bluuebunny/crossref_metadata_2025 huggingface dataset:
THU554 Unconventional Estrogen Receptor Antagonists Reveal Cryptic Therapeutic Anti-breast Cancer Transcriptional Pathways
Authors: Hancock Govinda , Young Kristen , Greene Geoffrey L , Fanning Sean William
Published: October 2023

Disclosure: G. Hancock: None. K. Young: None. G.L. Greene: None. S.W. Fanning: Advisory Board Member; Self; Olema Oncology. Grant Recipient; Self; Olema Oncology.

Breast cancer is the most diagnosed cancer and 2nd leading cause of cancer-related death in women worldwide. The luminal subtype accounts for ∼70% of this heterogeneous disease. Standard of care for these estrogen receptor alpha (ERα) positive diseases includes 5 years of adjuvant endocrine therapy in the form of aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs) or selective estrogen receptor degraders (SERDs). Despite therapeutic advances, approximately half of ERα+ patients develop resistance to these endocrine therapies. In this study, x-ray crystallography of SERMs and SERDs link structural characteristics to transcriptional activity in order to understand mechanisms of antiestrogen efficacy in ER+ drug resistant breast cancers. A new class of antiestrogen based on a tetrahydro-6-isoquinoline (T6I) scaffold was developed to antagonize ERα by adopting unique binding poses to inhibit coactivator binding to the ligand binding domain (LBD). Optimization of structure-activity relationships produced unique antiestrogenic activities and a lead compound that induces transcriptional programs similar to fulvestrant despite its SERM-like accumulation of ERα in the breast cancer cell. Like fulvestrant, this T6I uniquely induces the expression of small ubiquitin-like modifier-1 (SUMO1), in opposition to 17β-estradiol. Together, this study uses structurally unique antiestrogens to further the understanding of key functional components of estrogen therapies.

Presentation: Thursday, June 15, 2023
FRI225 Clinical Course Of Late-onset Adrenal Insufficiency Due To Treatment Of Childhood Acute Lymphoblastic Leukemia
Authors: Iwabuchi Masayasu
Published: October 2023

Disclosure: M. Iwabuchi: None.

Background: Some people who were treated for cancer during childhood may develop endocrine problems as because of changes in the function of endocrine system. Acute lymphoblastic leukemia is the most common type of cancer and leukemia in children and components of ALL treatment are induction, consolidation, maintenance, and central nervous system prophylaxis. It is recommended that people who had irradiation in a dose of 40 Gy or higher to the central area of the hypothalamic-pituitary axis should have a blood test done to check the cortisol level and should be done yearly for at least 15 years since this complication can occur many years after irradiation. Clinical Case: A man in his 40s was admitted with symptoms of diarrhea, low-grade fever, and drowsiness. The serum sodium level that caused his symptoms decreased to 100 mEq/L and was adequately corrected. Endocrinological examination confirmed the diagnosis of central adrenal insufficiency. Soon after starting hormonal replacement therapy with hydrocortisone, his general conditions improved. After establishing our relationship, he confessed to having a history of ALL in childhood. According to his medical records at the time, he underwent induction therapy with vincristine-prednisone in 1977, maintenance therapy with 6-mercaptopurine, and radiation therapy to the central nervous system of 25 Gy in 1983. In 2023, 40 years have passed since radiation therapy. He was able to lead a normal life on oral hydrocortisone 20 mg/day without recurrence of adrenal insufficiency. Clinical Lesson: A 40-old male survivor of ALL developed adrenal insufficiency in 30 years after cranial irradiation during childhood. Undiagnosed adrenal insufficiency is often the cause of death. We should consider childhood cancer survivors have the risk of a central adrenal insufficiency. The Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers (COG LTFU Guidelines) are a resource for healthcare professionals who provide ongoing care to survivors of pediatric malignancies. The screening recommendations in these guidelines are appropriate for asymptomatic survivors of childhood, adolescent, or young adult cancer presenting for routine exposure-based medical follow-up. It is recommended that people who had irradiation in a dose of 40 Gy or higher to the central area of the hypothalamic-pituitary axis should have a blood test done to check the cortisol level and should be done yearly for at least 15 years since this complication can occur many years after irradiation. This case highlights the importance of long-term follow-up of cancer survivors after irradiation and the delayed presentation of adrenal insufficiency. This is the first report of the subsequent treatment course of late-onset adrenal insufficiency that developed 30 years after irradiation for childhood central nervous system ALL.

Presentation: Friday, June 16, 2023
OR27-06 Identification And Functional Analyses Of Therapeutic Targets For Testicular Germ Cell Tumors
Authors: Horie Kuniko , Kitayama Sachi , Ikeda Kazuhiro , Suzuki Takashi , Kawakami Satoru , Inoue Satoshi
Published: October 2023

Disclosure: K. Horie: None. S. Kitayama: None. K. Ikeda: None. T. Suzuki: None. S. Kawakami: None. S. Inoue: None.

