 years (1). Given the aging population together with increased utilisation of cross-sectional imaging in the UK (eg CT urogram, MR angiogram), we explored the proportion of patients with adrenal incidentaloma by age based on current imaging trends. Furthermore, there is no information currently available on the relationship between age and pattern of endocrine referrals. We extracted data for all CT and MRI scans from Jan 2018-Oct 2019 and used key phrases in radiology reports (eg adrenal adenoma/lesion/mass/nodule/incidentaloma, incidental adrenal, indeterminate adrenal) to identify potential lesions. We also extracted data on patient age and referral patterns as identified by a logged referral or an attendance (new or follow-up) to endocrine clinic 3 months post index scan, stratified by 10 year age groups. Where possible, we excluded false hits (eg no adrenal lesion). Preliminary data showed that, of the 2604 potential lesions identified by CT and MRI scans, 78.7% were on patients aged over 60 years. The numbers of identified lesions gradually increased with age to a peak in the 71-80 year age group after which these declined. Whilst patients younger that 60 years had fewer potential lesions identified, they were more likely to be referred to endocrine services (73 out of 55 patients; 13.2%) than those in the older age group (168 out of 2049; 8.2%; p<0.001). Indeed there was a statistically significant trend towards decreasing referral with age group (Chi-squared test for trend; p<0.001). In conclusion, patients over 60 years have a higher number of potential adrenal incidentalomas. However, this group is less likely to be referred for endocrine evaluation. This is particularly concerning given the large number of scans requested and the higher prevalence of incidentalomas in this age group. This study represents preparatory work on innovations to enhance case detection, particularly in the older age groups (2). 1. Fassnacht M, Arlt W, Bancos I, et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline. Eur J Endocrinol. 2016;175:G1-G34 2. Hanna FWF, Issa BG, Lea SC, George C, Golash A, Firn M, Ogunmekan S, Maddock E, Sim J, Xydopoulos G, Fordham R, Fryer AA. Adrenal lesions found incidentally: how to improve clinical and cost-effectiveness. BMJ Open Quality. 2019;In press.
MON-724 Crude Protein Extract of Pyropia Yezoensis Protects Against Tumor Necrosis Factor-á-Induced Apoptosis and Atrophy in C2C12 Myotubes
Authors: Lee Min-Kyeong , Nam Taek-Jeong , Choi Youn Hee
Published: May 2020

Proinflammatory cytokines such as tumor necrosis factor (TNF)-α play an important role in the development of skeletal muscle atrophy, and TNF-α-induced apoptosis may mediate skeletal muscle atrophy. Therefore, we evaluated the effect of Pyropia yezoensis crude protein (PYCP) on TNF-α-induced apoptosis and identified the involved signaling pathways. For this purpose, C2C12 myotubes were treated with 20 ng/mL TNF-α in the presence or absence of 25-100 μg/mL PYCP for 48 h. Treatment with TNF-α markedly increased the protein level of TNF-receptor 1 (TNF-R1). In contrast, treatment with PYCP downregulated the TNF-α-induced increase in the TNF-R1 protein level. Also, the expression of Bax, Bcl-2, cytochrome C, and apoptosis-inducing factor, markers of apoptosis in myofibers, was increased by TNF-α, but this effect was inhibited by PYCP in a concentration-dependent manner. In addition, exposure of C2C12 myotubes to TNF-α for 48 h enhanced the activity of caspase-3, which was significantly inhibited by PYCP. Furthermore, poly[ADP-ribose] polymerase cleavage and histone-associated DNA fragmentation were markedly increased by TNF-α and attenuated by PYCP in a concentration-dependent manner. In conclusion, the ability of PYCP to inhibit the apoptosis induced by TNF-α suggests that it has therapeutic potential for skeletal muscle atrophy.
OR20-06 Kisspeptin as a Biomarker for Pregnancy Complications
Authors: Phylactou Maria , Abbara Ali , Al-Memar Maya , Eng Pei Chia , Comninos Alexander N , Izzi-Engbeaya Chioma , Clarke Sophie A , Mills Edouard , Nadir Rans , Sykes Mark , Ewa Pacuszka , Yang Lisa , Fourie Hanine , Bech Paul , Kelsey Tom , Bourne Tom , Dhillo Waljit Singh
Published: May 2020

Background:

Placentation (invasion of the placenta into the maternal endometrium) is hypothesised to be critical for healthy placental function and is abnormal in two thirds of miscarriage. Kisspeptin has emerged as a putative regulator of physiological placentation; it is highly expressed in placental syncitio-trophoblasts, whereas its receptor is expressed in both syncitio- and cyto-trophoblasts, such that kisspeptin is hypothesized to play an important paracrine role to regulate placentation. Circulating kisspeptin levels are considerably raised during healthy pregnancy and are reduced in women with miscarriage.

Aim:

We aimed to investigate the utility of circulating kisspeptin concentrations in the assessment of pregnancy complications and assess whether kisspeptin provides additional diagnostic information compared to beta human chorionic gonadotropin (βhCG) alone.

Methods:

This study was performed in collaboration with the Early Pregnancy Outcome Study (EPOS), which aims to identify novel pregnancy biomarkers. Women were invited to attend every fortnight for blood-sampling, clinical and ultrasound assessment during the first trimester, and repeated during the second and third trimesters. Asymptomatic women with healthy pregnancy (n=265) provided 960 blood-samples. Women with pregnancy complications including miscarriage (n=95), pre-eclampsia (PET; n=24), pregnancy induced hypertension (PIH; n=14), gestational diabetes (GDM; n=41), preterm birth (PTB; n=14) and intrauterine growth restriction (IUGR; n=24) provided 569 blood-samples.

