bluuebunny/crossref_metadata_2025 huggingface dataset:
SUN-139 Luminescence-Based Drug Screen for Novel Androgen Receptor Antagonists for Prostate Cancer Therapy
Authors: Azur Romie Angelo G , Padolina Isagani D , Bagamasbad Pia D
Published: May 2020

The development and maintenance of the adult prostate is dependent on the action of androgens, which mediate its effect by binding to the androgen receptor (AR). Dysregulation in the AR signaling axis disrupts transcriptional homeostasis, shifting the balance towards uncontrolled proliferation and driving the progression towards prostate cancer (PCa). The prominent role of AR signaling in prostate carcinogenesis led to the development of androgen deprivation therapy (ADT) as the primary treatment strategy for managing PCa. Despite the success of ADT in early PCa cases, most patients develop resistance to ADT and the cancer ultimately recurs towards a lethal state termed castration-resistant prostate cancer (CRPC). Remarkably, AR signaling is still active in CRPC, suggesting that the progression towards CRPC is still reliant on AR activity. Current treatments are ineffective against CRPC, highlighting the need for alternative therapeutics that can combat the resistant nature of CRPC. To address the need for innovative approaches against CRPC, we used a robust luminescence-based bioassay that can identify novel AR antagonists. We screened plant extracts derived from local fauna by measuring their effect on AR-driven activity using a luciferase-based reporter assay in HeLa cells stably overexpressing hAR (HeLa-hAR). To identify candidate hits, HeLa-hAR cells were treated with DHT to induce AR-dependent luciferase activity, DHT with the AR antagonist bicalutamide as a positive control, and DHT plus the plant extracts. We identified one extract, A32, which showed significant inhibition of AR-dependent luciferase activity without having deleterious effects on cell viability. Secondary validation tests also showed that A32 exhibits a dose-dependent inhibition of AR-driven reporter activity. When testing the effect of A32 on gene expression in LNCaP cells, we observed a down-regulation in the expression of canonical AR target genes such as PSA to degrees similar to bicalutamide. These results suggest that A32 may be an AR antagonist or may target the AR signaling axis. Collectively, this study establishes the use of a luminescence-based reporter assay for the identification of novel AR antagonists from a plant extract library.
MON-077 A Case of Growth Hormone Deficiency in Sturge-Weber Syndrome
Authors: Hwang Jeongju , Yu Jeesuk
Published: May 2020

Introduction: Sturge-Weber syndrome (SWS) is a congenital neurocutaneous disorder characterized by a port wine stain on the skin in the distribution of the ophthalmic branch of the trigeminal nerve (vascular malformation of skin), glaucoma, and leptomeningeal angiomas. Central nervous system abnormalities may increase the risk of hypothalamic-pituitary dysfunction. One previous study showed that SWS patients had higher prevalence of growth hormone deficiency than the general population although the etiology is unclear. This case report describes a patient who was initially diagnosed with SWS and later confirmed with complete growth hormone deficiency.

Case: A 7-year-and-11-month-old boy who had been diagnosed with SWS visited a tertiary center for the evaluation of short stature [111.1cm (<3 percentile)]. He was born at 37 weeks of gestational age with birth weight of 3230g by cesarean section and had a port wine nevus on the right side of the face since birth. He had a history of epilepsy first occurring at 6 months of age when he was diagnosed with SWS. There were two more attacks of seizure till 32 months of age. Brain magnetic resonance imaging revealed leptomeningeal angioma, choroidal hemangioma, and diffuse brain atrophy. He was diagnosed with glaucoma and had been managed with surgery and medication. There was no family history of SWS or any other brain anomaly. His mid-parental height was 167.7cm. All blood tests were normal including complete blood count, chemistry, and thyroid function test. Hand x-ray showed delayed bone age. Cocktail test was performed for the evaluation of short stature. As a result, he was diagnosed with complete growth hormone deficiency (peak GH on L-dopa test: 2.46 ng/mL, peak GH on glucagon test: 3.71 ng/mL). The recombinant growth hormone therapy was started at the age of 8 years and 1 month. He showed good response to GH treatment. His height became 125.8cm at the age of 9 years and 5 months (height velocity 9.2 cm/year), and 134.3cm at the age of 10 years and 6 months.

Conclusion: We experienced a case with Sturge-Weber syndrome and complete growth hormone deficiency which was successfully managed by recombinant growth hormone therapy. It may be better to consider the possibility of GH deficiency even if there are certain conditions that affect the growth itself.
SUN-272 Significant Response to Temozolomide in Two Aggressively Growing Pituitary Adenomas
Authors: Kreitschmann-Andermahr Ilonka , Grzywotz Agnieszka , Möller-Hartmann Claudia , Junker Andreas , Führer-Sakel Dagmer , Unger Nicole
Published: May 2020

Introduction: Aggressive atypical pituitary tumors are characterized by invasive growth, recurrence and resistance to standard therapies. We present two female patients with pituitary adenomas in whom multiple other therapies had failed, who presented with significant response to temozolomide. Case presentations: In patient #1 (w, 78y), the diagnosis of macroprolactinoma had been made in a community hospital and dopaminagonistic treatment with bromocriptin had been initiated. After failure to achieve significant tumor reduction under this treatment and persisting visual field disturbances, first transnasal-transphenoidal surgery (TSS) was performed in 07/2011, followed by cabergoline exposure in increasing dose due to failure to control prolactin levels. Repeat TSS and stereotactic radiosurgery were performed in both 2014 and 2018 because of invasive tumor growth and double vision. She was then put on temozolomide. Patient #2 (w, 58y) presented with apoplectic gonadotropinoma in 2013. She also underwent 3 courses of TSS as well as stereotactic radiosurgery because of repeated tumor growth leading to visual field disturbances and double vision. Despite these measures, the tumor could not be controlled and she, as well, was put on temozolomide in 2018. In both cases costs were reimbursed by the patient’s health care insurance and in both the first cycle was conducted with 150 mg/ body surface area (BSA) with escalation to 200 mg/BSA in the second. After only 2 cycles, double vision resolved in both patients and the tumor had shrunk by approximately 20% on MRI in patient #1 and even more in patient #2. In both patients, temozolomide dose was reduced again to 150 mg/BSA due to side effects. Nevertheless, in both patients tumor volume further continued to decrease under therapy. Conclusion: This promising clinical course after exposure to temozolomide with early, significant tumor shrinkage in two heavily pretreated patients with aggressive pituitary adenomas indicates that this therapy can be considered also in older patients and may yield astonishing results. Although temozolomide is increasingly becoming a therapeutic option for those patients whose pituitary tumors are refractory to standard therapies, further research and observance over time of temozolomide therapy in aggressive pituitary adenomas and carcinomas is indicated.
MON-062 46 XX DSD Due to POR Deficiency
Authors: Reddy Nithin Modhugu , Sethi Bipin Kumar , Kandula Srinivas G N S V , Chethan Dev
Published: May 2020