Testicular germ cell tumor (TGCT) is the most common cancer among adolescent and young adult males. While cisplatin is a key drug that efficiently reduces TGCT growth, the acquisition of drug resistance is often life-threatening. To elucidate molecular mechanisms underlying the pathophysiology of TGCT, we established patient-derived TGCT spheroid cultures from nonseminomatous tumors, in which cancer stem cell population can be preferentially enriched. The TGCT spheroid cultures can be applied to the generation of in vivo xenograft models, which successfully recapitulated the pathological features of patient tumors with microenvironment. Transcriptomic analysis revealed that hypoxia-related genes were upregulated in TGCT spheroid cultures, and HIF1α inhibitor 2-methoxyestradiol could substantially repress the in vivo tumor formation. We further generated cisplatin-resistant TGCT models from embryonic cancer patient-derived spheroids and cell line, and found that transcription-related gene high mobility group nucleosome binding domain 5 (HMGN5) and meiosis-related gene testis-expressed 11 (TEX11) were remarkably upregulated in cisplatin-resistant TGCT cells compared with their parental cells. Either HMGN5 or TEX11 knockdown could reduce the viability of cisplatin-resistant TGCT cells in the presence of cisplatin. Of note, TEX11 knockdown increased cleaved PARP1 protein expression and the percentage of double-strand break marker γH2AX-positive cells in cisplatin-resistant TGCT cells. We demonstrated that siRNA-mediated TEX11 inhibition is a promising therapeutic option for cisplatin-resistant TGCT as we showed the efficacy in in vivo xenograft models generated from cisplatin-resistant patient-derived TGCT spheroids. Furthermore, chromatin immunoprecipitation sequencing for histone H3K27 acetylation status in the TGCT spheroid cultures revealed that the enrichment of “super-enhancers”, identified by the Rank Ordering of Super-enhancers algorithm [http://younglab.wi.mit.edu/super_enhancer_code.html], was well observed at chromosome 12p, where copy number gains are often observed in the tumors, and genes in the vicinity of super-enhancers identified in patient-derived TGCT models can be potential diagnostic and therapeutic targets for the advanced disease. Overall, the present study provides useful insights into the biology and chemoresistance of TGCT.

Presentation: Saturday, June 17, 2023
FRI236 Primary Adrenal Insufficiency Due To Coccidiomycosis
Authors: Duro Teodor
Published: October 2023

Disclosure: T. Duro: None.

Introduction: Primary adrenal insufficiency due to infectious adrenalitis is not common in the United States. When it occurs, the most common culprits are tuberculosis, histoplasmosis, and HIV-related manifestations. We present a rare case of disseminated coccidiomycosis presenting with hypercalcemia, adrenal insufficiency, and a right adrenal mass. Case Report: A 73-year-old Hispanic man living in New Mexico with history of paraesophageal hernia and a thoracic aortic aneurysm was admitted in the hospital during a COVID-19 infection due to severe weakness, poor oral intake, and abdominal pain. His labs on admission showed: mild eosinophilia, serum calcium corrected for albumin 13.8 mg/dL (n 8.4 - 10.4 mg/dL), PTH <6 pg/mL(n 18 - 84 pg/mL), PTH-rp 4.4 pmol/L (n 0.0 - 2.3 pmol/L), Vitamin D25-OH 18 ng/mL (n >29 ng/mL), Calcitriol 8.1 ng/mL (n 19.9 - 73.9 ng/mL), serum kappa/lambda light chain ratio 2.09 (n 0.29 - 1.65), SPEP and UPEP no M-spike, normal pattern, 8AM serum cortisol 0.9 ug/dL (n5.27 - 22.45 ug/dL), ACTH >1250 pg/mL (n 0 - 46 pg/mL), DHEA-S 20ug/dL (n 80 - 560 ug/dL), plasma normetanephrine 3.29 nmol/L (n 0.00 -0.89 nmol/L), plasma metanephrine <0.10 nmol/L (n 0.00 - 0.49 nmol/L). Abdominal CT scan showed a right hypodense adrenal mass measuring4.8 x 2.4 x 3.7 cm, with small areas of calcification. His left adrenal gland showed thickening and nodularity. Primary adrenal insufficiency was diagnosed based on labs above. He was given high dose IV hydrocortisone which was tapered to PO Hydrocortisone 15mg QAM and 5mg QPM. Fludrocortisone 0.1mg PO daily was also added. His presenting symptoms resolved. Work up for HIV, tuberculosis, and syphilis was negative. His hypercalcemia was thought to be due to acute adrenal insufficiency and less likely related to malignancy or other causes. His mildly elevated PTH-rp was thought to be due to his renal dysfunction, and his mildly elevated kappa/lambda ratio was thought to be non-specific by the oncology consultants after the patient had a negative nuclear bone scan. He was treated with IV fluids and his hypercalcemia resolved. Due to elevated plasma normetanephrines a pheochromocytoma could not be excluded. CT adrenal protocol imaging showed a 4.2 cm right adrenal mass with unenhanced attenuation: 40.6 HU. Absolute washout: 4.0 %, suggestive of hemorrhage. The left adrenal gland was unremarkable on this scan.Alpha and beta blockade were instituted, and the patient underwent aright adrenalectomy. Pathology showed: Necrotizing granulomatous inflammation and coccidioides-like organisms on GMS stain. His coccidioides serum antibodies were positive. He was referred to infectious diseases and was started on fluconazole 400mg daily. He is doing well. Clinical Lessons: Disseminated coccidiomycosis is a rare cause of infectious adrenalitis, but it should remain on the differential diagnosis of primary adrenal insufficiency, especially in endemic areas.

Presentation: Friday, June 16, 2023
FRI239 Oncocytic Adrenocortical Neoplasm Of Uncertain Malignant Potential
Authors: Barnett Katherine , Sandhu Ariel , Hasan Farhad
Published: October 2023

Disclosure: K. Barnett: None. A. Sandhu: None. F. Hasan: None.

