bluuebunny/crossref_metadata_2025_split huggingface dataset:
SAT440 DRESS/DHIS-associated Thyroiditis And Hypophysitis
Authors: Ranasinghe Indika R , Elston Marianne Susan , Boyle Veronica 
Published: October 2023

Abstract
Disclosure: I.R. Ranasinghe: None. M.S. Elston: None. V. Boyle: None.
Introduction: Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DRESS/DIHS) is a severe life-threatening adverse reaction to specific drugs, including cephalosporin antibiotics (1). It is characterised by rash, fever, eosinophilia, lymphadenopathy, and inflammation of internal organs. Endocrine complications in the form of thyroid disease and Type 1 Diabetes have been reported following DRESS/DIHS (2). We report a case of thyroiditis and hypophysitis following cephalosporin-associated DRESS/DIHS. Case: A 21-year-old male farmer suffered a tractor crash accident resulting in hospitalization for bilateral compound distal femur fractures. He had no past medical history of note. One month later, he developed a maculopapular rash involving his limbs, mouth ulcers, fever, liver function derangement and eosinophilia. Punch biopsy was consistent with DRESS/DHIS. A 2- week tapering course of prednisone was initiated at 40mg daily in conjunction with a topical corticosteroid for 9 days with resolution of rash. Review of medication charts identified the most likely causative agent as cefazolin. An Endocrine consult was requested a month later due to new hypercalcemia. Investigations revealed new onset thyrotoxicosis and a decreasing morning cortisol over the following week despite having stopped all steroids one month earlier, normal ACTH, mildly elevated prolactin and secondary hypogonadism. Short Synacthen test showed suboptimal response. TRAb were negative and technetium thyroid scanning demonstrated a thyroiditis. MRI pituitary was unremarkable. He was commenced on hydrocortisone replacement for symptomatic cortisol deficiency. Biochemical abnormalities gradually normalized and his hydrocortisone ceased with symptomatic resolution. Endocrine involvement, particularly pancreas and thyroid has previously been reported in cases of DHIS/DRESS (3) (4). In this case, DHIS/DRESS-associated hypophysitis with thyroiditis may explain the clinical findings of pituitary dysfunction affecting multiple pituitary axes and the gradual recovery to normal pituitary function.
References: (1) Hama, N et al., Drug-Induced Hypersensitivity Syndrome (DIHS)/Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS): Clinical Features and Pathogenesis. The Journal of Allergy and Clinical Immunology: In Practice, Volume 10, Issue 5, 1155 - 1167.e5
(2) Kano, Y. et al., Visceral Involvements and Long-term Sequelae in Drug-induced Hypersensitivity Syndrome, Medical Clinics of North America, Volume 94, Issue 4,2010,
(3) Deng, M et al., Co-Occurrence of Multiple Endocrine Abnormalities Induced by the DIHS/DRESS. Int J Endocr 2019; 2019: 7959615
(4) Klimas, N et al., Drug-Induced Delayed Multi-organ Hypersensitivity Syndrome. In: Hall J, Hall B. (eds) Cutaneous Drug Eruptions. 2015. Springer, London.
Presentation: Saturday, June 17, 2023
SAT447 Gaps In Care: Endocrine-disrupting Chemicals And Metabolic Disease Management Guidelines
Authors: Obeid Michele , Majid Aaish , Sargis Robert Michael 
Published: October 2023

Abstract
Disclosure: M. Obeid: None. A. Majid: None. R.M. Sargis: None.
In recent decades, global rates of obesity, diabetes, and non-alcoholic fatty liver disease have increased substantially, imposing significant morbidity and mortality on patients and severe economic strain on healthcare systems. Discussions of modifiable risk factors responsible for metabolic dysfunction have classically centered upon the role of excess energy intake and insufficient energy expenditure. Consequently, clinical practice guidelines have largely focused upon these factors when addressing disease risk and treatment. In recent years, however, new metabolic risk factors have emerged, including exposure to endocrine-disrupting chemicals (EDCs). Because exposure to EDCs is potentially modifiable through individual action and/or public policy, we sought to understand how practice guidelines for metabolic disorders have incorporated this new knowledge into clinical care. To accomplish this, we searched PubMed for the years 2007 to 2022 for European, Asian, and American clinical practice guidelines related to obesity, diabetes, non-alcoholic fatty, dyslipidemia, chronic kidney disease, and cardiovascular disease. Each guideline was then searched by two reviewers for 83 terms related to environmental factors linked to metabolic dysfunction. Environment-related statements were then adjudicated by three reviewers for relevance. Select guidelines for non-metabolic disorders linked to environmental factors were similarly reviewed for comparison, including asthma, chronic obstructive pulmonary disease (COPD), and obstetrics/gynecology guidelines. In total, 68 guidelines and statements were systematically reviewed. While environmental risk reduction was partially addressed in COPD, asthma, and cardiovascular guidelines, those focused on obesity, diabetes, and non-alcoholic fatty liver disease did not address the contribution of EDCs or other ambient environmental factors. Across all guidelines only air pollution received substantive attention, leaving other EDCs nearly entirely neglected. A clear but inadequately considered component of the social and structural determinants of health, environmental exposures have emerged as modifiable risk factors for multiple metabolic disorders. While further work is needed, future clinical practice guidelines should incorporate clinical interventions, research initiatives, and policy recommendations to address the impact of poor environments on human metabolic health.
