bluuebunny/crossref_metadata_2025_split huggingface dataset:
SUN-925 Carcinoid: A Crisis in the Upside Down
Authors: Arzeno Luis E , Lessard Kimberly Kochersperger , Jabbour Serge A 
Published: May 2020

Abstract
Unrecognized carcinoid tumors can rarely present as a life-threatening condition known as carcinoid ‘crisis’ which typically presents as significant but transient hypotension if there is no appropriate preventive treatment. Somatostatin analogs such as Octreotide are agents of choice to avoid such crises. However, there is minimal literature and a lack of guidelines regarding the management of an active, labile carcinoid crisis in patients exhibiting both hypotension and hypertension, as will be presented here.
Case: A 76-year-old female with end-stage renal disease, status post kidney transplant on immunosuppressants, who was initially admitted for workup of hematuria. Abdominal CT revealed a bladder mass with various features concerning for malignancy and an incidental mesenteric mass, followed by bladder biopsy suggestive of neoplasm. The patient was taken to the OR where she first underwent resection of the bladder mass with subsequent proceeding to the removal of the mesenteric mass. Within minutes of manipulation of the mass, the patient became significantly hypotensive with a mild response to fluid resuscitation, requiring vasopressors. A frozen section suggested the possibility of a neuroendocrine tumor. Given concerns of carcinoid crisis the patient was started on Octreotide infusion achieving some degree of hemodynamic stabilization but soon developed extremely labile blood pressure with rapidly alternating hypotension (SBP &lt;60mmHg) and hypertension (SBP &gt;200mmgHg). During hypotensive episodes, the aid of adjunctive beta-adrenergic agents was required, while the doses for the Octreotide infusion were as high as 200mcg/hr. Initial Endocrinologic workup revealed a Chromogranin A level 1,178 ng/mL (25 - 140 ng/mL), VIP &lt;50 pg/mL (&lt;75 pg/mL), 24 hr 5HIAA 23.5 (&lt;=6.0 mg/24 h), Serotonin 2,334 ng/mL (56 - 244 ng/mL) consistent with carcinoid. Repeat Serotonin levels 5 days after octreotide infusion was 674 ng/mL. The patient was successfully weaned from vasopressors but required continuation of Octreotide for additional 5 days due to intermittent episodes of hypotension.
Carcinoid crisis is a life-threatening condition associated with hypotension, and less commonly hypertension, from the release of vasoactive agents from tumor manipulation. Preparation with Octreotide before any manipulation or anesthesia is recommended to avoid a carcinoid crisis. However, if a crisis develops management is mainly with a continuous Octreotide infusion. The use of beta-adrenergic agents is debated, due to a possible “paradoxical effect” which could further worsen hypotension. Others argue that there is a role in preventing prolonged episodes of hypotension. In this case, it was required high doses and the infusion was needed for 5 days, probably related to the presence of ESRD which could have prolonged the bioavailability of the vasoactive agents.
MON-239 Pituitary Apoplexy Induced by Gonadotropin-Releasing Hormone Agonist Administration: A Rare Complication of Prostate Cancer Treatment
Authors: Barbosa Mariana Marques , Paredes Sílvia Cristina de Sousa , Machado Maria João , Almeida Rui , Marques Olinda Castro 
Published: May 2020