Introduction: Oncocytic adrenocortical neoplasms are a rare histological subtype of adrenal mass, characterized by their abundant eosinophilic cytoplasm. Like other adrenal masses, they can be functional, or hormone-producing, and present on a spectrum from benign to malignant. Case: Our patient is a 31 year old female with a past medical history of anxiety who presented to the ER for right upper quadrant abdominal pain. She described it as a colicky, aching pain, lasting for several minutes at a time. She could identify no known trigger. A CT abdomen with contrast showed cholelithiasis and a hypodense lesion on the right adrenal gland. Her primary care physician (PCP) ordered a follow-up MRI abdomen with contrast that showed an indeterminate, 2.9 cm x 2 cm mass on the right adrenal gland without evidence of microscopic fat. After consultation with an oncologist, her PCP then recommended a PET scan, which showed that the mass was mildly hypermetabolic. She presented to the endocrinology office for further evaluation shortly thereafter. Though her abdominal pain had subsided, she did endorse a 7 lb weight loss, attributed to decreased appetite from anxiety. Additional review of systems was grossly negative. Hormonal work-up, including DHEA, renin, AM cortisol, ACTH, aldosterone, and plasma metanephrines was normal. CT-guided biopsy was deferred in favor of a repeat CT abdomen with adrenal protocol, which showed the adrenal nodule measured 40 HU on unenhanced images, with an absolute contrast washout of 50%. As this was less than the 60% threshold typically utilized to indicate a lipid-poor adenoma, the nodule was deemed indeterminate. Given the concerning features of the mass: its lipid-poor nature on unenhanced CT, metabolic activity on PET scan, and washout that was below the threshold for an adenoma, adrenalectomy was recommended. She underwent a laparoscopic right adrenalectomy, with final pathology showing oncocytic adrenocortical neoplasm of uncertain malignant potential, based on Lin-Weiss-Bisceglia criteria. She was seen by oncology, and they recommended no adjuvant treatment at this time. A repeat CTAP abdomen with adrenal protocol is planned for 1 year after this procedure. Discussion: Given the rarity of oncocytic adrenocortical neoplasms, their classification into benign, uncertain malignant potential, or malignant using Lin-Weiss-Bisceglia criteria is essential to determining appropriate treatment and surveillance. A recent retrospective cohort study showed oncocytic neoplasms with uncertain malignant potential have favorable outcomes, however, patients require continued radiographic surveillance due to the risk of late recurrence. Reference: Shirali AS, et al. Differences in Clinicopathologic Behavior of Oncocytic Adrenocortical Neoplasms and Conventional Adrenocortical Carcinomas. Ann Surg Oncol. 2022;29(9):5555-5563. doi:10.1245/s10434-022-11626-w

Presentation: Friday, June 16, 2023
FRI247 Case Of Metabolic Resolution Of Non-classic Congenital Adrenal Hyperplasia Post Roux-En-Y Gastric Bypass
Authors: Romo Karina G , Shu Sharon , Gabriel Mary , Bhamre Sneha , Iqbal Qasim Z , Noor Abdulla A , Uwaifo Gabriel I
Published: October 2023

Disclosure: K.G. Romo: None. S. Shu: None. M. Gabriel: None. S. Bhamre: None. Q.Z. Iqbal: None. A.A. Noor: None. G.I. Uwaifo: None.

Background: Non-classic congenital adrenal hyperplasia (NCCAH) is an autosomal recessive disorder resulting from loss of function mutations of the 21-hydroxylase gene. It is characterized by mild cortisol deficiency, excess ACTH production, and androgen excess, often with various features of dysmetabolic syndrome. Elective bariatric surgery is one of the most effective long-term management strategies for morbid and complicated obesity. This case presents a woman with NCCAH and complicated morbid obesity who s/p Roux-en-Y Gastric Bypass (RYGB) had metabolic resolution of NCCAH and no longer required glucocorticoid (GC) therapy. Clinical Case: A 34-year-old G1P1 woman with NCCAH on glucocorticoid therapy, treated hypothyroidism with thyroid nodular disease, dyslipidemia, and morbid obesity (pre-RYGB BMI 60-69.9) initially presented to endocrinology on account of hirsutism and secondary amenorrhea attributed to PCOS. Work-up then confirmed diagnosis of NCCAH with 21-hydroxylase genetic testing showing deletion of one copy of CYP21A2 and the pathogenic variant p.V282L in the remaining copy. Outside the peripartum period, she was managed with OCP therapy, spironolactone, and metformin. She was additionally prescribed GC therapy of hydrocortisone 10mg TID following her diagnosis of NCCAH. She subsequently became pregnant unexpectedly. Post-partum course was complicated by significant weight gain, which led her to seek elective bariatric surgery for long-term weight management. At 5 months post-op, she had a weight deficit of ∼100lbs. Although she self-discontinued GC therapy due to fear of weight gain, her amenorrhea resolved, her hirsutism significantly improved, and lab testing revealed normalization of all NCCAH markers, including ACTH, 17-OHP, and androstenedione. Thus, GC therapy was not restarted. At 11 months post-op and still off GC therapy, she had a total weight deficit of ∼160lbs and continued metabolic resolution of NCCAH markers. Conclusions: This case presents a patient with NCCAH and morbid obesity who no longer required GC therapy post-RYGB. Presently, GC therapy remains the only available treatment for CAH; however, long-term GC therapy has the potential for myriad possible complications and side effects. Our case presents elective bariatric surgery as a potential and unique treatment option for patients with classic or non-classic CAH who have associated morbid obesity. The exact pathophysiologic basis for this effect and its potential role in long-term management of appropriate CAH patients requires further in-depth study.

Presentation: Friday, June 16, 2023
FRI261 A Case Of Cushing Syndrome And Hyperandrogenism Secondary To An Adrenal Cortical Oncocytoma
Authors: Hall Elizabeth , Gupta Suruchi , Lee Jennifer
Published: October 2023

Disclosure: E. Hall: None. S. Gupta: None. J. Lee: None.