Results:

Gestation-adjusted circulating kisspeptin and βhCG levels were lower, by 66% and 57%, respectively, in women with miscarriage compared to healthy pregnant controls (p<0.0001). Area under ROC curve for diagnosis of miscarriage was greater for the combination of both kisspeptin and βhCG together (0.92) than for either measure alone (βhCG 0.859, kisspeptin 0.874). An adjusted logistic regression model revealed that an 100pmol/L increase in plasma kisspeptin reduced the odds of miscarriage by 42%. Gestation-adjusted kisspeptin levels were lower in women with GDM (P=0.002), or IUGR (P<0.0001), and higher in women with PTB (P=0.004). Kisspeptin increased with gestation greater in PET (P=0.008) and PIH (P<0.0001) than in healthy controls.

Conclusions:

Plasma kisspeptin is a promising biomarker for pregnancy complications and provides additional diagnostic capability over that provided by βhCG alone.
SAT-017 Relationship Between Vitamin D Levels and Signs of Polycystic Ovary Syndrome
Authors: Smykalova Anastasia , Kalinchenko Svetlana , Safi Aigul , Orazov Mekan , Nizhnik Alexander
Published: May 2020

An analysis of the structure of the causes of infertility shows that up to almost 25% of women of reproductive age ovulation disorders are observed. Hormonal disorders leading to the absence of ovulation, began to play a leading role in the etiology of infertility, special vitamin D deficiency, while today it has been established that its D receptors (VDR) are localized in most organs, including reproductive ones. VDR affect the expression of 1000 genes and play a crucial role in the implementation of sex hormones function.

The aim of the study was to assess the vitamin D level in women of reproductive age, depending on the presence of signs of PCOS and waist circumference (WC).

71 women from 19 to 44 years old were examined of these, 41 patients were diagnosed with PCOS and impaired ovulatory function, in 30 patients the ovulatory cycle was preserved, and signs of PCOS were not detected. The level of vitamin 25 (OH) D3 in the serum of the subjects was evaluated by tandem chromato-mass spectrometry at the ArchiMed clinic of new medical technologies, Moscow.

In the recommendations of the Canadian “The Vitamin D society”, 40-60 ng/ml the optimal level of serum vitamin D, a concentration of 20-40 ng/ml insufficiency, <20 ng/ml as a deficiency.

Vitamin D deficiency was detected in 57% of women in both groups, with a pronounced deficiency (<10 ng/ml) in 17%, insufficiency was observed in 43% of cases, a sufficient level was not detected in any of the subjects. The average level of vitamin D in patients with PCOS was 18.2 (2 to 32.3) ng/ml, the value in patients without signs of PCOS was 18.5 (6.8 to 31) ng/ml.

Comparison of the vitamin D value with WC showed that in women with PCOS with an WC <80 cm the value of this indicator was 18.8 ng/ml, and for WC ≥ 80 cm it was statistically significantly lower - 13.3 ng/ml (p<0.05).

Conclusion. High prevalence of vitamin D deficiency among patients of reproductive age, with no differences in the magnitude of this indicator depending on the presence of signs of PCOS and persistent ovulation.

Difference was established between the levels of vitamin D in patients with PCOS depending on the waist circumference - its insufficiency increases with an increase in WC.

The results of the study suggest that the deficiency of vitamin D in the body increases with the aggravation of hormonal dysfunction in PCOS, which should be taken into account by specialists during the management of this category of patients and the treatment of infertility.
SUN-134 Estrogen Induces Granulocytic Myeloid Derived Suppressor Cell Production to Potentially Modulate Lymphangioleiomyomatosis (LAM) Tumor Progression
Authors: Minor Briaunna , Hammes Stephen R
Published: May 2020

Affecting almost exclusively women, lymphangioleiomyomatosis (LAM) is a rare lung disease characterized by estrogen-sensitive metastatic smooth muscle cell-like adenomas that grow slowly, resulting in cystic lung change and loss of pulmonary function. LAM tumors are caused by mutations in tuberous sclerosis complex 1 or 2 genes (TSC1 or TSC2). Mutations in TSC1 or TSC2 genes results in deficient inhibitory regulation of the mammalian target of rapamycin complex 1 (mTORC1), which in turn leads to increased mTORC1 activity and cell proliferation. There is no consensus amongst LAM researchers regarding the origin of these estrogen receptor-positive smooth muscle like LAM cells; however, we previously reported inactivation of TSC2 in the mouse uterus results in notable LAM features in the setting of primary myometrial tumors. Approximately 50% of the TSC2-null mice had metastatic myometrial tumors present in the lung, suggesting that LAM tumor cells might in fact originate from the uterus, thus explaining the female sexual dimorphism, the estrogen sensitivity, and the metastatic nature of the LAM tumors.