Presentation: Saturday, June 17, 2023
THU045 WIP1 Phosphatase Is A Novel Specific Target For Epithelial GH Action
Authors: Apaydin Tugce , Zonis Svetlana , Zhou Cuiqi , Barrett Robert , Chesnokova Vera , Melmed Shlomo 
Published: October 2023

Abstract
Disclosure: T. Apaydin: None. S. Zonis: None. C. Zhou: None. R. Barrett: None. V. Chesnokova: None. S. Melmed: None.
Deficient DNA repair and accumulated DNA damage underlie age-associated pathological changes, tissue fragility, and neoplastic development. ATM kinase, an activator of DNA damage responses (DDR), phosphorylates DDR effectors including CHK2, p53, and γH2AX to ensure DNA repair. We have shown that GH suppresses epithelial DDR activity by suppressing ATM phosphorylation, resulting in DNA damage accumulation due to repressed DNA repair. Wip1 dephosphorylates ATM thereby attenuating DNA damage repair. We found that GH significantly induced Wip1 expression (1.6-fold) in both human normal colon cells (hNCC) and in human 3-dimensional intestinal organoids, resulting in dephosphorylated ATM, CHK2, γH2AX, and p53. Mice bearing GH-secreting tumors with high circulating GH also exhibited induced colon Wip1 expression with lower phospho-ATM, γH2AX, and p53 as well as increased DNA damage. Twofold higher Wip1 expression was observed in blood buffy coats derived from patients with GH-secreting adenoma vs patients with non-functioning pituitary adenoma. Specificity of these observations was validated by showing that in GH-treated cells, blocking GH receptor (GHR) with pegvisomant or blocking STAT5 phosphorylation with the inhibitor CAS 285986-31-4 constrained Wip1 induction and restored ATM phosphorylation, indicating that GH effects on Wip1 are GHR/STAT5-mediated concordant with the observed decreased colon Wip1 expression in GHR-/- mice devoid of GH signaling. Furthermore, Wip1 inhibition with the small molecule inhibitor (GSK2830371) reversed GH-induced DNA damage by restoring phosphorylation of ATM and other key DDR proteins. To determine a mechanism for Wip1 induction, we tested homeodomain-interacting protein kinase 2 (HIPK2) which is regulated by AMPK and potentiates Wip1 proteasomal degradation and its activity. We observed that GH increased phospho-AMPK expression, while blocking AMPK kinase activity with Compound C abrogated GH induction of Wip1. Src upregulates AMPK and triggers HIPK2 cytoplasmic relocation thereby inactivating HIPK2. We found that GH, by activating Src/AMPK phosphorylation, elicits HIPK2 cytoplasmic relocation, thus suppressing Wip1 ubiquitination and increasing its stability. Consistent with these findings, blocking Src phosphorylation with the tyrosine kinase inhibitor dasatinib abolished Wip1 upregulation and induced phosphorylation of its downstream targets. These results indicate that GH suppresses DDR by inducing Wip1 expression, and suppression of Wip1 may prevent epithelial accumulation of unrepaired DNA damage. These findings identify Wip1 as a specific novel target for GH action mediating GH-attenuation of DNA repair.
Presentation: Thursday, June 15, 2023
THU048 Determination Of Receptor Binding Affinity Of Growth Hormone Analogues To The Growth Hormone Receptor In A Drug Screening Context
Authors: Erlendsson Simon , Kulakova Alina , Poulsen Svend , Thygesen Peter 
Published: October 2023

Abstract
Disclosure: S. Erlendsson: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. A. Kulakova: Employee; Self; Novo Nordisk. S. Poulsen: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. P. Thygesen: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk.