Background: Adrenal cortical oncocytomas are rare neoplasms that are often non-functional, but there have been case reports of associated hypercortisolism, hyperandrogenism, and in even rarer cases, multiple hormonal excesses. Clinical Case: A 30 year old woman with history of hypertension, prediabetes and obesity presented with 3 years of oligomenorrhea, hirsutism, weight gain, and voice deepening. She did not take any medications and had no family history of endocrine diseases. Labs revealed hyperandrogenism: elevated total testosterone of 390 ng/dL and 435 ng/dL (nl 6-82), suppressed FSH of 0.2 mIU/mL (nl 1.7-21.5) and LH of <0.1 mIU/mL (nl 1.0-95.6), normal DHEA-S of 290 ug/dL (nl 98.8-340). Morning 17-hydroxyprogesterone was elevated to 944 ng/dL and increased to 1031 ng/dL (nl 23-431) on ACTH stimulation test, which did not meet diagnostic criteria for non-classical congenital adrenal hyperplasia. Also, genetic testing for CYP21A2 gene mutations was negative. Pelvic ultrasound was unremarkable. CT of the adrenal glands showed a 4.6 x 3.8 x 4.4 cm mildly heterogeneous left adrenal mass that measured 35 HU on non-contrast images with absolute washout of 50% and relative washout of 31%. The mass was concerning for malignancy based on HU >20, size >4cm, and 50% contrast washout (borderline). Overnight 1mg dexamethasone suppression test showed non-suppressed morning cortisol of 7.1 ug/dL (nl <1.8), with dexamethasone level of 246 ng/dL (nl 180-550) and ACTH of <5 pg/ml (nl 6-50). Twenty four hour urinary free cortisol level was slightly elevated to 52.3 mcg/24h (nl 4-50). Plasma metanephrines and aldosterone/renin ratio were normal. The patient underwent left laparoscopic adrenalectomy without complications. Pathology was consistent with adrenal cortical oncocytoma. Post-operatively, morning cortisol was <0.3 ug/dL, so she was started on hydrocortisone replacement twice daily but was tapered off within three months. Three weeks after surgery, total testosterone was <8 ng/dL. Two months after surgery, her menstrual cycles resumed. Fifteen months after surgery, she had regular menstrual cycles, 20 lb weight loss, resolution of hirsutism, hypertension and prediabetes. Conclusions: Adrenal cortical oncocytomas are rare tumors of the adrenal glands that should be considered in the differential for large adrenal tumors that appear suspicious for malignancy on imaging. They may or may not be functional, and in this case, the tumor secreted both androgens and cortisol. Although androgen-secreting tumors are frequently malignant, such as adrenocortical carcinomas, androgen-secreting oncocytomas are generally considered benign. However, there have been rare reports of malignant oncocytomas and oncocytomas of uncertain malignant potential.

Presentation: Friday, June 16, 2023
FRI270 A Rare Case Of Giant Benign Pheochromocytoma
Authors: Hossain Md Shajjad , Gautam Bharat , Mandal Kaushik , Liao Huijuan , Rosenthal David S , Kumar Salini Chellappan
Published: October 2023

Disclosure: M.S. Hossain: None. B. Gautam: None. K. Mandal: None. H. Liao: None. D.S. Rosenthal: None. S.C. Kumar: None.

Background: Pheochromocytomas are Catecholamine-secreting tumors that arise from the adrenal medulla. These tumors are rare however giant pheochromocytomas (>7 cm) are even rarer entities, which are thought to be more aggressive and malignant. Here we present a case of incidentally found giant but benign pheochromocytoma. Case Report: A 40-year-old female with no PMH presented to the hospital with fever & cough for 1 month which was associated with weight loss (10lb). Patient was started on antibiotics and CT revealed right-sided adrenal incidentaloma while searching for sources of infection. CT & MRI abdomen were done for better characterization, showed a round circumscribed right adrenal mass measuring 11.3 x 11.4 x 12.8 cm. Mass had irregular central necrosis, peripheral enhancement & neovascularization. Patient denied headache, sweating & palpitation; no personal or family history of pheochromocytoma. On physical examination BP: 103/70, HR: 98, Temp: 98F, BMI:25.9, unremarkable for cushingoid features, virilization & hirsutism. Hormonal workup showed elevated free normetanephrine 185 (<148pg/ml) & chromogranin A 801 (<311ng/ml), but normal free metanephrine <25 (<57pg/ml) & total metanephrines 185 (<205pg/ml). 24hr Urine study: elevated total metanephrines 1661 (182-739mcg/24h) & normetanephrine 1482 (88-649mcg/24h) but normal metanephrine 179(58-203mcg/24h), urine volume 2360ml/24h, urine creatinine 0.87(0.50-2.15g/24h). Patient Cortisol, ACTH, Aldosterone, Renin activity, DHEA-S, Androstenedione was normal. Patient was started on alpha-blockers. Patient underwent successful right-sided adrenalectomy & nephrectomy with IVC resection. Pathology reported pheochromocytoma stage II T2Nx, Ki 67 <5%. No vascular and extracapsular invasion & no mitosis. Post operative outpatient follow up showed elevated plasma free normetanephrine 199(<148pg/ml) & normal free metanephrine <25 (<57pg/ml) & total metanephrine 199 (<205pg/ml). 24hr urine study: normal metanephrine 61 (58-203mcg/24h), Normetanephrine 268 (88-649mcg/24h) & total metanephrines 329 (182-739mcg/24h). Patient was advised for Ga68 DOTATE/PET scan, genetic counseling & lifelong follow-up with endocrinology for surveillance. Discussion: Pheochromocytoma symptoms may vary regardless of tumor size. Giant pheochromocytoma may not have high secretory potential due to central necrosis resulting in reduced chromaffin cells or catecholamines that are restricted to capsular mass which may release into the bloodstream intraoperatively1. Therefore, initiating alpha-blockers before surgery in these cases may prevent perioperative complications.1. Minei S, Yamashita H, Koh H, Satoh T, Kobayashi S, Furuhata M, et al. Giant cystic pheochromocytoma A case report. Hinyokika Kiyo. 2001;47:561-3.

Presentation: Friday, June 16, 2023
SAT265 Stearoyl CoA Desaturase Knockdown Increases Saturated And Monounsaturated Fatty Acid Concentrations In SDHB KD Cells But Not In hPheo1 Wild-type Progenitor Cells
Authors: Ghayee Hans K , Bala Niharika , Xu Yiling , Tevosian Sergei G , Kozuch Marianne , Denslow Nancy D , Alli Abdel Ayube
Published: October 2023

Disclosure: H.K. Ghayee: Other; Self; Royalties form the University of Texas Southwestern Medical Center. N. Bala: None. Y. Xu: None. S.G. Tevosian: None. M. Kozuch: None. N.D. Denslow: None. A.A. Alli: None.