Background

PORD (P450 oxidoreductase deficiency) is a rare form of CAH with marked phenotypic variations due to differences in the degree of steroid hormone excess/deficiency. PORD results in17αhydroxylase/17,20lyase- CYP17, 21αhydroxylase- CYP21, and aromatase- CYP19A1 inhibition. In the absence of characteristic skeletal features of Antley Bixler phenotype, differentiating PORD from other types of CAH is challenging.

Case details

04 day child, second of the non-identical twins, product of 2nd degree consanguinity, third in birth order was brought with abnormal genitalia. The other male twin had no genital ambiguity but had pigmented scrotum. There was no adrenal crisis in index case or maternal virilization. First child is normal female. Child was hemodynamically stable weighed 02 kgs and measured 51 cms, had no hyperpigmentation, skeletal deformities or dysmorphic features. Phallus was 10mm, clitoral index 40mm2 with single urogenital opening and posteriorly fused labia (anogenital ratio 0.6).Gonads were not palpable. Karyotype was 46XX with normal Mullerian structures and non-visualized gonads on ultrasonography. Biochemical workup showed random plasma glucose level of 99mg/dl and normal electrolytes. Baseline serum 8am Cortisol was 1.15 mcg/dl (normal 5-18 mcg/dl) and 17OHP was 20 ng/ml (normal < 02 ng/ml). Serum Androstenedione level was 0.39 nmol/L (normal 0.5-3.4 nmol/L).

In view of clinical, laboratory and imaging findings, presumptive diagnosis of 46 XX DSD due to 21 alpha hydroxylase deficiency CAH was made. Oral Hydrocortisone 15mg/m2 and Fludrocortisone 0.05 mg were initiated. Therapy was monitored with serum 17(OH)P levels and Androstenedione. Genetic testing for 21 alpha hydroxylase gene however came negative.

This led to further genetic mutational analysis, and there was a homozygous R457H POR gene mutation at exon 12 leading to protein change p.Arg457His (nucleotide change c.1370G>A), confirming PORD. Retrospectively, maternal triple test done during the candidate pregnancy showed low serum estriol, suggestive of placental aromatase deficiency. Mineralocorticoid supplements were stopped thereafter.

Conclusions PORD needs to be considered and differentiated from garden variety of CAH in 46 XX DSD when elevation of 17(OH)P is modest with isolated cortisol deficiency and aromatase deficiency (evidenced by low maternal estriol levels and/or virilization), as its course and follow up are different.
MON-329 Diagnostic Utility of Overnight High Dose Dexamethasone Suppression Test for Differentiating the Etiology of ACTH Dependent Cushing’s Syndrome
Authors: Yadav Subhash B , Kumar Anand , Kanwar Jayabhanu
Published: May 2020

Background:

Bilateral inferior petrosal sinus sampling (BIPSS) has been the gold standard in differentiating a pituitary vs. an ectopic source of ACTH in Cushing’s syndrome however, it has many limitations. The ON-HDDST being simple to perform and the tests of choice in resource poor setting. The primary aim of our study was to consolidate the present knowledge regarding the diagnostic utility of ON-HDDST in localizing the source of ACTH.

Method:

We retrospectively studied 88 patients with ACTH dependent Cushing syndrome who underwent ONHDDST. Patient were considered as Cushing disease (CD) if either of the 3 criteria were met a) histopathological confirmed b) a central to peripheral gradient >2 was seen in BIPSS or c) pituitary adenoma ≥ 6mm seen in MRI of pituitary. Patient were considered as ectopic ACTH syndrome if the tumor was localized at any peripheral location by imaging or histopathological confirmed after surgery or if BIPSS shown a central to peripheral gradient of <2.

Result: Out of total 88 ACTH dependent Cushing syndrome patients, 68 (77.3%) were proven CD and 20 (22.7%) were ectopic. There was no difference in basal serum cortisol however, S. Cortisol after ONHDDST was significantly different between the two with a median of 547.7 nmol/l (341-770) in ectopic vs 273.5 nmol/l (142-689) in CD (p=0.02). A positive response to ONHDDST (≥50% suppression) was seen in about 44 (65%) patients with CD and 5 (25%) patients with ectopic disease (p = 0.002). Among CD patient, 35 (76.1%) of those with microadenoma, 7 (43.8%) amongst macroadenoma and 2 (33%) patient with no visible tumor on MRI shown positive response to ONHDDST. In ectopic group, cortisol suppressibility was seen in 3 (50%) patient with occult tumor but only in 2(14.3%) patient with. ROC curve plotted for percentage suppression of cortisol after ONHDDST shown as AUC equal to 0.68 (p = 0.01). The best test parameters with sensitivity (65%), specificity (85%) and Accuracy (69%) were seen at 50% cutoff level as were the likelihood ratio for positive test (4.3), AUC (0.75), PPV (93.6%), NPV (41.4%).