Interestingly, flow cytometry revealed large numbers of granulocytic myeloid derived suppressors cells (G-MDSCs) in the blood and myometrial tumors of uterine-specific Tsc2 null mice. MDSCs are known to accumulate in the setting of chronic inflammation caused by trauma, infection, and various cancers. This granulocytic subtype not only has the capacity to suppress anti-tumor immune cells of the tumor microenvironment, but also directly promotes tumor cell malignant neoplasicity. We found that Tsc2-null myometrial tumors required MDSCs for normal progression, as MDSC depletion or inhibition of MDSC recruitment reduced tumor growth. We have showed that these tumors expressed estrogen receptors and were exquisitely sensitive to estrogen, while other studies demonstrate that G-MDSCs are also positively influenced by estradiol. Therefore, we hypothesized that, in addition to direct effects of estrogen on tumor cells, estrogen also stimulates tumor growth by promoting MDSC production in the bone marrow. We have developed a technique to stimulate MDSC production from mouse bone marrow. Using this strategy, we found that estradiol is indeed a potent promotor of G-MDSC production. These effects occurred in both male and female bone marrow. Employing both pharmacologic agents and bone marrow from ERα; knockout mice, we showed that ERα; is necessary for promoting a G-MDSC fate for immature myeloid cells and precursors. Thus, estradiol may have duel effects in LAM, both directly promoting tumor growth and indirectly upregulating MDSC production, which in turn promotes tumor growth. We propose that these estrogen effects on MDSC production are not limited to LAM and may be important regulators of tumor growth in many tissues.
SAT-482 Simultaneous Hashimoto/Graves Disease or Prolonged Hashitoxicosis? A Diagnostic Challenge with Therapeutic Implications
Authors: Penaherrera Carlos A , Rodriguez Valentina
Published: May 2020

Background: Some individuals with Hashimoto’s thyroiditis (HT), characterized by anti-TPO antibodies (Abs), can also have positive TSI Abs in up to 20% of cases, without necessarily having Graves disease (GD). Patients with signs of both hyper-and-hypothyroidism with positivity to these two Abs can pose a diagnostic and therapeutic dilemma, as their course is often unpredictable. Clinical Case: A 49-year-old woman was diagnosed with hypothyroidism and took levothyroxine (LT4) for about 1 year, after which she developed symptoms of hyperthyroidism and was switched to methimazole (MMI), which she only took for 1 year. At her initial visit at our clinic she had been off of MMI for 12 months and she was biochemically hyperthyroid (TSH of 0.01 mcIU/ml, f-T4 of 2.26 ng/dl). TSI Abs were positive at 461, but she also tested positive for anti-TPO at 673. Thyroid receptor Abs (TRAb) were also elevated at 54.8. Her vital signs were stable, but she had marked proptosis and complained of eye dryness, so MMI was restarted. A RAIU scan could not be obtained, but a thyroid US showed a heterogeneous and hypervascular gland. On MMI, her thyroid function tests normalized, and her eye disease vastly improved over 2 years. Her MMI dose was progressively decreased until it was stopped completely. On re-evaluation a few months later, she had newly elevated TSH of 8.7 mcIU/ml and low f-T4 of 0.87 ng/dl, with no symptoms of hypothyroidism, so we opted for management with active surveillance instead of starting her on LT4. Her TSI level improved to 240, but remains elevated. Discussion: It is unclear if our patient has a mixed condition with features of both GD and HT, or if she has HT with a very prolonged hyperthyroid phase (hashitoxicosis). Extended periods of hashitoxicosis have been described, the longest reported lasted for 2 years[1]. Simultaneous presentation of GD and HT is very rare, with only a few cases described in the literature. RAIU scan is often diagnostic, showing increased uptake as seen in GD, but patchy areas of decreased uptake can also be seen. In our case it is likely that HT and GD were coexisting, with GD masking the hypothyroidism, until the former remitted with MMI, and her HT took over. Though no RAIU scan was available, the TSI positivity, clinical response of her hyperthyroidism to MMI and the presence of orbitopathy rule in favor of co-existing GD. Decision to treat with LT4 should be weighed against the risk of causing recurrence of hyperthyroidism. Special considerations should be taken in women of childbearing age due to the difficult management that overlapping hyper/hypothyroidism would entail during pregnancy. References: 1. Shahbaz, A et al. Prolonged Duration of Hashitoxicosis in a Patient with Hashimoto’s Thyroiditis: A Case Report and Review of Literature. Cureus. 2018; 10(6):e2804
SUN-635 Profiling of Activation Patterns of Placental mTOR in Pregnancies Complicated by Gestational Diabetes Mellitus
Authors: Papadopoulou Anna , Thymara Irene , Valsamakis Georgios , Laryngaki Anastasia , Theodorou Spyridoula , Papaevangelou Vasiliki , Grammatopoulos Dimitris , Mastorakos Georgios
Published: May 2020