Introduction: Pheochromocytoma and paraganglioma (PPGL) patients with mutations in the succinate dehydrogenase B subunit (SDHB) frequently develop metastatic lesions and have a poor prognosis. The stearoyl-CoA desaturase 1 (SCD1) protein plays an important role in lipid metabolism. SCD1 inhibitors have shown great potential as new treatments for various diseases including cancer. Hypothesis: siRNA mediated knockdown of SCD1 compared to non-targeting siRNA would result in differences in the concentrations of saturated fatty acids and monounsaturated fatty acids in SDHB KD cells compared to hPheo1 wild-type (WT) progenitor cells. Methods: Fatty acid concentrations were assessed by fatty acid methyl ester (FAME) analysis. SCD1 expression was assessed by quantitative polymerase chain reaction (qPCR) and Western blotting analysis. Results: Analyses showed a significant decrease in SCD1 in SDHB KD cells compared to hPheo1 WT cells. Fatty acid methyl ester analysis showed the concentrations of the saturated fatty acids myristic acid, palmitic acid, and stearic acid, and the monounsaturated fatty acids palmitoleic acid and oleic acid are increased at least 2-fold in SDHB KD cells transfected with SCD1 siRNA compared to non-targeting siRNA. Conclusions: Fatty acid changes noted in hPheo1 SDHB KD cells were not seen in hPheo1 WT cells after siRNA mediated knockdown of SCD1. This suggests that SDHB deficiency and loss of FADH2 production interacts specifically with lipid desaturation pathways.

Presentation: Saturday, June 17, 2023
SAT268 Regulation Of Stem/Progenitor Cells Of The HPA Axis During Stress Adaptation
Authors: Siatra Panagiota , Cozma Diana , Berger Ilona , Oikonomakos Ioannis , Theodoropoulou Marily , Bornstein Stefan Richard , Andoniadou Cynthia Lilian , Steenblock Charlotte
Published: October 2023

Disclosure: P. Siatra: None. D. Cozma: None. I. Berger: None. I. Oikonomakos: None. M. Theodoropoulou: None. S.R. Bornstein: None. C.L. Andoniadou: None. C. Steenblock: None.

Chronic stress is a pervasive concern in the modern society. A long-term hyper activation of the hypothalamic-pituitary-adrenal (HPA) axis leads to elevated amounts of stress hormones [e.g. ACTH and glucocorticoids (GCs)]. This can incur maladaptation that eventually contributes to mental illness, cardiovascular dysfunctions, diabetes, cancer and autoimmune diseases. Emerging key players for stress adaptation of the HPA axis are stem/progenitor cell populations. In this study, we aim to unravel the mechanisms involved in the regulation of stem/progenitor cells of the HPA axis during stress adaptation. To that aim, we incorporated an in vitro system of non-adherent spheroids from primary adrenocortical mouse cells that were stimulated with ACTH. The treatment resulted in the increased growth of the spheroids compared to unstimulated controls indicating a potential role of the hormone in cell proliferation and stem cell behaviour. This result is in line with the enlarged adrenals observed in patients with Cushing’s syndrome. To assess the contribution of stem cells during stress adaptation in the adrenal cortex in vivo, we performed immobilization stress and lineage tracing studies using the tamoxifen inducible Gli1:CreERT2/R26R:eYFP mouse line. By combining these results along with single-cell RNA-seq technology, we aim to shed light into molecular factors involved in the adult adrenal cortex regeneration and remodelling. To follow the effect of GC excesses on the negative feedback loop observed during a normal stress response on the pituitary gland, we stimulated adherent primary anterior pituitary colonies with dexamethasone and corticosterone. GC treatment led to downregulation of Pomc expression, a precursor polypeptide for ACTH and other hormones, in the treated colonies compared to the control. This downregulation caused by GCs could be mediated through different gene targets of the glucocorticoid receptor as well as via paracrine signalling from pituitary stem cells. Altogether, our results will provide us with more profound knowledge of mechanisms underlying interactions between stressors and stem/progenitor cells of the HPA axis along with novel therapeutic targets for stress-associated disorders.

Presentation: Saturday, June 17, 2023
SAT300 Use of Overnight Metyrapone Test In Suspected Adrenal Insufficiency: A Retrospective Single Center-Study
Authors: Saini Jasmine , Garcia Raul Gregg , Herndon Justine , Erickson Dana Z , Gruber Lucinda , Bancos Irina
Published: October 2023

Disclosure: J. Saini: None. R. Gregg Garcia: None. J. Herndon: None. D.Z. Erickson: None. L. Gruber: None. I. Bancos: None.

Context: Overnight metyrapone test (OMT) is a dynamic test used to diagnose secondary adrenal insufficiency (SAI). However, it is uncommonly used and the data on the OMT indications and performance are scarce. We aimed to characterize the indications, performance, and safety of outpatient OMT. Methods: Single center retrospective study in adults with OMT between April 1st, 2018 -July 31st, 2022. We evaluated three post-OMT cutoffs diagnostic of SAI: 1) 11-deoxycortisol ≤7 mcg/dL (11D≤7); 2) 11-deoxycortisol ≤10 mcg/dL (11D≤10), or 3) sum of cortisol and 11-deoxycortisol ≤15 mcg/dL (sum≤15), in comparison to pre-test probability and reference standard, defined as clinician-made diagnosis of SAI. When available, OMT-based SAI diagnosis was compared to results from the cosyntropin stimulation test (CST). Results: OMT was performed in 109 patients (76, 70% women) at a median age of 48 (IQR, 37-59) years. Pre-test probability for SAI was high in 13 (12%), moderate in 46 (43%), and low in 49 (45%) patients. Indications for OMT included evaluation of symptoms without clear SAI risk factors (38, 35%), suspected SAI due to chronic opioid use (25, 23%), pituitary pathology/therapies (25, 23%), exogenous glucocorticoid use (8, 7%), other (13, 12%). Overnight metyrapone was administered at a median dose of 2500 (IQR, 2125-3000). Adverse events were reported by 9 (8%) patients and were mild (nausea, fatigue) except for 1 patient who had to be hospitalized.