Conclusion: Our study has shown that ONHDDST has poor diagnostic value in differentiating between CD and ectopic ACTH syndrome whatever be the cutoff level of the cortisol suppression. However, this can still be utilized in setups where no alternative is available. For etiologic confirmation, another test with better sensitivity and specificity is preferable.
SUN-690 HNF4A Mutation in Siblings with Diazoxide Responsive Congenital Hyperinsulinism
Authors: Erkin-Cakmak Ayca , Chesser Hannah , Shieh Joseph , Ferrara Christine , Gitelman Stephen Eric , Capodanno Gina
Published: May 2020

Background: Congenital hyperinsulinism (HI) is the leading cause of severe, persistent hypoglycemia in infants. Transient HI seen at risk neonates due to prenatal stress and some of the congenital HI cases due to mutations in K-ATPase channel are responsive to diazoxide. It is not a common practice to obtain genetic evaluation for diazoxide responsive HI. However, children with dominant inactivating variants in HNF4A gene may present with diazoxide-responsive HI and mimic transient HI in infancy.

Objective: To describe two siblings with diazoxide responsive HI with HNF4A mutation associated with maturity onset diabetes of youth type 1 (MODY1).

Clinical Case: Case 1, term female with macrosomia and Case 2, preterm male appropriate for gestational age were born to same mother without gestational diabetes and with no perinatal stress. Siblings were non-dysmorphic and both presented with hypoglycemia during first week of life. Diagnosis of HI is confirmed based on inappropriately suppressed β-hydroxybutyrate at the time of hypoglycemia and inappropriate glycemic response to glucagon consistent with increased insulin action. Both siblings responded to diazoxide therapy. Family history was significant for late-onset diabetes in paternal extended family. Case 1 required very low dose diazoxide (2 mg/kg/day) during first year of life to sustain normoglycemia. She came off of diazoxide at 19 months of age. Case 2 is normoglycemic on 5mg/kg/day diazoxide at 4 months of age. Genetic evaluation through whole exome sequencing pursued upon diagnosis of Case 2 revealed paternally inherited heterozygous pathogenic start loss variant in HNF4A gene (c.3G>T) in both siblings. Father was completely asymptomatic without any history of hypo- or hyperglycemia.

Conclusion: HNF4A gene encodes hepatocyte nuclear factor-4-alpha that regulates hepatic gluconeogenesis and lipid metabolism. Dominant inactivating variants in HNF4A gene associated with familial HI, are typically associated with increased size for gestational age, mild diazoxide-responsive hypoglycemia (which may be transient) and monogenic diabetes during adolescence. HNF4A mutations were described as one of the most common genetic cause of diazoxide-responsive congenital hyperinsulinism and are associated with MODY1. It is important to consider genetic evaluation in diazoxide responsive HI cases. Identifying children with HNF4A variant early on will impact their long-term follow-up leading to earlier diagnosis and treatment of MODY-1 and potentially improve long-term outcomes.
SAT-157 Diagnostic Performance of 18F-fluorodeoxyglucose Positron Emission Tomography in Indeterminate Adrenal Tumors
Authors: Ladygina Daria , Beltsevich Dmitry , Dolgushin Michael , Odzharova Akgul , Martinovich Alexander , Tekeev Boris , Kruchkova Oksana , Roslyakova Anna , Zheleznyakova Anna
Published: May 2020

Evidence on the diagnostic performance of 18F-fluorodeoxyglucose(18FDG) positron emission tomography(PET)/CT imaging of adrenal lesions is limited. We aimed to assess the diagnostic performance of this diagnostic modality in a high risk population for adrenal malignancy using an optimal reference standard. We included 21 patients operated in our clinic during 2019 for whom 8FDG PET was performed before adrenalectomy. 3 patients with pheochromocytoma were later excluded from statistical analysis, they were sent to PET before increased urine metanephrines were received. Unenhanced abdominal CT was performed in all the patients; median size was 4,5 (2.3-10) cm and median radiodensity was 32 (-7 to 43) Hounsfield units (HU). All patients with adrenocortical carcinoma and metastasis to adrenals from other organs had radiodensity of >10 HU. Maximum standardized uptake (SUV max) was higher in malignant lesions when compared to benign lesions (median = 10,9 [5.4-29.6] vs 4.1 [2.6-7.22], respectively, P=.003). Similarly, median SUV max lesion to SUV max liver ratio (ALR) in malignant lesions was higher than in benign lesions (median = 2,18 [1.41-5.53] vs. 1.29 [0.67-2.13], respectively, P=.017).18FDG- PET/CT SUV max lesion > 6.7 diagnosed malignancy with a sensitivity of 83,3%, specificity of 91,7%.

Conclusion: Noncontract CT radiodensity of ≤10 HU excludes malignancy even in a high risk population. For indeterminate adrenal lesions, given a superior specificity, 18FDG PET/CT could be considered as a second stage imaging.
SAT-393 Cognitive Function Evaluation in an Italian Cohort of Patients with Post-Operative Hypoparathyroidism
Authors: Saponaro Federica , Alfi Gaspare , Cetani Filomena , Matrone Antonio , Mazoni Laura , Apicella Matteo , Lai Elisa , Laurino Marco , Brancatella Alessandro , Zucchi Riccardo , Marcocci Claudio , Gemignani Angelo
Published: May 2020