Growth hormone (GH) and GH analogues are characterized by their ability to bind and activate the GH receptor (GHR). Binding affinity and functional activity are pivotal parameters for development and characterization of new GH analogues for treatment of growth disorders. The GHR is a member of the class I cytokine family and obtains a tripartite structure consisting of two extracellular fibronectin type III domains (ECD), a single-pass transmembrane domain (TMD), and a disordered intracellular domain (ICD). These receptors lack intrinsic kinase activity but rely on recruitment of intracellular signalling kinases and regulatory proteins. Activation of the downstream JAK-STAT signalling cascade is initiated by formation of an asymmetric GHR dimer induced by binding of GH to the GHR ECDs via two partially overlapping binding sites designated site I and II. The structural rearrangement in the ECDs propagates through the TMD and results in a separation of the ICDs which leads to activation through cross-phosphorylation of the Janus kinases 2 (JAK2). Here we utilize isothermal titration calorimetry (ITC), surface plasmon resonance (SPR) and small angle x-ray scattering (SAXS) to characterize the binding of native GH and GH analogues including somapacitan and pegvisomant to the monomeric GHR as well as an artificial soluble stabilized dimeric GHR. The GH analogues with good binding properties were subsequently tested in vitro for biological activity using a STAT3-luciferase reporter gene assay (RGA) and a proliferation assay with BAF3 cells expressing the human GHR. Both assays were established in two formats enabling testing of both receptor agonists and antagonists. Using SPR we show that the binding of all tested compounds is preserved between the monomeric and dimeric GHR with affinities ranging from near-picomolar to lower micromolar and we are subsequently able to confirm the expected stoichiometry by utilizing a combination of ITC and SAXS. In the RGA and the proliferation assay we demonstrate that a 1:2 stoichiometry is critical for receptor activation regardless of the affinity and therefore we propose high throughput screening of receptor stoichiometry as key in discovery of new growth disorder therapeutics.
Presentation: Thursday, June 15, 2023
THU052 Serum Growth Hormone Increases At The Onset Of Lactation And Promotes Mitochondrial Activity In Human Mammary Cells
Authors: Elajnaf Taha , Rostom Hussam , Meng Xin , Fry Alexandria , Hannan Fadil 
Published: October 2023

Abstract
Disclosure: T. Elajnaf: None. H. Rostom: None. X. Meng: None. A. Fry: None. F. Hannan: None.
Growth hormone (GH) administration is reported to increase milk yield in breastfeeding women. However, the role of endogenous GH in human lactation is unknown. We investigated whether serum GH is associated with the initiation of lactation after child birth, and recruited n=30 pregnant women (age range 24-41 years) following informed consent (1). Serum GH was measured at 36 weeks’ gestation and during postpartum days 1-4. All women had term births and initiated lactation between postpartum days 2-4. The mean maternal serum GH value progressively increased from 0.2±0.01 mIU/L at 36 weeks’ gestation to a peak value of 0.9±0.2 mIU/L on postpartum day-3 (p&lt;0.0001), with serum GH then decreasing to 0.2±0.03 mIU/L by postpartum day-4. We hypothesised that this early postpartum rise in serum GH may increase mammary metabolism in order to stimulate milk synthesis after child-birth. Reverse transcription-quantitative PCR (RT-qPCR) demonstrated that lactating human mammary epithelial cells (HMECs) isolated from breast milk express the GH receptor. We next assessed the effects of GH in cultured HMECs. Recombinant human GH (rhGH) caused a dose-dependent increase in the phosphorylation of Akt, which is a key signalling protein required for initiating lactation. Thus, 50ng/mL and 500ng/ml rhGH caused ∼1.5-fold and ∼2-fold increases in Akt phosphorylation, respectively (p&lt;0.05, n=4 experiments). We further evaluated the effects of rhGH on HMECs by untargeted proteomics involving nano liquid chromatography and tandem mass spectrometry. This demonstrated that the major mammary cell biological processes induced by GH involve the mitochondria. Indeed, HMECs treated with rhGH for 8 hours showed a significant upregulation of mitochondrial proteins involved in electron transport chain assembly, namely COQ9 (&gt;4-fold increase, p&lt;0.05) and IBA57 (&gt;4-fold increase, p&lt;0.05); and upregulation of CHCHD3 (6-fold increase, p&lt;0.05), which influences mitochondrial cristae structure. We assessed whether these mitochondrial protein changes affect mammary cell respiration. Extracellular O2, which is an indicator of oxidative phosphorylation, was measured in cultured HMECs treated with 50ng/mL rhGH for up to 5 days. Administration of 50ng/mL rhGH caused a significant increase in the rate of O2 consumed by these cells (579±28 vs. 456±14 pmol O2/min/106 cells for control HMECs, p&lt;0.01, n=4 experiments), consistent with increased oxidative phosphorylation. In summary, these clinical and cellular studies highlight a pivotal role for GH in promoting mammary cellular metabolism at the onset of lactation.