The final diagnosis of SAI was made in 25 (48%) patients: 92%, 52%, and 12% of patients with high, moderate, and low pre-test probability. When compared to the clinician-made SAI diagnosis, OMT-based diagnosis of SAI was made in 60% of patients using the 11D≤7 cutoff, and in 81% of patients using the other cutoffs (11D≤10 or sum≤15).

In 50 patients with concomitant CST, the final diagnosis of SAI was made in 23 (46%) patients, despite the normal CST results (post-cosyntropin peak cortisol ≥18 mcg/dL) in 12/23 patients. In patients with post-cosyntropin peak cortisol ≥18 mcg/dL, OMT was abnormal in 14% of patients (using post-OMT cutoff 11D≤7), 29% of patients (based on cutoff 11D≤10), and in 30% of patients (based on sum≤15).

Conclusions: Outpatient OMT is well tolerated and was mostly used in patients with low/moderate pre-test probability for SAI. In patients with normal CST, OMT may diagnose SAI in additional 30% of patients, especially if the pre-test probability is high. Post-OMT sum of 11-deoxycortisol and cortisol <15 mcg/dL performs well in diagnosing SAI while allowing confirmation of adequate cortisol suppression.

Presentation: Saturday, June 17, 2023
SAT326 Massive Adrenomyelolipomas Due To Longstanding CAH
Authors: Aziz Qurrat-ul-ain , Champion Amber
Published: October 2023

Disclosure: Q. Aziz: None. A. Champion: None.

Introduction: Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder caused by deficiency in adrenal corticosteroid biosynthesis. 21 Hydroxylase Deficiency is common in 90-95% of CAH cases and have a defect in converting 17 OH Progesterone to 11 deoxycortisol. Therefore, they have an increase in ACTH secretion due to the decrease negative feedback drive along with excess adrenal androgens. Adrenal myelolipoma are common in patients with CAH and the tumors are benign and lipomatous. Clinical Case: Patient is a 47 year old female with past medical history of CAH presents to the clinic for evaluation of generalized fatigue and abdominal pain. She was diagnosed with CAH- 21 hydroxylase deficiency at birth and required vaginal reconstruction surgery. She was on hydrocortisone and fludrocortisone until age 18, but thereafter stopped taking medications or seeing physicians for nearly 30 years. CT abdomen/pelvis showed large bilateral adrenal myelolipomas, right adrenal gland measuring 23.2 cm and left adrenal gland measuring 20 cm. MRI confirmed enlarged adrenal glands. Initial labs included ACTH 299, 17-OH Progesterone >2000, 11 deoxycorticosterone 23.6, total testosterone 160, free testosterone 30.3, DHEA-S 192, Cortisol 2.8. She was started on fludrocortisone 50 mcg and Hydrocortisone 10 mg in the morning and 5 mg in the evening and was referred to an endocrine surgeon out of state, but surgery was not offered due to concerns of medication nonadherence. She returned to clinic 6 months after presentation, she admitted to missing multiple doses of her hydrocortisone. Repeat CT Abdomen and Pelvis showed severe compression of the IVC and right lobe of the liver along with mild compression of the kidneys and pancreas. To improve adherence, she was switched to prednisone, and eventually dexamethasone 0.75mg and fludrocortisone 100mcg. She complains of fatigue but improved abdominal pain. After a period of good adherence with medication administration, she was referred to a local surgical oncologist who agreed to do bilateral adrenalectomy due to mass effect. Conclusion: CAH is a challenging chronic disease with variable penetrance in phenotype, ranging from mild hirsutism to frank adrenal insufficiency. Massive adrenomyelolipomas are thought to be ACTH driven, especially seen in undertreated and longstanding CAH. Without the 21 hydroxylase enzyme to convert 17 OH Progesterone to 11 deoxycortisol, levels of ACTH rise. While these myelolipomas are benign and can generally be monitored, surgery should be considered if the size impairs function of surrounding organs. Bilateral adrenalectomy can also be considered in patients with CAH for refractory hypertension, hyperandrogenism and virilization, Cushing syndrome, infertility, or mass effect.

Presentation: Saturday, June 17, 2023
SAT345 Disappearing Adrenal Masses: A Tale Of Two Lesions
Authors: Arooj Aneela , Lansdown Andrew
Published: October 2023

Disclosure: A. arooj: None. A. Lansdown: None.

Introduction: Adrenal lesions are being increasingly detected on CT scans performed for other reasons. Adrenal lesions that “disappear” on subsequent imaging are rare, most commonly due to adrenal hematomas, cysts or infection.

Case: 1 73-year-old man was admitted with a collapse and fall. CT head & angiogram demonstrated cerebral sinus thrombosis, subarachnoid hemorrhage and right parietal hematoma. Furthermore, high density4cm left adrenal lesion on CT abdomen(Fig 1) Consideration was given to COVID vaccine induced thrombotic thrombocytopenia. ACTH, aldosterone, renin, aldosterone renin ratio normal. Slightly low cortisol (386) after short synacthen test. Later, CT showed the left adrenal lesion had disappeared in Fig 2.