Post-operative hypoparathyroidism (PoHypo) is the most common cause of hypoparathyroidism and it is the result of accidental parathyroid removal/injury during neck surgery. The lack of PTH alters calcium homeostasis and patients are at risk of renal complications, bone involvement, infections and psychiatric syndromes. Conventional therapy, that includes calcium supplements and activated vitamin D, does not restore the complete calcium homeostasis. From a neuropsychological point of view, patients complain with neurocognitive symptoms such as “brain fog”, impaired ability to focus, memory loss, depression. Poor quality of life (QoL), evaluated by non-specific questionnaires, has been demonstrated in these patients. The aim of this study is to evaluate the cognitive function by neuropsychological specific tests in patients with PoHypo and matched controls and their relationship with biochemical parameters. This is a prospective monocentric study; we enrolled outpatients who underwent total thyroidectomy for malignant cured disease, 34 with chronic (>6 months) PoHypo (mean age 50.7 ys) and 31 without PoHypo (mean age 49.9 ys). The two groups did not differ significantly in TSH; PoHypo group had a relatively controlled serum calcium adjusted for albumin (SAlbCa) levels in therapy (mean 8.8±0.1mg/dl, 4 patients with <8.2 mg/dl) and control group had normal SAlbCa levels (9.4 ±0.2mg/dl). In PoHypo patients a significant correlation was found between serum calcium, SAlbCa levels and the scores at the Trail-Making Test_A (a specific test evaluating attention capacity; r= -0.36; p<.05, r= -0.37; p<.05) and at the Semantic Fluency Test (validated for cognitive function; r= 0.32; p<.05, r= 0.34; p<.05). No significant correlations were found in the control group. A median split based on serum calcium levels (> or < than 9 mg/dl) was performed in both patients groups. PoHypo patients with serum calcium levels <9 mg/dl performed worse than PoHypo patients with calcium>9mg/dl, either at the Trail-Making Test_A (scores:34.00 vs 21.05, p<.05) and Semantic Fluency Test (39.62 vs 47.4, p<.05). Moreover, PoHypo patients with serum calcium <9 mg/dl performed worse than matched control patients, either at the Trail-Making Test_A (scores:34.00 vs 27.61, p<.05) and Semantic Fluency Test (39.62 vs 46.16, p<.05). These findings suggest that PoHypo patient’s performance in cognitive tests is worse than matched controls and that this is correlated with serum calcium levels.
MON-188 The Diagnostic Value of DHEAS in Subtyping Patients with Cushing Syndrome
Authors: Liu Mengsi , Zhu keying , Chen Huan , Feng Wenhuan , Zhu Dalong , Li Ping
Published: May 2020

Objective: Serum dehydroepiandrosterone sulfate (DHEAS) can be used to assess the integrity of the hypothalamic-pituitary-adrenal (HPA) axis. The aim of this study was to evaluate the clinical value of DHEAS in differentiating adrenal Cushing syndrome (ACS) from Cushing’ disease (CD). Methods: We recruited 100 patients with Cushing syndrome, 36 with CD and 64 with ACS. 72 sex-, age- and BMI-matched nonfunctional adrenal adenomas (NFAAs) were served as controls. Clinical and laboratory data were collected. DHEAS levels were measured and DHEAS ratio was calculated by dividing the measured DHEAS by the lower limit of the respective reference range (age- and sex-matched). Results: 1) No significant differences in age, sex, or BMI were detected among the NFAAs, ACS and CD groups. Compared to NFAAs group, ACS patients had lower plasma ACTH levels [1.11(1.11,1.74) vs 5.0 ± 2.9 pmol/L, P<0.01], lower DHEAS levels (24.00 ± 20.72 vs 189.05 ± 82.03 ug/dL, P < 0.01) and lower DHEAS ratio [0.58(0.27,0.98) vs 5.34 ± 3.0]; Plasma ACTH (22.12 ± 14.22 pmol/L), DHEAS (309.4 ± 201.1 ug/dL) and DHEAS ratio (10.51 ± 7.65) in CD patients were significantly higher compared to those in NFAAs and ACS patients (all P<0.01). 2) In ACS patients, there were 53 patients with suppressed ACTH level of <2.0 pmol/L, 11 patients without plasma ACTH suppression (≥2.0pmol/L). Compared to NFAAs, lower DHEAS and DHEAS ratio were detected in these two groups, and no significant differences were found in the DHEAS [15(15, 23.5) vs 23.8 ± 14.4 ug/dL, P=0.86] and DHEAS ratio [0.58(0.27, 0.80) vs 1.0(0.25,2.09) ug/dL, P=0.40] between the two groups. 3) ROC analysis showed that the area under the curve (AUC) of plasma ACTH, serum DHEAS and DHEAS ratio in diagnosing 0.954, 0.997 and 0.990 respectively. The optimal cut-off values for DHEAS and its ratio were 79.1ug/dL, and 2.09, respectively. The diagnostic sensitivity and specificity of plasma ACTH (<2.0pmol/L) were 84.1 and 100%, those of DHEAS were 97.5% and 100%, and those of DHEAS ratio were 95% and 100%, respectively. Conclusions: Patients with different subtype of Cushing syndrome showed distinctive DHEAS levels and DHEAS ratio. DHEAS and DHEAS ratio are useful in differential diagnosis of Cushing syndrome. Especially, when the plasma ACTH level is not conclusive. The measurement of DHEAS may offer a supplementary test to diagnosis ACS from CD.

Keywords: Adrenal Cushing syndrome; Cushing disease; Adrenocorticotropic hormone; Dehydroepiandrosterone sulfate
SAT-273 Case of Mistaken Identity?
Authors: Pla Carlos
Published: May 2020

Introduction Pituitary adenomas occur in 10-15% of patients and the majority are benign. Prolactinomas are the most common form of secretory pituitary adenoma. Pituitary apoplexy, a medical emergency with resulting visual loss and hormonal hyposecretion, requires rapid surgical intervention. We present a case of pituitary macroadenoma that underwent pituitary resection for acute visual disturbance which was later discovered to be caused by undiagnosed demyelinating disease.