The mammalian target of rapamycin (mTOR) couples’ energy and nutrient abundance to cell growth and is critically involved in the onset and progression of diabetes, cancer and ageing. Placental mTOR is involved in nutrient sensing and transfer to the fetus; animal models suggest that placental mTOR is upregulated in pregnancies complicated by hyperglycaemia (1). In this study we investigated expression patterns and activation of placental mTOR and possible effects of gestational diabetes (GDM). Our study consisted of GDM-mothers (n=28) and their offspring and ii) mothers (n=33) with normal pregnancies (non-GDM) and their infants. Total and phospho-mTOR (Ser2448) expression were determined in placental biopsies using either immunoblotting and immunohistochemistry (IHC) analysis. Newborn anthropometric parameters were also determined at delivery. GDM pregnant women presented with higher fasting glucose levels than non-GDM (98.12±22.82mg/dL; 73.61±9.89mg/dL; p<0.001). No significant difference was found in birth weight or baby length between GDM and non-GDM infants. IHC analysis showed that both total and activated mTOR were predominantly expressed in trophoblasts and to a lesser extend in syncytiotrophoblasts, in both GDM and non-GDM placentas. GDM placentas exhibited a higher mTOR H-score (2) compared to non-GDM (p<0.012), and WB analysis showed a higher phosphor-mTOR signal intensity (p=0.047) in the same group, most likely due to increased total mTOR expression. mTOR expression was also increased in both GDM syncytiotrophoblasts and endothelial cells compared to non-GDM (p<0.001) whereas a reduced signal was detected in stromal phospho-mTOR (p=0.004). No difference was found in trophoblasts or endothelial cells between the 2 study groups suggesting that activation of this kinase is tightly regulated and is relatively independent of changes in total kinase levels. Interestingly bivariate correlation analysis identified an extensive network of significant associations in the expression levels of total, phosphor-mTOR and P/T mTOR between trophoblasts, stroma, endothelial and syncytiotrophoblastsin control placental biopsies; this network was significantly disrupted in GDM placentas, identifying a disheveled regulation of placental mTOR activity. In conclusion, placental mTOR/PmTOR expression is differentially regulated across different placental cell types and is sensitive to hyperglycaemia associated with gestational diabetes mellitus.(1)M. Castillo-Castrejon and TL. Powell. Front Endocrinol (Lausanne). 2017; 8: 306. (2) E. Lakiotaki, et al., Scientific Reports 2016; 6, 21252.
OR19-05 Steroid:Corticosteroid-Binding Globulin Interactions; Effects of Neutrophil Elastase Cleavage, Pyrexia and Acidosis
Authors: Meyer Emily Jane , Torpy David J , Chernykh Anastasia , Thaysen-Anderson Morten , Nenke Marni Anne , Lewis John , Rankin Wayne , Polyak Steven
Published: May 2020

Context Corticosteroid-binding globulin (CBG) transports cortisol and other steroid hormones1,2. High-affinity CBG (haCBG) undergoes proteolysis of the reactive centre loop (RCL) by neutrophil elastase (NE) at inflammatory sites, liberating immunomodulatory cortisol and altering conformation to low-affinity CBG (laCBG). Pyrexia reduces CBG:cortisol binding affinity, an interaction at the RCL is speculated3. Objective To measure the equilibrium binding constants of a panel of steroids to glycosylated haCBG and laCBG over temperature and pH ranges mimicking the pathophysiological conditions of septic shock. Design Surface plasmon resonance was used to determine the binding profiles of 19 steroid ligands to haCBG and laCBG at temperatures 25°C, 37°C and 39°C and pH 7.4 and 7.0. The RCL-recognizing 9G12 antibody was used to assess cleavage and epitope availability of the RCL across conditions. Results A 4–8 fold reduction in affinity for cortisol, cortisone, corticosterone, 11-deoxycortisol, progesterone, 17-hydroxyprogesterone and prednisolone occurred with NE-mediated haCBG-to-laCBG conversion, cortisol expectedly displayed the highest binding affinity. Binding affinity consistently decreased at higher temperatures and at acidic pH for both haCBG and laCBG. 9G12 antibody RCL binding was preserved for haCBG across temperatures. Conclusions These studies reveal that steroid binding to CBG is selective and in all cases reduced upon NE-mediated haCBG-to-laCBG transition. Moreover, reduced CBG:cortisol binding affinity at elevated temperature occurs with an intact and accessible RCL epitope, suggesting a non-RCL mechanism for the delivery of anti-inflammatory cortisol in pyrexia. Synergy of NE cleavage and pyrexia/acidosis may serve for local inflammatory site cortisol delivery and increase free cortisol. These findings demonstrate the modifiable hormone binding characteristics of CBG in (patho-)physiological conditions, supporting its significance in cortisol delivery in obviating systemic inflammation and multiorgan-organ failure in patients with septic shock and its association with mortality4.

1. Pemberton PA, Stein PE, Pepys MB, et al. Hormone binding globulins undergo serpin conformational change in inflammation. Nature. 1988;336(6196):257–258.

2. Pugeat MM, Dunn JF, Nisula BC. Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab. 1981;53(1):69–75.

3. Cameron A, Henley D, Carrell R, et al. Temperature-responsive release of cortisol from its binding globulin: a protein thermocouple. J Clin Endocrinol Metab. 2010;95(10):4689–4695.

4. Meyer EJ, Nenke MA, Rankin W, et al. Total and high-affinity corticosteroid-binding globulin depletion in septic shock is associated with mortality. Clin Endocrinol (Oxf). 2019;90(1):232–240.
SAT-290 Food Restriction Effects on the Hypothalamus-Pituitary-Gonadal Axis
Authors: Mansano Naira Silva , Bohlen Tabata Mariz , Frazao Renata
Published: May 2020