Case 2: 36-year-old man following a road traffic collision, fell from his electric scooter at a speed of 30mph, also noted to have high blood pressure on admission. He had small laceration of the liver which was managed conservatively. CT abdomen and pelvis, showed a low density 28mm right adrenal nodule, measuring 37 Hounsfield Units,(fig 3) that was completely resolved in subsequent imaging (Fig4). His biochemistry reports of dexamethasone suppression test, renin, aldosterone, 24hr metadrenaline urinary profile and urinary cortisol remained normal.

Learning points: "Disappearing", adrenal mass lesions are rare, though reported, and most commonly due to adrenal hematomas, cysts or infection.

References: I G Hermsen , M P J Polak, H R Haak. Disappearing adrenal masses. Endocrine. 2010 Oct;38(2):153-7. doi: 10.1007/s12020-010-9368-7. Epub 2010 Jul 11,

Presentation: Saturday, June 17, 2023
THU393 An Internal NPT2A Cryptic PDZ Motif Is A Novel Regulator of PTH- And FGF23-sensitive Phosphate Transport
Authors: Sneddon Bruce W , Friedman Peter A , Mamonova Tatyana
Published: October 2023

Disclosure: B.W. Sneddon: None. P.A. Friedman: None. T. Mamonova: None.

The Na+-dependent NPT2A (SLC34A1) phosphate co-transporter is a major regulator of phosphate homeostasis. Its most notable structural element is a carboxy-terminal PDZ ligand that binds Na+/H+ Exchanger Regulatory Factor-1 (NHERF1, SLC9A3R1), a multidomain PDZ protein that determines apical NPT2A localization and is required for phosphate transport. NPT2A also possesses an uncharacterized internal PDZ ligand. Two recent clinical reports describe congenital hypophosphatemia in children harboring Arg495His or Arg495Cys variants within the internal PDZ motif. Wild-type internal 494TRL496 PDZ binds NHERF1 PDZ2, which we consider a regulatory domain. Ablating the internal PDZ ligand with a 494AAA496 variant blocked hormone-sensitive phosphate transport. Complementary approaches, including CRISPR/Cas9 technology, side-directed mutagenesis, confocal microscopy, and modeling, showed that NPT2A Arg495 His or Arg495Cys variants do not support PTH or FGF23 action on phosphate transport. CoIP experiments indicate that both variants bound NHERF1 similarly to WT NPT2A. However, in contrast to WT NPT2A, NPT2A Arg495His or Arg495Cys variants remain at the apical membrane and are not internalized in response to PTH. We predict that His or Cys substitution of the charged Arg495 changes the electrostatics, preventing phosphorylation of the upstream Thr494, interfering with phosphate uptake in response to hormone action, and inhibiting NPT2A trafficking. We advance a model where the carboxy-terminal PDZ ligand defines apical localization of NPT2A, while the internal PDZ ligand is essential for hormone-triggered phosphate transport.

Presentation: Thursday, June 15, 2023
THU395 Phosphate Inhibits Calcium-sensing Receptor Expressed Endogenously In TT Cells
Authors: Alghamdi Khaleda Ali , Ward Donald
Published: October 2023

Disclosure: K.A. Alghamdi: None. D. Ward: None.

Calcium-sensing receptor (CaR) is the key controller of parathyroid hormone (PTH) secretion and extracellular calcium homeostasis. Hyperphosphataemia increases PTH secretion and we reported recently that pathophysiologic phosphate (Pi) concentrations can attenuate CaR activity directly in transfected HEK-293 cells and can increase PTH secretion from human and murine parathyroid cells (1). This was investigated further using thyroidal C cell-derived TT cells (ATCC), which express CaR endogenously. Intracellular Ca2+ (Ca2+i) mobilisation was assayed by epifluorescence microscopy, calcitonin secretion by ELISA, protein expression by immunoblotting and CaR mRNA expression by qRT-PCR. Co-stimulation of TT cells with the (CaR-activating) calcimimetic R568 (1µM) and spermine (1mM) elicited robust Ca2+i mobilisation, that was inhibited (33±4%; P<0.001; N=4) by 2mM (pathophysiologic) Pi-containing buffer vs 0.8mM Pi control. In contrast, raising Pi concentration was without effect on carbachol-induced Ca2+i mobilisation (acting via muscarinic receptors) (P=0.89; N=3). Also, 1.2mM (high) sulphate elicited a similar CaR inhibition as for Pi vs 0.3mM control (-28±16%; P<0.05; N=4). Next, it was found that CaR-mediated stimulation of the TT cells with 1µM R568 & 1mM spermine (in 2mM Ca2+ and 0.8mM Pi) increased calcitonin secretion, as expected, whereas the same stimulation in 2mM Pi (in the presence of 2.2mM Ca2+ to correct for any reduction in free Ca2+) significantly blunted this response (-59.7±15%; P<0.05;N=4). Interestingly, CaR mRNA expression was significantly downregulated 45±13%; P<0.05;N=6) after 48 hours treatment with media containing 2mM Pi (vs 0.8mM control). However, while CaR protein expression in the TT cells was confirmed by immunoblotting, its abundance was unaffected by the same 2mM Pi cotreatment (P=0.79; N=8). Therefore, pathophysiologic Pi treatment inhibits endogenous CaR-induced signalling, calcitonin secretion and CaR mRNA expression in thyroidal TT cells but without affecting CaR abundance. These results further support the idea that the CaR represents a mineral sensor, at which Pi acts directly as a non-competitive antagonist to limit CaR-induced suppression of PTH secretion. Reference: (1) Centeno et al. Nat Commun. 2019;10:4693.

Presentation: Thursday, June 15, 2023
THU415 Trabecular Bone Score In Hospitalized Patients With Heart Failure
Authors: Bandeira Francisco , Oliveira Lucian B , Siqueira Mariana A F M , Litvin Mirela A , Garcia Jessica M A , Bandeira Leonardo
Published: October 2023

Disclosure: F. Bandeira: None. L.B. Oliveira: None. M.A. Siqueira: None. M.A. Litvin: None. J.M. Garcia: None. L. Bandeira: None.