Abstract
Background: Pituitary apoplexy is a potentially life-threatening clinical condition associated with bleeding and/or infarction into the pituitary gland, usually within a tumor. Gonadotropin-releasing hormone (GnRH) agonists, currently used in the treatment of advanced prostate cancer, have been described in the literature as a rare cause of pituitary apoplexy.
Case: We report the case of a 69 year-old man with a known pituitary macroadenoma incidentally detected in 2016, without further investigation. He was diagnosed with prostate cancer in 2017 and underwent retropubic prostatectomy. Two years later there was evidence of histologic prostate tumor progression, so he started treatment with leuprorelin 45mg (GnRH agonist). Immediately after the first subcutaneous injection he presented with acute-onset severe headache, followed by left eye ptosis, diplopia and vomiting. Left cranial nerve III palsy was confirmed by examination in the emergency department. Head computed tomography showed a lesion in the sellar region; laboratory endocrine workup was significant for total testosterone 72.07 ng/dL (86.49 – 788.22), with no other abnormalities. Magnetic resonance imaging of the pituitary revealed tumor enlargement and a T1-hyperintense signal, compatible with recent haemorrhagic sellar content. The patient was managed conservatively with high dose steroids, and symptoms were significantly improved on discharge.
Discussion: Pituitary apoplexy induced by GnRH agonist administration is a rare complication, described in only 20 documented cases to date. The pathophysiologic mechanism involved is not clearly established and several hypotheses have been proposed: a combination of metabolic hyperactivity, cell division/tumor growth and increased intrasellar pressure, inducing ischemia in a poorly perfused adenomatous tissue given the demand. Although uncommon, healthcare professionals should be aware of this serious consequence of GnRH agonist administration and recognize the signs, preventing a delay in diagnosis and treatment.
SUN-044 Gonadotropin Releasing Hormone (GnRH) Agonist Therapy Induces a Sustained Reduction in Plasma Testosterone Levels and Is Well Tolerated in Transwomen Veterans
Authors: Gondin Lyan , Trejo Jonathan , Pinkson Sheila , chen xi , Case Emina , Wortham Joy , koops Maureen , Tripathy Devjit 
Published: May 2020

Abstract
Gender affirming hormone therapy (GAHT) is the mainstay of long-term management of transgender individuals. In transwomen, treatment with physiologic doses of estrogen alone is often insufficient to suppress testosterone to the desired level. Although GnRH agonist therapy is usually prescribed for puberty suppression in trans youth, in adult transwomen, GnRH agonist may be added. The durability of long-term GnRH agonist in lowering testosterone as well as the long-term safety is not clear. We examined the effect of leuprolide a GnRH agonist, on testosterone as well as clinical and metabolic features in transwomen Veterans. Out of 91 subjects with gender dysphoria followed at a VA Endocrinology clinic, 65 were transwomen (age 49 ± 3 years) who had a detailed clinical, biochemical and hormonal profile (lipid profile, HbA1C, FPG, testosterone, estradiol). We performed a retrospective cohort study of the 31 (48%) transwomen on Leuprolide (3.375mg q month) and 33 transwomen who were not on Leuprolide. Plasma testosterone, lipid profile, were analyzed before, 6 months, 1 year and at the last follow-up visit. The median follow-up of subjects on Leuprolide was 2.7 (1.7-3.8) years. Plasma testosterone concentration declined by 89% from 432±32 ng/dl to 47±9 ng/dl within 3-6 months after initiation of GnRH agonist treatment. Plasma testosterone remained persistently low 39±4ng/dl at 1 year and at the end of 2.7 yrs, most subjects on Leurprolide had plasma testosterone concentration &lt;50ng/dl. Leuprolide therapy led to similar rapid decline in testosterone concentration in both younger (&lt;40yrs) or relatively older (&gt;50yr) transwomen. Leuprolide was in general well tolerated requiring discontinuation in just one patient due to severe fatigue. Three subjects (10%) experienced hot flashes which did not lead to discontinuation of medication. In the non-Leuprolide group, of 33 subjects, the follow-up was relatively inconsistent and only 12 subjects were regularly followed throughout a year with stable treatment. The decline in plasma testosterone was of a lower magnitude versus the leuprolide group (55% vs 89%, p &lt;0.05). The testosterone levels declined from 393±42 to 180±44 ng/dl at 6 months. Body weight, and lipid profile: triglyceride, and plasma HDL concentration did not change significantly with or without GnRH agonist therapy. In conclusion, GnRH agonist therapy led to a sustained suppression of plasma testosterone levels in transwomen and was not associated with worsening lipid profile, was effective, and well tolerated in transwomen regardless of their age and may be considered an adjunct to the ant-androgen and estrogen therapy.
SUN-140 TMEPAI Inhibits SMAD 2/3 Mediated Muscle Wasting
Authors: Kharoud Swati , Walton Kelly Louise , Hagg Adam , Goodchild Georgia , Chen Justin , Thomson Rachel , Qian Hongwei , Gregorevic Paul , Harrison Craig Anthony 
Published: May 2020