It is well known that nutritional status affects the reproduction, since an adequate amount of energy is necessary for puberty onset and fertility. However, the neural mechanisms by which energy homeostasis affects reproduction is not completely elucidated. To determine if acute or chronic food restriction (FR) are able to modulate the estrous cycle, adult female mice were used in the experiments. The estrous cycle was evaluated by daily observation of vaginal smear. To determine the effects of an acute FR protocol on estrous cycle, females were individualized and kept on ad libitum diet (control, n=17) or fasted for 24 hours (n= 21). A subgroup of animals was euthanized shortly after the 24-hours test to collect hypothalamus and determinate Kiss1 mRNA levels, while another group of mice were regrouped and fed ad libitum. To determine the effects of a chronic FR protocol on estrous cycle, control mice were individualized and maintained with 100% of daily food content (average of 5 g per day, n = 6), or submitted to 60% of FR (n= 12). Animals were fed ad libitum after test. As expected, mice fasted for 24-hours exhibited a significant weight loss (control: 21.7 g ± 0.5 vs 21.6 ± 0.5 g; fasted: 22.7g ± 0.5 vs 18.7g ± 0.4, P=0.0001). This effect was followed by a significant reduction of hypothalamic Kiss1 mRNA expression (control: 1.0 ± 0.2; fasted: 0.3 ± 0.05, P=0.04, n=4/4 per group). Surprisingly, even under lower Kiss1 mRNA levels, 24-hours fasting induced no changes on estrous cycle. On the other hand, chronic FR induced a gradual weight loss (body weight at the 5th day of FR, control: 21.5g ± 0.2; FR: 17.3g ± 0.7, P=0.0002). The chronic FR was follow by the disruption of estrous cyclicity. While control mice exhibited a regular pattern of cyclicity during the period of evaluation, only leukocytes were identified in the vaginal smear of mice submitted to 60% of FR, even though they had a normal cycling pattern before the test. Therefore, by comparing 30 days of estrous cycle evaluation, including the period before chronic FR, while control mice exhibited cornified cells in the vaginal smear 58.5 ± 4.9% of days, female mice submitted to FR exhibited cornified cells in 38.3 ± 3.8% of days (P= 0.0068). Approximately 3-4 days after the end of the chronic FR females returned to exhibit estrous cyclicity, however the length of the estrous cycle was prolonged compared to control group. Our data suggest that chronic nutritional status variations are required to disrupt the hypothalamus-pituitary-gonadal axis and therefore the estrous cyclicity.
SAT-655 Bile Acid Sequestration Synergistically Accelerates Glucagon Receptor-Stimulated Body Weight Loss in Diet-Induced Obese Mice
Authors: Kim Teayoun , Nason Shelly R , Antipenko Jessica , Presedo Natalie , Finan Brian , DiMarchi Richard D , Habegger Kirk M
Published: May 2020

Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss in obese mice. We have shown that hepatic Farnesoid X Receptor (FXR, a bile acid receptor) and bile acids (BA) play an important role in the anti-obesity effect of glucagon in mice. Specifically, glucagon-receptor (GCGR) agonism is a potent regulator of BA metabolism, increasing total plasma BA levels and preferentially raising cholic and chenodeoxycholic acid levels. These findings led us to hypothesize that BA, signaling via hepatic FXR, contributes to GCGR-stimulated weight loss. Furthermore, we reasoned that BA sequestration may impair GCGR-mediated weight loss by reducing the availability of BA to stimulate FXR-action. Thus, to elucidate the role of BA in GCGR-mediated weight loss, we utilized anion-exchange BA-binding resins (BARS; Cholestyramine and Colesevelam) to prevent intestinal (ileal) re-uptake and reduce plasma total cholesterol, LDL, and BAs via fecal excretion. Diet-induced obese (DIO) C57Bl/6J mice were randomized to groups matched for body-weight and administered daily GCGR agonism (IUB288, 10 nmol/kg, s.c.) or vehicle, in the presence or absence of BARS. Consistent with our prior findings, IUB288-treatment reduced body weight in DIO mice. Counter to our original hypothesis, IUB288+Cholestyramine (3% in high fat diet, HFD [58% kcal%]) enhanced IUB288-stimulated weight loss. Similar body-weight loss effects following combined IUB288 and BARS treatment were replicated both at a lower dose of Cholestyramine (1.5% in HFD), as well as in combination with both low- (2% in HFD) and high- (4% in HFD) dose Colesevelam. IUB288-stimulated weight loss is accompanied by suppression of food intake (FI), while Colesevelam alone did not significantly lower FI at either dose (2 or 4% in HFD). However, 4% Colesevelam with IUB288 completely suppressed FI, while 2% Colesevelam stimulated a reduced, though not complete suppression. GCGR agonism is a potent stimulus of weight loss; however, its impairment of glucose tolerance reduces its value as a monotherapy. Excitingly, Cholestyramine (3% in HFD) rescued IUB288-induced glucose intolerance, restoring glucose excursion to levels observed in control (vehicle-treated) mice. Together these studies suggest BARS may enhance the anti-obesity effect of GCGR agonism, beneficially regulate feeding behaviors, and prevent GCGR-stimulated glucose dysregulation in DIO mice. Furthermore, these studies argue that GCGR agonsim combined with BARS treatment may represent a novel therapeutic approach for obesity and obesity-associated glucose intolerance.
MON-358 Hypercalcemia During Teriparatide Therapy
Authors: Milosavljevic Jovan , Thomas Asha Mary
Published: May 2020

Background : Teriparatide (TPTD) is a recombinant PTH analog used as an anabolic agent in the treatment of osteoporosis that stimulates bone formation and activates bone remodeling. The most common side effects are nausea, vomiting, hypertension and dizziness. Transient hypercalcemia is a known adverse effect which is usually seen a few hours after administration and resolves within 16 hours. However, marked late hypercalcemia is a rare event and may be of concern in clinical practice.