Clinical Case Patient is a 32-year-old male who presented initially with complain of fatigue and decreased libido. Work up revealed elevated prolactin level and low testosterone. MRI showed a 2x3cm pituitary macroadenoma. At moment of diagnosis, patient was otherwise asymptomatic. He was started on bromocriptine. During follow up visits, patient reported visual disturbance. First MRI in our clinic showed no suprasellar extension, no impingement of optic chiasm and nonspecific white matter disease. At that time, visual field testing showed left temporal defect in superior quadrant. Follow up MRI 1 year later continued to show a stable macroadenoma without impingement of the optic chiasm, but patient reported progressive left vision disturbance and new right vision loss. He was evaluated in the emergency room where he was treated for pituitary apoplexy with steroids and surgery. Vision improved the next day. Despite uncomplicated post-operative course, patient developed proximal muscle weakness and exam notable for diffuse motor deficit in bilateral lower extremities with hyperreflexia. Endocrinology workup was negative for hypercortisolism and ophthalmology diagnosed him with optic neuropathy. Neurology evaluation led to a diagnosis of multiple sclerosis (MS). Patient was started on natalizumab with complete resolution of all visual and muscle symptoms.

Clinical lesson Our patient presented with complaints of fatigue, decreased libido and work up that showed a macroprolactinoma without MRI evidence of optic chiasm impingement. During treatment, he developed acute visual deficits that were attributed to pituitary apoplexy. This visual disturbance improved after surgery and use of high dose IV steroids, with the latter likely treating what had been an MS flare. In hindsight, ophthalmologic evaluation before surgery had shown new color blindness, a sign of optic neuropathy. Despite temporary relief, patient progressed to develop new muscle weakness and recurrent visual disturbance which led to the diagnosis of MS. Since being diagnosed and treated for MS, he has had complete resolution of his symptoms. This case stresses the importance of considering other etiologies for visual defects in patients with pituitary adenomas.
MON-905 A Case of Cushing’s Disease with Glucocorticoid Positive-Feedback
Authors: Shichi Hiroki , Fukuoka Hidenori , Tsujimoto Yasutaka , Yamamoto Masaaki , Nakamura Tomoaki , Ishida Atsushi , Yamada Shozo , Takahashi Yutaka , Chihara Kazuo
Published: May 2020

Background: Although paradoxical response of cortisol (F) during high dose dexamethasone (Dex) suppression test (DST) is observed in a part of ectopic ACTH syndrome, few reports have been shown in Cushing’s disease (CD). It suggests a presence of glucocorticoid (GC)-driven positive-feedback loop. However, the underlying mechanism remains elusive. Here we present a case of CD showing clear clinical and pathophysiological evidences of GC positive-feedback using ex vivo 3-dimensional (D) culture method.

Case: A 62-year-old woman manifested typical Cushing’s symptoms, including moon face, central obesity, hypertension, hypokalemia, and vertebral fractures. Endocrinological data were consistent with a diagnosis of CD; morning plasma ACTH 299 pg/mL, serum F 28 μg/dL, midnight serum F 43 μg/dL, and 24hr urinary free cortisol 988 μg/day. CRH test showed a slight increase in plasma ACTH levels (1.4 fold), and pituitary MRI revealed a 14 mm macroadenoma invading into the left cavernous sinus. Interestingly, both 1 mg and 8 mg DST showed a paradoxical increase in serum cortisol levels (27.7→64.7μg/dL and 17.17→35.68μg/dL, respectively). These data indicated a presence of positive-feedback response to GC in the tumor. Indeed, after the initiation of metyrapone (1,000 mg/day) administration for the treatment of hypercortisolemia, plasma ACTH levels were decreased to 147.5 pg/mL accompanied with the decrease in serum F levels to 4.12 μg/dL. Moreover, pituitary tumor obviously shrank during the metyrapone treatment. Thereafter, we undertook transsphenoidal surgery and plasma ACTH and serum F levels decreased to 35.8 pg/mL and 7.6μg/dL, respectively.

ex vivo studies: To prove the presence of the positive feedback response and explore the underlying mechanisms, we performed a primary culture experiment using the tumor and applied 3D culture method. The resected tumor tissue was enzymatically digested, dispersed and embedded into the Matrigel. Then cells were treated with Dex (0.1-10 nM), and ACTH concentrations were measured after 72 hrs. Interestingly, ACTH levels significantly increased by 10 nM Dex treatment at 72 h (129 %, p <0.01), indicating a paradoxical response to Dex in the tumor ex vivo.

Conclusions: To our knowledge, this is the first case of CD who showed clinically obvious GC positive-feedback that was proved by ex vivo 3D primary culture cell models. Notably, tumor shrinkage was observed during the metyrapone treatment, suggesting that GC positive-feedback mechanisms also involve tumor proliferation. Further investigation is required for elucidating the underlying mechanisms.
OR25-07 A Multi-Center, Open-Label, Pivotal Phase 2 Study of Azedra® (HSA I-131-MIBG) in Patients with Unresectable, Locally Advanced or Metastatic Pheochromocytoma or Paraganglioma: Updated Long-Term Survival and Safety
Authors: Jimenez Camilo , Chin Bennett B , Noto Richard B , Dillon Joseph Stephen , Solnes Lilja B , DiPippo Vincent A , Stambler Nancy , Wong Vivien , Pryma Daniel A
Published: May 2020