Abstract
Inhibition of myostatin and activin activity using ligand traps, such as soluble receptors, follistatin and propeptides, can markedly increase skeletal muscle mass in healthy mice and ameliorate wasting in models of cancer cachexia and muscular dystrophy. Though effective, clinical translation of these approaches has been hindered by off-target effects. Toward the goal of developing tissue-specific myostatin/activin interventions, we explored the ability of transmembrane prostate androgen-induced (TMEPAI) to promote growth of skeletal muscle. TMEPAI, a transcriptional target of activin in muscle, is a known inhibitor of TGF-β1-mediated SMAD 2/3 signalling. In this study we show that TMEPAI also blocks activin A, activin B, myostatin and GDF-11 in vitro activity. Adeno-associated viral (AAV) gene delivery of TMEPAI into healthy mice increased local muscle mass by as much as 30%. Increased muscle mass was attributed to hypertrophy of fibres in TMEPAI-expressing muscles, and was coincident with an upregulation in markers of protein synthesis (pAkt, pMTOR, p70S6K). The ability of TMEPAI to block activation of the canonical activin/myostatin-SMAD 2/3 axis, was demonstrated by co-injecting AAV6:activin A and AAV6:TMEPAI into healthy mice. In this setting, TMEPAI blocked activin-induced phosphorylation of SMAD3 and associated skeletal muscle wasting. Finally, delivery of AAV6:TMEPAI into tibialis anterior muscles of mice bearing C26 tumours prevented muscle atrophy normally associated with this model. The results support that viral gene delivery of TMEPAI can effectively increase muscle mass via inactivation of the activin/myostatin-SMAD 2/3 pathway.
SUN-015 Developmental Programming: Depot-Specific Inflammatory State and Distribution of Thermogenic Adipocytes Programmed by Gestational Testosterone Excess
Authors: Ciarelli Joseph Norman , Puttabyatappa Muraly , Padmanabhan Vasantha 
Published: May 2020

Abstract
Prenatal testosterone excess induces insulin resistance, dyslipidemia and cardiovascular defects in ewes. Considering adipose depots influence systemic metabolic status, disruptions in visceral (VAT), subcutaneous (SAT), pericardiac (PCAT) and perirenal (PRAT) adipose depots may contribute to these metabolic defects. While the changes in PCAT and PRAT in the prenatal T-treated sheep are unknown, we found an increase in the oxidative stress and inflammatory state in the VAT but not SAT, while insulin sensitivity is maintained in both depots (Biol Reprod 2016;94:113). Although all four depots are rich in white adipocytes that specialize in lipid storage, it is not clear what underlies the depot-specific differences. A potential contributor may relate to depot-specific differences in presence of brown/beige adipocytes. Brown/beige unlike white adipocytes are thermogenically active due to their expression of uncoupled protein 1 (UCP1), which uncouples mitochondrial oxidative phosphorylation to release stored energy as heat. Because they favor lipid utilization rather than storage they promote a metabolically healthy phenotype. We hypothesized that the relative distribution of brown/beige adipocytes may contribute to the depot-specific changes in inflammatory state. To test this, adipose depots from control (n=6) and prenatal T- (100mg T propionate twice a week from days 30-90 of gestation)-treated (n=5) female sheep were studied at 21 months of age. The changes in expression of inflammatory and thermogenic adipocyte markers were assessed by real time RT-PCR and data analyzed by Student’s t-test and Cohen’s effect size analysis. Prenatal T-treatment induced 1) significant increase in inflammatory cytokine interleukin 6 in VAT and PRAT while decreasing it in PCAT 2) significant increase in tumor necrosis factor in the VAT and a trend (evident by effect size analysis only) for an increase in SAT and PCAT and 3) significant increase in PRAT and a trend toward increase in the macrophage marker CD68 expression in VAT. Among the thermogenic gene markers, the expression of UCP1 was significantly increased in VAT and PCAT with a trend for an increase in PRAT. The expression of UCP2 and PPAR gamma co-activator 1 beta (PPARGC1B) were also significantly elevated in VAT with a trend for an increase in SAT. These findings are indicative of depot-specific differences in prenatal T-induced inflammatory status with effects being pronounced in VAT compared to other depots. The increases in thermogenic markers in adipose depots do not support our hypothesis but rather are reflective of a compensatory response to promote adipose depot insulin sensitivity and may have a bearing on function of organs in the proximity of respective depots. These findings are likely of translational significance in metabolic disorders associated with hyperandrogenic state.
OR14-02 Circadian Regulation of Chromatin State Mediates Pancreatic Islet Incretin Response
Authors: Weidemann Benjamin John , Kobayashi Mikoto Alfred , Marcheva Biliana , Bass Joseph T 
Published: May 2020