Clinical Cases : Case 1 is a 54-year-old man with a history of osteoporosis (lumbar spine T-score of -2.8), previously treated with bisphosphonates and who had been on a course of TPTD for about 6 months in but had not been consistent in taking the medication. Prior to subsequently restarting TPTD, his initial labs were notable for a normal Ca 9.3 mg/dl (8.5 - 10.1 mg/dl), vitamin D 25 OH 49 ng/ml (30.0 - 100.0 ng/ml) and PTH 41.3 pg/ml (8.7 - 77.1 pg/ml). Six months into the treatment, he was noted to have asymptomatic hypercalcemia of 11.2 mg/dl approximately 24 hrs after the last TPTD injection. A repeat calcium of 10.7 mg/dl was obtained while still on therapy with TPTD with normal levels of vitamin D 25 OH of 45 ng/ml.

Case 2 is a 75-year-old woman with a history of osteopenia and severe scoliosis, who had been on a course of raloxifene and then preventive doses of alendronate previously. Prior to starting TPTD, her Ca levels were normal at 9.3 mg/dl, PTH was 24 pg/ml and vitamin D 25 OH was 33 ng/ml. However, six months into the treatment she was noted to have elevated Ca of 12.5 mg/dl (24 hrs after the last TPTD dose), with low levels of vitamin D 25 OH of 24.2 ng/ml. Ca levels returned to the baseline of 9.3 mg/dl when TPTD was held.

Conclusion : Teriparatide has a long track record of safety and does have the rare side effect of hypercalcemia. 1-3% of patients may have mild hypercalcemia after administration. Intake of calcium and vitamin D should be monitored at the start of therapy given these concerns. Although almost never a cause of discontinuation of treatment in clinical practice, it is important to be aware of this side effect in patients who may be at risk of complications of hypercalcemia.
OR12-04 Regulatory Sharing between Estrogen Receptor Alpha Bound Enhancers
Authors: Gertz Jay , Carleton Julia , Ginley-Hidinger Matthew
Published: May 2020

Mammalian genomes encode an order of magnitude more gene expression enhancers than promoters, suggesting that most genes are regulated by combinations of enhancers. We previously found that neighboring estrogen-responsive enhancers exhibit cooperative/synergistic contributions to an estrogenic transcriptional response1. However, when the same combinations of enhancers are targeted with synthetic activators in the absence of estrogens, then the regulatory regions exhibit independent effects on gene expression2. Taken together, these findings indicate that estrogen receptor alpha (ER) bound enhancers cooperate with each other in cis but influence target gene promoters independently. To determine the molecular underpinnings of enhancer cooperativity, we generated genetic deletions of individual ER bound enhancers. We discovered “regulatory sharing” between enhancers in which loci containing full estrogen response elements (EREs) contribute ER binding to neighboring sites, while enhancers with pre-existing histone acetylation/accessibility contribute this permissible chromatin environment to the neighboring enhancers upon estrogen induction. Genome engineering revealed that a cluster of two half ERE enhancers could not compensate for a full ERE site loss within the cluster. However, two full ERE enhancers produced a transcriptional response greater than the wild-type locus, suggesting that combinations of enhancers are not necessarily configured for a maximal response. By swapping genomic sequences, we found that the genomic location in which a full ERE resides strongly influences enhancer activity. Our results lead to a model in which a full ERE is critical for ER recruitment, but the presence of pre-existing histone acetylation and accessibility within an enhancer cluster is also needed in order for estrogen-induced gene regulation to occur.

References 1. Carleton JB, Berrett KC, Gertz J (2017). Multiplex Enhancer Interference Reveals Collaborative Control of Gene Regulation by Estrogen Receptor α-Bound Enhancers. Cell Syst, 5(4), 333-344.e5.2. 2. Ginley-Hidinger M, Carleton JB, Rodriguez AC, Berrett KC, Gertz J. Sufficiency analysis of estrogen responsive enhancers using synthetic activators. Life Sci Alliance, 2(5).
SUN-517 Methimazole-Induced Neutropenia in Premature Twins with Graves’ Disease
Authors: Ballestas Estefania Rodriguez , Ejaz Sehar
Published: May 2020

Introduction: Neonatal Graves’ disease (NGD) occurs in approximately 1-5% of infants born to women with Graves’ disease. It is caused by trans-placental crossing of thyroid stimulating immunoglobulin (TSI) antibodies during third trimester. Hyperthyroidism during pregnancy can lead to craniosynostosis, goiter, premature bone maturation, developmental delay or even heart failure in the neonate. Neonatal Hyperthyroidism is usually transient and resolves in few weeks. Treatment consists of beta blockers and Methimazole. Studies in adults recommend discontinuing of Methimazole if patients develop neutropenia. However due to lack of alternatives, we present a case of continued use of Methimazole with neutropenia in newborn twins.