Background: Pheochromocytoma/Paraganglioma (PPGL) are rare neuroendocrine tumors with a 5-yr survival rate as low as 12%. There is a high unmet medical need for effective treatment options for patients with advanced disease. AZEDRA®, a high-specific-activity iodine-131 meta-iodobenzylguanidine (HSA I-131-MIBG), is the first and only FDA-approved therapeutic radiopharmaceutical agent indicated for the treatment of adult and pediatric patients with iobenguane scan positive, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. Methods: Patients with advanced PPGL who were heavily pre-treated and were ineligible for curative surgery or chemotherapy received a dosimetric dose followed by up to two therapeutic doses (each at 296 MBq/kg to a max of 18.5 GBq). The primary endpoint, defined as the proportion of patients with at least 50% reduction of all antihypertensive medication(s) lasting ≥6 months, was met and previously reported. Updated secondary endpoints including overall survival (OS) and safety are reported. Results: A dosimetric dose of HSA I-131-MIBG was administered to 74 patients. Of those, 68 patients received one therapeutic dose and 50 received two doses of HSA I-131-MIBG. Clinical benefit rates (objective tumor responses defined by RECIST 1.0 and stable disease) were observed in 71.4% and 98.0% of patients receiving one and two therapeutic doses, respectively. As of October 10, 2019, median survival time for all patients was 43.2 months (95% CI 31.4, >60). Median survival time was 19.3 months (95% CI 4.5, 32.4) and 49.1 months (95% CI 36.9, >60) in patients receiving one and two doses, respectively. The overall survival was 73.8% at 2 yrs, 47.5% at 4 yrs and 41.5% at 5 yrs. The most common (≥50%) adverse events were nausea, fatigue, and myelosuppression. Myelosuppressive events resolved within 4-8 wks without requiring stem cell transplantation. Late radiation toxicity included 7 patients with secondary malignancies (myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), colon cancer, and lung carcinoma) of which MDS, ALL and AML were considered related to I-131 radiotherapy. Conclusions: Results from this pivotal phase 2 study suggest that HSA I-131-MIBG is an efficacious and safe treatment for advanced PPGL.
MON-241 Dome Shaped Pituitary Enlargement Warrants Detailed Endocrine Evaluation Prior to Neuro-Surgical Intervention: Case Series & Analysis
Authors: Chakraborty Satyam
Published: May 2020

Pituitary tumours diagnosed incidentally on imaging as sellar-suprasellar masses, often undergo unwarranted Neuro-surgical intervention, often leading to the requirement of life-long post-operative hormone supplementation. Although surgery remains the primary modality in most of the Functional (except Prolactinomas) & Non-Functional Pituitary Macro-Adenomas abutting the Optic Chiasma, Several cases are feed-back adenomas due to untreated Hypothyroidism or Drug- Induced Hyperprolactinemia which require a conservative approach.

These Pituitary enlargements may not only be Sellar but also at times extend Supra-sellar mimicking a surgically resctable one. In adolescents they come with a constellation of features like severe short stature & primary Amenorrhea in Females. Noteworthy that these symptoms appear commonly in both groups of surgically resectable masses as well as the secondary pituitary enlargements which need conservative approach, thus often resulting in inadvertent Surgical misadventures.

We report 3 cases of Adolescent females referred from peripheral centre to the Neuro-Surgical take of our Institute. Both the females had severe short stature with primary amenorrhea. The imaging characteristics in all the three patients were unique in the sense that they had uniform enlargement of the entire Pituitary extending supra-sellar without any focal hypo-intensities without any obvious mid-line shift of the Pituitary stalk & enhanced uniformly in Post-Contrast studies. We also observed that the upper margin of the masses had a uniform convexity resembling a “DOME”. Thorough Endocrine work-up revealed severe Untreated Hypothyroidism with S.TSH greater then 100micro IU/ml. The patients were treated conservatively with Levo-thyroxine supplementation. The patients had significant Height gain with menarche in the following 4-6 months of Therapy. S.TSH normalized after 2-3 months of therapy. Repeat imaging after 6 months of therapy revealed normal Pituitary architecture without the presence of any focal lesions or enlargement.

Feedback Adenomas of the Pituitary have been depicted in the literature. “DOME” shaped Pituitary enlargement seems quite unique to all Pituitary masses which can be treated with conservative means. Pituitary masses should therefore undergo thorough Endocrine intervention before any Neuro-Surgical intervention is contemplated, specifically when the incidentally discovered masses have a “DOME” shaped symmetrical upward convexity on imaging.
OR17-05 Hypospadias Is a Predictor of Adverse Cardiometabolic Risk in Adulthood - a Case-Control Study
Authors: Lucas-Herald Angela K , Padmanabhan Sandosh , Brooksbank Katriona , McCallum Linsay , Montezano Augusto C , Touyz Rhian M , Ahmed S Faisal
Published: May 2020

Introduction: Abnormal development of the genital tract during the first trimester can lead to hypospadias. This stage coincides with the programming window during which androgens are required for normal masculinisation of the genital tract. Since fetal development may also be associated with long-term effects on cardiometabolic outcome and testosterone is itself an important vascular hormone, we questioned whether adults with a history of hypospadias are at increased risk of long-term cardiovascular and metabolic disease. Aim: This retrospective study determined if hypospadias is associated with increased risk of cardiometabolic disease later in life. Methods: Cardiovascular and diabetes admissions data were extracted through record linkage for all males with a history of hypospadias (ICD10 Q54) from 1981 to 2019 through the NHS Scotland Information Services Division after ethics approval. Controls were matched for age, birthweight, gestation and deprivation index. Incident admissions for angina, arrhythmia, diabetes, heart failure, ischaemic heart disease, myocardial infarction, peripheral arterial disease, renal failure and stroke were obtained for each individual. Case control analysis was performed using Chi square test using R. Results: Admission data on 13,481 men with hypospadias and 9,615 matched controls were reviewed. Men with hypospadias had a 10- fold higher risk of diabetes (9.7 [8.4-11.2], p<0.0001); 9- fold higher risk of ischaemic heart disease (OR [95% CI] 9.1[8.1-10.2], p<0.0001); 8- fold higher risk of renal failure (7.9 [6.9-9.1], p<0.0001); 6- fold higher risk of stroke (6.2 [5.2-7.2], p<0.0001); 6- fold higher risk of myocardial infarction (6.4 [5.6-7.3], p<0.0001); 6-fold higher risk of angina (5.9 [5.3;6.8], p<0.0001); 5-fold higher risk of arrhythmia (4.8 [4.2-5.4], p<0.0001) 5- fold higher risk of peripheral arterial disease (4.8 [3.7-6.1], p<0.0001) and 4- fold higher risk of heart failure (3.6 [3.1-4.1], p<0.0001). Conclusions: Men with a history of hypospadias are at significantly increased risk of admission for treatment for cardiovascular and metabolic conditions, especially ischaemic heart disease, diabetes and renal failure. The mechanisms underlying this observed increase are unclear and merit further evaluation.
SUN-289 Childhood-Onset, Adamantinomatous Craniopharyngioma and Successful Pregnancy: Results of Kraniopharyngeom 2000/2007
Authors: Sowithayasakul Panjarat , Boekhoff Svenja , Muller Hermann Lothar
Published: May 2020