Introduction: Heart failure (HF) is a clinical syndrome directly associated with functional impairment, which may be interrelated with skeletal consequences and an increased risk of fractures. The trabecular bone score (TBS) allows an indirect assessment of the bone microarchitecture, a helpful tool in fracture risk stratification. Objective: To evaluate the TBS and its relationship with bone mineral density (BMD) and cardiometabolic parameters in patients admitted with HF. Methods: Cross-sectional study was conducted in a Cardiology center, with patients aged 40 to 85 years hospitalized with HF. Clinical, echocardiographic, laboratory and BMD were evaluated. TBS <1.230 was characterized as bone degradation. Results: A total of 103 patients were evaluated, of which 53.4% were female. The mean age was 64.1 ± 9.4 years. The median left ventricular ejection fraction (LVEF) was 50.0% (interquartile range [IQR] 34.0-61.0%), with 50.5% having preserved LVEF (≥50%), 5.8% having mildly reduced LVEF (41-49%), and 43.7% having reduced LVEF (≤40%). 50.4% of patients had New York Heart Association Functional Classification (NYHA-FC) I-II and 49.6% NYHA-FC III-IV. The majority (67%) of patients had HF of ischemic etiology; 43.7% had diabetes mellitus and 30.0% had prediabetes. Bone degradation indicated by TBS was present in 33.0% of the sample, while BMD in the osteoporosis range was observed in 22.3%. There was no statistically significant difference between genders in the presence of bone degradation (22.9% of men vs. 36.4% of women, p = 0.138). Low TBS was associated with higher mean age (67.5 ± 9.1 vs. 62.7 ± 9.2 years, p = 0.016) and lower T-scores in the lumbar spine (−1.9 ± 1.3 vs. −0.7 ± 1,8, p = 0.001), femoral neck (−1.6 ± 1.2 vs. −1.1 ± 1.2, p = 0.030), and total femur (−1.3 ± 1.1 vs. −0.5 ± 1.3, p = 0.005). There was no association between low TBS and body mass index (28.0 ± 4.4 vs. 27.8 ± 5.3 kg/m², p = 0.828), LVEF (50.0% [30.0-59.0] vs. 55.0% [34.3-61.8], p = 0.183) and hemoglobin A1c (6.4% [5.7-7.9] vs. 6.2% [5.7-8.2], p = 0.920). Patients with NYHA-FC III-IV had lower mean TBS when compared to those with NYHA-FC I-II (1.273 ± 0.138 vs. 1.335 ± 0.149, p = 0.031). Conclusion: We found that bone microarchitecture deterioration was more frequent than osteoporosis in patients hospitalized with HF, with greater symptomatology being associated with lower TBS.

Presentation: Thursday, June 15, 2023
THU432 Severe Osteoporosis Associated With A Novel Plastin 3 (PLS3) Mutation
Authors: Ibrahim Amira , Esper Layal , Gandhi Shruti Mahendra , Nylen Eric S
Published: October 2023

Disclosure: A. Ibrahim: None. L. Esper: None. S.M. Gandhi: None. E.S. Nylen: None.

Early Onset Osteoporosis (EOOP) affects children and young adults and can be caused by endocrinopathies, chronic medical conditions, nutritional deficiencies, and/or genetic mutations. The most common inherited cause is osteogenesis imperfecta(OI), and a rare variant linked to OI includes a defect in the X chromosomal gene encoding Plastin 3 (PLS3). In our case, a 34-year-old male was referred for severe osteoporosis. He had been diagnosed with osteopenia at age 21. At age 24, imaging revealed multiple vertebral compression fractures and DXA scan confirmed severe osteoporosis. He required L3-L5 kyphoplasty and started on oral bisphosphonates for presumed OI despite negative gene mutation (i.e., COL1A1/COL1A2). He continued treatment for only 2 years. 8 years later, he had persistent osteoporosis (DXA L2-4 Z-score -3.6, LFN Z-score -3.2). He had no evidence of kyphosis or scoliosis and no extraskeletal manifestations such as blue-grey sclera or any dysmorphic features. The workup was negative for secondary causes of EOOP and he denied a family history of osteoporosis. Labs showed normal 24-hour urine calcium, bone markers, and bone Alkaline Phosphatase. Karyotyping showed normal XY and gene analysis was again negative for OI. He started treatment with intravenous Zoledronic acid, however, had a 2-year gap between doses initially causing BMD to drop by 6.5% in L2-L4 (Z -4.1) and by 5.7% in LFN (Z -3.1). Subsequently, he received a total of 5 doses of Zoledronic acid to date and had no further fractures. DXA significantly improved by 10.4% in L2-4 (Z -2.6), and 16.3% in LFN (Z -2.0). Repeated expanded gene testing showed a novel PLS3 hemizygous mutation (deletion at site C.234_237+10del of Exon 3). This case demonstrates a novel PLS3 mutation variant to be a plausible cause of adulthood EOOP which was responsive to bisphosphonate treatment. PLS3 is an F-actin binding and bundling protein involved in cytoskeletal remodeling and may have roles in calcium homeostasis, cell migration, endocytosis, DNA repair, and membrane trafficking. Currently, less than 30 loss of function variants of PLS3 have been identified and all lead to severe osteoporosis- particularly in children. However, our patient’s known onset of bone loss occurred much later- in his twenties and he had no evidence of extra-skeletal manifestations. The cause for such late presentation is unclear but may be attributed to this specific variant of PLS3. This case highlights that PLS3 mutation should be on the differential for EOOP even in early adulthood. Our patient’s BMD has markedly improved with bisphosphonates and he sustained no further fractures after starting therapy. Timely diagnosis and earlier detection will allow for appropriate genetic counseling, earlier screening, and treatment of affected family members.

Presentation: Thursday, June 15, 2023