Case Report:

33 weeks gestational age mono-chorionic/di-amniotic twins born to a 34-year-old woman with poorly controlled hyperthyroidism. Mother diagnosed with Graves’ disease during 2nd trimester with poor control throughout pregnancy. At the time of delivery, maternal TSH was <0.005uIU/mL(0.358-3.74uIU/mL) and FT4 2.18ng/dL(0.76-1.46ng/dL). Antenatal ultrasound at 32 weeks showed homogeneous enlargement of fetal thyroid glands with increased vascularity in both twins. Babies found to have diffuse goiter and exophthalmos at birth. Thyroid tests remained normal for first 3 days of life. By day 3, babies labs showed TSH <0.005uIU/mL, FT4 -8 ug/dL and TSI >700%. Baseline CBC showed ANC of 4.95K/mm3. Babies were started on Methimazole 0.5mg/kg/day and Propranolol 2mg/kg/day. TFTs fluctuated throughout their stay in NICU and they developed neutropenia with ANC 1.23K/mm3 on day 20 of life. Methimazole was initially discontinued then restarted at 0.25 mg/kg/day 3 days later. There is no recommended protocol for restarting Methimazole. Further follow up showed persistent neutropenia despite multiple dose adjustments in Methimazole, including dosing every other day. ANC was maintained around 800-1100K/mm3. At age 2 months, Methimazole was discontinued completely after TSI antibodies decreased to 400%. ANC remained low until 6 months of life, even after discontinuing Methimazole. Both babies ultimately developed central hypothyroidism and were started on l-thyroxine.

Discussion:

NGD can range anywhere from transient hyperthyroidism to persistent central hypothyroidism. Early diagnosis and treatment is crucial to prevent significant morbidity and mortality. Methimazole is the only approved treatment at this age, and management of Methimazole-induced neutropenia has not been established. Adult studies recommend discontinuing Methimazole in context of neutropenia; we took an approach of decreasing dose gradually. Further studies are needed to establish step-wise approach in managing Methimazole-induced neutropenia.
SUN-906 To Function or Not to Function: A Rare Case of Metachronous Hormone Syndrome
Authors: Amine Adele , Ghanta Neelima , Reynolds Raymond
Published: May 2020

This is a 51-year-old female with a history of metastatic neuroendocrine tumor of the pancreas diagnosed four years ago who was admitted to the to the hospital for hypoglycemia. She initially had come to the hospital for alternative treatment of her disease using PRRT (peptide receptor radionuclide therapy). Prior to receiving treatment the patient had been asymptomatic. After receiving her first dose of PRRT the patient developed acute encephalopathy. Upon evaluation she was noted to be oriented only to person, lethargic and confused. Finger stick blood glucose at the time of her symptoms had read 17. The patient was immediately placed on D10 with improvement of her symptoms and increase of glucose to the 70s. An attempt was made to wean the patient off of dextrose however the patient continued to experience persistent hypoglycemia. Thus investigation of an insulin-secreting tumor was done. C-peptide was 3.98 ng/mL (0.81 - 5.30 ng/mL), insulin level was 26.7 uU/mL (3.0-16 uU/mL) and proinsulin level was 556 pmol/L (<22 pmol/L), while her serum glucose was below 45. Given her biochemical markers as well as improvement in glucose when treated the patient was started on Diazoxide for presumed insulinoma. Due to intolerance to the medication she was switched to Octreotide with success.

Here we present an unusual case of Metachronous Hormone Syndrome (MHS) in a patient who at presentation of her diagnosis was already found to have metastatic pancreatic neuroendocrine tumor. Typically NET present in the 4th to 6th decades of life and have the potential to secrete peptide hormones. Occasionally patients with tumors that appear to be nonfunctional develop symptoms of hormone secretion later in their disease such as our patient. Furthermore it is uncommon for a patient to present with metastatic NET; such was not the case for our patient. Metachronous hormone syndrome is not fully understood but may be an indication of tumor progression. In addition its mechanism of action is unknown and its been theorized to be induced by anti-tumor treatments. Perhaps this case may allow us to better understand MHS in a broader context, as this patient was found to have progression of her disease when she initially was diagnosed 4 years ago and recently presented with symptoms consistent with an insulinoma. Lastly her case may further guide us in studying various treatments for NET and their role in triggering MHS.

References 1. De Mestier, Louis et al. Metachronous hormone syndromes in Patients With Pancreatic Neuroendocrine Tumors: A Case Series Study. Annals of Internal Medicine. 2015; 162 (10): 682-689. 2. Mathur, A, Gorden, P and Libutti SK. Insulinoma. The Surgical Clinics of North America. 2009-10-01, Volume 89, Issue 5, Pages 1105- 1121. 3. Igarashi, H, Hiijoka, M, Lee, L and Ito, T. Biotherapy of pancreatic neuroendocrine tumors using somatostatin analogs. Journal of Hepatobilliary Pancreatic Sciences. 2015, Volume 22, Issue 8.
SUN-312 Strikingly Low Prevalence of Pituitary Incidentalomas in Our Hospital
Authors: Sosa Natalia , Rivero Florencia , Tripodi Diego , Negrotto Matias , Lima Ramiro , Pineyro Maria Mercedes
Published: May 2020