Background: Hypopituitarism is associated with an increased risk of pregnancy complications, such as abortion, anemia, pregnancy-induced hypertension, placental abruption, premature birth, and postpartum hemorrhage. The advance of assisted reproductive techniques makes it possible to improve the pregnancy rate in hypopituitary patients. Data on female fertility, pregnancy, and outcome of offspring after childhood-onset, adamantinomatous craniopharyngioma (CP) are rare.

Study design: Observational study on pregnancy rate and outcome of offspring after childhood-onset CP in adult, female patients recruited in KRANIOPHARYNGEOM 2000/2007.

Patient cohorts: Since 2000, 451 CP patients (223 f / 228 m) have been recruited with high grade of completeness. 263 CP patients (128 f / 135 m) have reached adult age. 6 of 128 adult, female CP patients (5%) reported on 9 pregnancies giving birth to 10 healthy newborns.

Results: The median age at time of CP diagnosis was 14.9 years. Complete surgical CP resections were achieved in 3 patients. No patient underwent postoperative irradiation. 5 natural pregnancies occurred in 3 CP patients presenting with postoperative normal pituitary function. 4 pregnancies were achieved in 3 CP with hypopituitarism under assisted reproductive techniques (after in median 4.5 cycles, range: 3-6 cycles). Median maternal age at pregnancy was 30 years, ranging from 22 to 41 years. 6 of 10 babies were delivered by caesarean section. Gestational age at delivery was in median 38 weeks, ranging from 34 to 43 weeks; median birth weight was 2,920 gram (range: 2,270-3,520 gram), the rate of preterm delivery (<38 weeks of gestation) was 33%. The rate of breastfeeding was 56%. Enlargements of CP cysts occurred in 2 women during pregnancy. Other severe complications during pregnancy, delivery and postnatal period were not observed.

Conclusions: Pregnancies after CP are rare (5%) and almost half of the patients (45%) achieved pregnancies after assisted reproductive techniques, which are effective and safe in CP patients. With regard to existing deficiencies of hypothalamic-pituitary axes, close monitoring and care by an experienced reproductive physician is necessary. Furthermore, MRI monitoring especially of CP cysts is recommended during pregnancy. Severe perinatal complications, birth defects, and postnatal morbidity of the mothers and their offspring were not observed. Most CP patients complained about their initial lack of information on potential fertility under assisted reproductive techniques.
MON-341 New Diagnosis of Hypophosphatasia in a 79-Year-Old Woman with Low Bone Density
Authors: Manavalan Anjali , Mathias Priyanka , Khoshbin Katayoun , Tabatabaie Vafa
Published: May 2020

Introduction: Hypophosphatasia is a rare metabolic bone disease caused by one of several mutations in the ALPL gene which encodes tissue nonspecific alkaline phosphatase (ALP). It is usually diagnosed in childhood and can have a heterogenous clinical presentation depending on the extent of enzyme deficiency. Here we report the oldest known patient with hypophosphatasia.

Clinical Case: A 79-year-old woman with a history of medullary thyroid cancer (MTC) in remission, was referred to our metabolic bone disease clinic for the evaluation and treatment of osteopenia. She had suffered from numerous musculoskeletal complaints for several years and had received a diagnosis of polymyalgia rheumatica. However, her symptoms persisted despite a six month trial of prednisone. Although she had developed dental caries at a young age, she denied premature tooth loss. Her family history was significant for arthralgias and vertebral disc disorders in multiple family members, including both her children. Her mother carried a diagnosis of rheumatoid arthritis and osteoporosis. The only pertinent physical exam finding was short stature (Height -4’6”). A DEXA scan was performed using a Hologic unit and revealed a T Score of -1.0 at the L-spine and -1.9 at the femoral neck. A FRAX score predicted a 14% risk of major osteoporotic fracture and 4% risk of hip fracture.

Laboratory data revealed: Serum Calcium 9.3 (8.5-10.5 mg/dL), Albumin 4.3 (3.5-5.0 g/dL), ALP 21 (<130 U/L), Vitamin D 25OH 46.2 (>30 ng/ml), Intact PTH 28.3 (15.0-65.0 pg/ml), Vitamin B6 87.7 (2-21 ng/ml).

On review of her medical record, low ALP levels ranging between 20-30 U/L were noted to be present for the last twenty years. Given her history of musculoskeletal complaints, short stature, elevated Vitamin B6 and low ALP, genetic testing for hypophosphatasia was performed. Her results confirmed a known pathogenic mutation in the ALPL gene.

Conclusion: This case highlights the importance of reviewing ALP levels and relevant patient history to rule out hypophosphatasia prior to initiating therapy for osteoporosis. This condition is often unrecognized. Bisphosphonates, which are often the first line of treatment in osteoporosis, are contraindicated in hypophosphatasia as they can increase the risk of atypical fractures.1 Teriparatide may improve bone density depending on the extent of ALP deficiency. Asfotase alfa is a new agent that is currently available for the management of certain cases of hypophosphatasia.