Abstract
The circadian clock is programmed by an autoregulatory transcription feedback loop present in brain and peripheral tissues that coordinates metabolism with nutritional state and the sleep-wake cycle. Epidemiologic and genetic studies indicate circadian disruption as a risk factor in the development of diabetes. We have demonstrated that conditional ablation of the β cell clock in adult life leads to hypoinsulinemic diabetes, and through mRNA-sequencing in mouse and human islets we revealed clock control of gene networks involved in insulin secretion, nutrient sensing, and exocytosis. A remaining question is: How does the core molecular clock modulate time-of-day dependent chromatin state to regulate pancreatic islet response to glucose and insulin secretagogues? Here we report that loss of the pancreatic β cell molecular clock results in closed chromatin at cAMP-responsive gene regulatory elements and dysregulated cAMP-dependent coregulator recruitment following cAMP agonism, consistent with a role for the molecular clock in mediating cell response to environmental stimuli. Further, tandem analyses of ATAC- and ChIP-sequencing in synchronized islets revealed dynamic chromatin accessibility across the 24-hour cycle at genes regulating insulin secretion and at genomic regions enriched for signal-inducible and circadian transcription factor motifs. Our genome-wide sequencing reveals a new role for the clock in global chromatin remodeling underlying the incretin response in pancreatic β cells.
MON-016 Neural Circuits and Hormonal Mechanisms Underlying the Negative Impact of Stress on Pregnancy Outcomes
Authors: Gotlieb Neta , Wilsterman Kathryn E , Finn Samantha L , Browne Madison , Hu Damhee , Cornejo Diana , Hutchinson Gwyneth , Iwakoshi-Ukena Eiko , Ukena Kazuyoshi , Bentley George E , Kriegsfeld Lance J 
Published: May 2020

Abstract
Despite numerous findings detailing the negative impact of stress on female reproductive health, the means by which stress acts on the CNS and periphery to compromise reproductive success remains poorly understood. As a result, the current study sought to clarify the neuroendocrine mechanisms by which stress acts on the brain to deleteriously influence pregnancy outcomes. Reproduction is regulated by the hypothalamo-pituitary-gonadal (HPG) axis, with hypothalamic gonadotropin-releasing hormone (GnRH) neurons representing the final, common pathway of this axis. Cells expressing the inhibitory neuropeptide, RFamide-related peptide-3 (RFRP-3), lie upstream of the GnRH system and are markedly regulated by environmental and psychosocial factors, including stress. In the present study, we asked whether RFRP-3 neurons mediate the effects of stress on pregnancy outcomes through the regulation of prolactin secretion, as prolactin is critical for pregnancy maintenance. More specifically, because specialized hypothalamic dopaminergic neurons, namely tubero-infundibular dopaminergic (TIDA) neurons, are major regulators of prolactin secretion, we hypothesized that RFRP-3 neurons directly target TIDA cells to negatively influence fetal development. To test this possibility, we subjected pregnant mice to chronic restraint stress for the first half of pregnancy and performed a broad screen of hypothalamic neuroendocrine function compared to non-stressed controls. Stressed mice exhibited elevated baseline concentrations of corticosterone that remained high at least 6 days after the final exposure to stress. Whereas progesterone concentrations were reduced by stress early in pregnancy, stressed mice recovered typical progesterone secretion during late gestation. These early, stressful experiences resulted in persistent developmental delays, reduced embryo weight, and abnormal placental histology. Significantly, a small percentage of TIDA cells receive close contacts from RFRP-3 axons, providing a mechanism for the control of prolactin secretion by stress. However, contrary to expectation, the percentage of TIDA neurons receiving input from RFRP-3 cells was not impacted by stress. Together, these findings identify a potential pathway of control for the impact of stress on neuroendocrine factors critical to pregnancy success, although further work using more sensitive approaches is needed to examine the putative role of RFRP-3 on stress-induced pregnancy outcomes.
MON-510 Patients with Large Multinodular Goiters Operated for Presumed Benign - Large or Growing Thyroid Nodules, Have a High Likelihood of Significant Synchronous Thyroid Cancers
Authors: Bantouna Dimitra , Paparodis Rodis , Karvounis Evangelos , Livadas Sarantis , Chourpiliadis Charilaos Paulos , Hourpiliadi Hara , Shanawaz Imam , Jaume Juan Carlos 
Published: May 2020