Introduction: Pituitary incidentalomas (PIs) have been reported in 10.6% of autopsies, 4-20% in computed tomography scans (CT) and 10-38% in magnetic resonance imaging (MRI), most of them microincidentalomas(<1cm). They may be have autonomous hormonal activity or impair normal gland function. The frequency of PIs in Uruguay is unknown. We aimed to investigate the prevalence of pituitary incidentalomas in our Hospital. Methods: We retrospectively identified all patients who underwent brain CT and MRI at our hospital over a 1-year period for disorders other than known or suspected pituitary disease. The period covered was from January 1 to December 31, 2017. We reviewed all scans; anamnesis and biochemical evaluation was performed on patients who presented PIs. Results: During this period 3894 patients underwent imaging studies. MRI was performed in 1146 patients, and CT in 2748 of them. Mean age was 53,1 ± 19 years, with similar gender distribution (50.6% women). Most imaging studies where ordered in the emergency department (43%), followed by the outpatient clinics (29%) and inpatient wards (28%). Most common reasons that led to request the image were trauma (20.4%), headaches (11.3%) and stroke (10.9%). We detected two PIs, which accounts for a prevalence of 5 cases per 10,000 individuals per year (0.05%). Both where detected by CT, with a MRI done later to further evaluate them. Final diagnosis was of a vascular aneurysm and a sellar meningioma. Work-up showed a secondary hypothyroidism in the patient with the sellar meningioma. No cases of pituitary adenomas were found. Discussion: We observed a strikingly lower prevalence of PIs than that reported in the literature. In addition, no PIs where found in MRI. Moreover, no pituitary adenoma was discovered. The reasons for these findings are unknown. In our study scans were not focused to the pituitary fossa so small lesions may have been missed. However, Esteves et al(1) reported a prevalence of PIs 5.8% in 1232 patients who had head MRI/CT, not pituitary MRI. In addition, the majority were pituitary adenomas, almost 40% of them microadenomas. Slices of 2-mm thickness were obtained in the scans, similar to imaging techniques used in other studies. Most reports have longer study duration (3-5 years).Our hospital is a teaching hospital where fellows evaluate scans initially, which are then reevaluated by neuroradiologists. This may account for the prevalence found, as sensitivity may be lower when professionals in training evaluate scans. In addition, frequency of pituitary hipointensity areas may decrease as the number of reviewers increase. Furthermore, this low prevalence could be related to difference in population characteristics.Conclusions: We found a very low prevalence of PIs in our hospital. More studies are warranted to further investigate frequency of PIs in our country. (1)Esteves et al. Pituitary. 2015;18(6):777-81.
MON-498 Thyroseq V3 GC for Bethesda III and IV: An Institutional Experience
Authors: Desai Dimpi , Lepe Marcos , Kim Caroline S , Kobaly Kristen , Baloch Zubair Wahld , Mandel Susan J
Published: May 2020

Background:

Molecular testing of thyroid nodules classified as indeterminate on fine-needle aspiration (FNA) is used for patient management. ThyroSeq® v3 genomic classifier is a commercially available test that examines a wide spectrum of genomic alterations in a thyroid FNA sample based on algorithmic analysis and reports test results as either negative (including currently negative) or positive. This study reviews our institutional experience with Thyroseq® V3 to distinguish between benign disease versus cancer in thyroid nodules diagnosed as Bethesda III or IV on cytology.

Methods:

Thyroid nodules with Bethesda III or IV cytology diagnoses and available Thyroseq® V3 results from 12/17 to 8/19 were retrieved from the pathology database. Cytopathology diagnoses were correlated with molecular testing and histopathology.

Results:

416 cases (Bethesda III n=252, Bethesda IV n=164) were retrieved: 295 (71%) were reported as Thyroseq® V3 negative and 121 (29%) as positive. The 82.1% (207/252) benign call rate (BCR) of Thyroseq® v3 for Bethesda III was significantly higher (p<0.001) than that for Bethesda IV, BCR 54% (88 /164). Histopathologic follow-up was available for 128 cases (96 ThyroSeq® v3 positive, 32 ThyroSeq® v3 negative): 57 benign and 71 malignant (including NIFTP). For Bethesda III and IV diagnoses respectively, the test demonstrated 91.7 % (95% Cl 73%-99%) and 91.5% (95% Cl 80%-98%) sensitivity, 94% (95% Cl 90%-97%) and 82.4% (95% Cl 74%-89%) specificity, 99% (95% Cl 96%-99%) and 95% (95% Cl 89%-98%) negative predictive value and 63% (95% Cl 50%-74%) and 70.5% (95% Cl 61%-79%) positive predictive value, given malignancy rates 10% Bethesda III; 32% Bethesda IV. 45 unique combinations of genetic alterations were detected in the 96 operated ThyroSeq® v3 positive cases—34 combinations (76%) were present in <2 cases and only 3 combinations occurred 7 or more cases. Forty-six (48%) nodules had RAS mutations, either combined with other mutations 31% (23/30, 77% malignant) or alone, 17% (10/16, 63% malignant), followed by

THADA/IGF2BP3 gene fusion changes,11.5% (10 /11 malignant). Three cases with BRAF mutations (1 V600E, 1 K601E, 1 K601N) were malignant. Copy numbers alterations alone were present in 10 (5/ 10 malignant) and the gene expression profile alone was positive in 5 cases (all malignant). Mutations that were associated with benign pathology were PTEN, DICER1, E1F1AX and TP53. There were 6 false negative cases, 5 low risk cancers by American Thyroid Association criteria and 1 NIFTP.

Conclusion:

The high BCR of Thyroseq® v3 for Bethesda III category avoids surgery for majority of patients. A more comprehensive mutational and fusion panel reveals the complexity of the genetic signature of indeterminate nodules. Future larger and likely multicenter studies will be required to define the associated cancer risk and potential prognosis associated with adjunct molecular testing.