Reference: (1) Rostom, H. et al. Protocol for an observational study investigating hormones triggering the onset of sustained lactation: the INSIGHT study. BMJ Open 12, e062478.
Presentation: Thursday, June 15, 2023
THU109 An Interesting Case Of Infiltrative Panhypopituitarism Due To Metastatic Melanoma
Authors: Arora Neha , Maxwell Carolyn , Kim Julie Minjae 
Published: October 2023

Abstract
Disclosure: N. Arora: None. C. Maxwell: None. J.M. Kim: None.
Introduction: Metastases to the pituitary gland are a rare phenomenon only accounting for 1% of surgically treated pituitary tumors. The majority of cases, approximately 60%, in reported literature of hypopituitarism related to metastatic malignancy are associated with metastatic breast and lung cancer. These cases typically involve loss of posterior pituitary function rather than anterior. More specifically, the reported cases of panhypopituitarism related to melanoma have been associated with treatment with check point inhibitors with resultant hypophysitis. This case illustrates an unusual presentation of panhypopituitarism from direct infiltration and destruction of the pituitary gland from metastatic melanoma. Case Description: This was a 56-year-old post-menopausal female with a past medical history of Diabetes Mellitus type II who presented with a four-week history of generalized malaise, headache, dipoplia, and right eye ptosis. On physical exam, she was found to have right periorbital swelling, proptosis, and absent extraocular movement with right cranial nerve six palsy. MRI with pituitary protocol demonstrated a destructive, infiltrative process involving the pituitary, sella turcica, and cavernous sinus suggestive of either fungal infection or malignancy. Labs were indicative of panhypopituitarism including central hypothyroidism (TSH 0.008 uIU/mL, FT4 0.82 ng/dL), hypogonadism (FSH&lt;17 mIU/mL; LH 0.3 mIU/mL), and low prolactin (0.3 ng/ml). Labs were also notable for a random low cortisol at 11AM (1.6 ug/dL, n&gt;2.7ug/dl) and hyponatremia (125 mmol/L, n 135-146 mmol/L). A cosyntropin stimulation test failed to stimulate appropriately and stress dose steroids were initiated. A biopsy of the mass invading the pituitary gland was performed with pathology revealing metastatic melanoma with lymphovascular invasion. The patient’s hospital course was further complicated by multiple cerebral vascular infarcts, atrial fibrillation with rapid ventricular response, and heparin induced thrombocytopenia with rapid decline in functional status and patient soon passed. Post-mortem autopsy demonstrated friable hemorrhagic tissue (6.0 x 5.0 cm) involving the sellar and parasellar regions with diffuse lymphadenopathy consistent with metastatic melanoma. Discussion: This is a rare case of infiltrative metastatic melanoma with resultant panhypopituitarism. Although rare, metastatic disease should be considered when evaluating loss of pituitary function.
Presentation: Thursday, June 15, 2023
THU110 Wrong Tissue At Wrong Place—Rare Case Of Hypopituitarism Secondary To Metastatic Renal Cell Carcinoma
Authors: Avula Sreekant , Ahmed Ammar , Salim Michael , Alameddine Hind 
Published: October 2023

Abstract
Disclosure: S. Avula: None. A. Ahmed: None. M. Salim: None. H. Alameddine: None.