Abstract
Introduction: Despite the current state of evidence suggesting that thyroid nodules’ size should not be the sole criterion for the decision to undergo thyroidectomy, many patients are still operated for large, or growing nodules. In order to ascertain whether this is a justifiable approach, we performed the present study.
Methods/ Subjects: We reviewed the data from two prospectively collected databases of patients undergoing thyroid surgery in two tertiary referral centers, one in the USA (A) and the other one in Greece (B) over 14 consecutive years. We collected data on the preoperative surgical indication, FNA cytology and surgical pathology. We included subjects with multinodular goiters, operated solely for large or growing thyroid nodules, who did not have any known or presumed thyroid cancer, or indications of high risk for malignancy (FNA suspicious for thyroid cancer, follicular neoplasm, suspicious for follicular neoplasm, FLUS/AUS, cellular specimen), family history of thyroid cancer or prior neck radiation exposure.
Results: We reviewed 5523 consecutive cases of thyroid surgery (A:2711, B:2812). After excluding n=3059 subjects, we included n=2464 subjects in the present analysis. Overall 535 thyroid cancers were identified (21.7%): 349 (65.2%) were microcarcinomas (&lt;1cm), 161 (30.0%) were macrocarcinomas (≥1cm) and 25 of undetermined size. The histology was consistent with papillary cancer (PTC) n=500, follicular cancer (FTC) n=14, Hurthle cell cancer (HCC) n=9, medullary cancer (MTC) n=4, thyroid lymphoma n=1 and mixed histology cancers n=4. In n=68 (2.75%) cases, a thyroid cancer was found in the large or growing thyroid nodule, which was the original indication for surgery. The cancers were multifocal in n=165 subjects; there was extrathyroidal extension in n=61, capsular invasion was present in n=80, lymph node involvement in n=35 and bone metastasis in n=2 subjects.
Conclusions: Although the likelihood of identifying a clinically relevant thyroid cancer in a large or growing nodule, in the absence of risk enhancing features, is low; the risk of synchronous, clinically important, thyroid cancers is high in patients with large multinodular goiters. Therefore, more precise screening strategies are urgently needed to identify the patients, who would clearly benefit from thyroid surgery and protect those who do not need to be operated on.
SAT-718 Inhibition of Androgen Receptor Activity by DDE Is Affected by Mutations in the BF3 Site
Authors: Lozano Andrea , Kotsikorou Evangelia , Dean Frank B 
Published: May 2020

Abstract
The androgen receptor (AR) plays an important role in the development of the male phenotype and traits. Some diphenyl compounds inhibit AR activity by binding to a hydrophobic surface binding site, BF3. A similar diphenyl structure is found in 4,4’ DDT and its breakdown product 4,4’ DDE. Previous results showed that DDT and DDE induced the release of bound dihydrotestosterone from the AR ligand binding domain, with IC50 values ranging from 54 to 82uM. This suggested that DDT and related compounds may act as endocrine disrupting chemicals by binding to the BF3 site and inducing allosteric changes in the AR structure, disrupting binding of the steroid to the ligand binding domain. Here, an AR reporter system was transiently transfected into HEK293 cells and AR activity was measured using a dual luciferase assay. The system was used to measure the response of the AR protein to varying concentrations of dihydrotestosterone in the presence and absence of DDE. DDE inhibited the activation of AR by dihydrotestosterone under these conditions. Five mutant AR genes with amino acid changes in the BF3 site were tested for alterations in the ability of DDE to disrupt AR activity. The five mutations tested were F673K, F673W, G724R, G724M, and L830D. The ability of DDE to inhibit AR activity was reduced by the mutations in the BF3 site. These results suggest that DDE acts as an endocrine disrupting chemical (EDC) by binding to the BF3 site and allosterically regulating AR activity.