References:

1.”Atypical femoral fractures”during bisphosphonate exposure in adult hypophosphatasia; Sutton,RA; Mumm,S;Coburn SP; Ericson,KL; Whyte, MP; Journal of Bone and Mineral Research 2012 May;27(5):987-94.
SUN-243 Deletion of KNDy Neuron-Specific KISS1 Disrupts Estrous Cyclicity and LH Pulsatility in Female Mice
Authors: Nandankar Nimisha , Negron Ariel L , Levine Jon E , Radovick Sally
Published: May 2020

Kisspeptin (encoded by Kiss1), a neuropeptide critically involved in neuroendocrine regulation of reproduction, is primarily synthesized in two discrete hypothalamic nuclei: the anteroventral periventricular area (AVPV) and arcuate nucleus (ARC). AVPV Kiss1 is important for the pre-ovulatory luteinizing hormone (LH) surge unique to females as well as estrogen-induced positive feedback control of GnRH and LH. In contrast, ARC Kiss1 neurons, which largely co-express the neuropeptides NKB and dynorphin (collectively known as KNDy neurons), are major regulators of pulsatile release of GnRH and LH, and mediate estrogen-induced negative feedback control of both GnRH and LH. Previous studies have not fully separated the specific roles for Kiss1 in the AVPV versus KNDy-ARC neurons in the downstream control of GnRH and LH release. Therefore, we generated a Pdyn-Cre/Kiss1fl/fl (KO) mouse model to target Kiss1 in the KNDy neurons to differentiate KNDy neuron-specific function from AVPV Kiss1 function in the maturation and maintenance of the reproductive axis. qRT-PCR data documented a significant reduction of Kiss1 expression in the mediobasal hypothalamus (containing ARC) compared to controls, whereas Kiss1 in the preoptic area (containing AVPV) was similar in both KO and controls. Immunofluorescent IHC confirmed a loss of kisspeptin immunoreactivity in the ARC of KO animals while expression in the AVPV remained intact. Markers of pubertal onset (day of vaginal opening and first estrus in females; day of preputial separation in males) were normal in KO mice, suggesting that AVPV Kiss1 and/or other neural signals may be sufficient for pubertal onset. In addition, body weight throughout pubertal growth was comparable between KO and control animals of both sexes. Interestingly, KO female mice had disrupted estrous cycles presenting with persistent diestrus and a small vaginal opening. In order to test our hypothesis that conditional deletion of Kiss1 in KNDy neurons disrupts or ablates episodic GnRH/LH pulsatile release, we collected serial tail blood samples from mice at diestrus and measured LH. KO female mice exhibited significantly fewer LH pulses in a 3-hour timespan compared to controls, suggesting that KNDy neurons were functionally compromised. These observations indicate the central role of KNDy neurons in the regulation of GnRH/LH pulsatility and estrous cyclicity. The functional effects of disrupted estrous cyclicity and slower LH pulses observed in KO females are currently under study to assess potential abnormalities in ovarian folliculogenesis and fertility. Future experiments will determine whether ARC Kiss1 deletion disrupts the KNDy-driven negative feedback response of LH to gonadectomy, as well as address potential sex differences in ARC Kiss1-mediated negative feedback control of LH release.
MON-385 Insulin Resistance and Osteoporosis in People Living with HIV
Authors: Premaor Melissa Orlandin , Caeran Gabriela , Almeida Luciana , Carvalho Jose , Stein Carolina , Moresco Rafael , Haygert Carlos , Comim Fabio Vasconcellos
Published: May 2020

The life expectancy of people living with HIV (PLHIV) increased considerably after the advent of antiretroviral therapy (ARV). Nowadays, it is almost the same as the general population. However, this increase in survival exposes PLVH to age-related morbidities, including chronic metabolic and bone diseases. PLHIV has a low bone mineral density (BMD) and a high prevalence of osteoporosis. Moreover, the frequency of diabetes mellitus (DM) seems to be twice the frequency of the general population. Insulin resistance and DM might be associated with bone diseases in PLHIV. Our study aim was to evaluate the association between insulin resistance and osteoporosis in PLHIV. We carried out a cross-sectional study at the municipality of Santa Maria, South Brazil. PLHIV age 50 yrs or over on treatment with ARV were included. All subjects registered to receive ARV in the university hospital during the period 2016 to 2018 were invited to participate. Those who accepted responded to a standardized questionnaire, performed a bone density scan and a lateral spinal X-ray, underwent peripheral blood collection, and had their weight and height measured. Insulin resistance was considered present when HOMA-IR> 2.7 (Gelonese, 2009). The TyG index was also calculated (VASQUES, 2011). Of the 101 PLHIV who agreed to participate, 84 underwent both insulin and BMD measurements. The prevalence of osteoporosis was 19%. Vertebral fractures were twice as frequent in individuals with osteoporosis (73.3% vs. 36.5%, p = 0.018). Participants with osteoporosis had lower BMI and triglyceride values than those without it. The frequency of insulin resistance calculated by HOMA-IR was 68.2%, and it was associated with glucocorticoid use, smoking, and BMI. HOMA-IR [4.8(6.6) vs. 8.68(9.6), p =0.013], and TyG [5.0(0.3) vs. 5.2 (0.4), p=0.029] mean values were lower in the group with osteoporosis; however, this association disappeared after correction for BMI in the logistic regression model. In conclusion, in our study, PLHIV with osteoporosis have lower insulin resistance than PLHIV without it. Nevertheless, this finding appears to be relating to a lower BMI. Further studies are needed to assess the effect of insulin resistance on fracture risk in PLVH.

GELONEZE, B. et al. HOMA1-IR and HOMA2-IR indexes in identifying insulin resistance and metabolic syndrome: Brazilian Metabolic Syndrome Study (BRAMS). Arq Bras Endocrinol Metabol. 2009 Mar;53(2):281-7

VASQUES, A. C. et al. Análise Crítica do Uso dos Índices do Homeostasis Model Assessment (HOMA) na Avaliação da Resistência à Insulina e Capacidade Funcional das Células-C Pancreáticas. Arq. Bras. Endocrinol. Metab., 2008;52/1:32-39.