Introduction: Metastasis to pituitary is very rare occurrence, accounting for 1-4%. Most common primary cancer that metastasis to pituitary are Breast cancer in females and Lung cancer in males. Most of the pituitary metastasis are asymptomatic with symptomatic patient account for around 7 %. Most common symptoms reported are anterior pituitary dysfunction, visual field defects, headache, diabetes insipidus. Metastasis from Renal cell carcinoma (RCC) is very rare with only 25 cases reported so far. Metastases to the pituitary from RCC cause more severe hypopituitarism and visual dysfunction in comparison to those from other primaries. We present a rare case of hypopituitarism due to metastatic RCC presenting after Clinical Case: A 59-year-old male who initially presented in 2010 with complains of abdominal pain, underwent abdominal imaging and was found to have 7 cm solid mass in the right kidney. He underwent right nephrectomy in France and pathology confirmed RCC with no lymph node involvement. Patient didn’t have any adjuvant therapy. He had 5 years of follow up surveillance scans in Palestine which didn’t show any recurrence. In 2021 patient started to notice vision changes with loss of peripheral vision loss on right side but he didn’t seek any medical attention. In 9/2022 he noticed to have excessive fatigue, low libido, low appetite, excessive thirst and worsening of his vision. He had hormonal evaluation done in Palestine which showed low testosterone, cortisol, thyroid levels and was diagnosed with panhypopituitarism and was started on Hydrocortisone, Levothyroxine, Testosterone and Desmopressin. In 9/2022 had MRI brain in Palestine and showed 2cms suprasellar enhancing mass arising in the suprasellar cistern and appears inseparable from the pituitary stalk infundibulum. In 11/2022 he came to USA for further evaluation and management. In November 2022 patient complained of hallucinations, memory loss, personality changes and bitemporal vision loss. MRI brain showed sellar and suprasellar mass, 2.1 x 2.3 x 3.8 cm, extending to the suprasellar cistern and elevates the optic chiasm with possible third ventricle involvement and had increased in size compared to previous scan. On 11/29/22 patient underwent Endoscopic Endonasal Transplanum, Transtuberculum approach for tumor removal, biopsy of sellar and suprasellar tumor which returned as metastatic RCC. Patient was discussed in tumor board and is scheduled for gamma knife. Conclusion: Metastatic RCC to pituitary is very rare and most of them are asymptomatic leading to delay in diagnosis. Treatment of pituitary metastases is not standardized and should be tailored to patients’ clinical conditions, histology, and presence of extra-pituitary metastases. We need more prospective studies to formulate guidelines for management of pituitary metastases.
Presentation: Thursday, June 15, 2023
THU111 Diffuse Large B-Cell Lymphoma Pituitary Metastasis
Authors: Martinez Cruz Maria S , Haas Christopher J , Bhat Salman Zahoor 
Published: October 2023

Abstract
Disclosure: M.S. Martinez Cruz: None. C.J. Haas: None. S.Z. Bhat: None.
Background: The Hypothalamus-Pituitary axis (HPA) is a rare location for metastasis of non-Hodgkin’s lymphoma. Case description: A 57-year-old woman presented to the emergency department with a one day of acute, severe fatigue, nausea, and anorexia. She reported a history of stage IIIB diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) treated with R-CHOP three months prior, complicated by a recent recurrence in the lumbar spine requiring a short dexamethasone taper and radiation therapy two weeks prior to admission. On presentation, she remained hemodynamically stable with an otherwise unremarkable exam. Diagnostics revealed severe hypotonic hyponatremia suggestive of syndrome of inappropriate antidiuretic hormone (SIADH). CT scan of the head revealed thickening of the paramedian hypothalamic structures and the pituitary infundibulum. Subsequent pituitary MRI w/wo contrast demonstrated marked thickening and enhancement of the infundibulum with restricted diffusion, as well as T2/FLAIR hyperintensity and thickening in multiple hypothalamic areas concerning for HPA metastasis. Hormonal workup demonstrated panhypopituitarism for which she was started on hydrocortisone and levothyroxine. Lumbar puncture was performed with CSF flow cytometry revealing phenotypically abnormal monoclonal B-cells consistent with DLBCL leptomeningeal metastasis. Three days prior to induction chemotherapy, she developed massive polyuria, with a rapid increase in the serum sodium and markedly low urine-specific gravity consistent with acute diabetes insipidus (DI). Management included vasopressin, as needed, followed by standing doses of desmopressin. She was initiated on methotrexate and leucovorin chemotherapy. However, three week later, she developed acute onset diplopia, headache, nausea and vomiting, urinary and bowel incontinence, and fatigue. Follow-up pituitary MRI revealed progression of her known HPA metastatic disease, and she passed away one month later. Conclusion: This is an unprecedented case of metastatic DLBCL to the leptomeninges, hypothalamus, and pituitary infundibulum confirmed by CSF cytologic analysis that presented in the context of associated panhypopituitarism that manifested initially as SIADH followed by sudden DI. Abbreviations: R-CHOP: Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone
Presentation: Thursday, June 15, 2023