bluuebunny/crossref_metadata_2025 huggingface dataset:
Somatostatin, as a Bridge Between the GH-Axis and the Gth-Axis
Authors: Mizrahi Naama , Hollander-Cohen Lian , Levavi-Sivan Berta
Published: May 2021

Somatostatin (SST) is a 14-amino acid peptide produced in the hypothalamus of vertebrates, including fish. It regulates many physiological processes such as growth development and metabolic processes in the animal’s body. Negative control of growth hormone in vivo and in vitro was characterized in several fish species such as salmon, goldfish, rainbow trout and tilapia. Although very important, the SST/SST-R system in Nile tilapia (Oreochromis niloticus) was not deeply characterized. The somatostatin system in tilapia possess two ligands (Somatostatin1b and Somatostatin 2), and five receptors (SST-R 1-5). Unlike mammals, in fish, FSH and LH are secreted from different cell populations in the pituitary. By performing cell specific transcriptome analysis of double-labelled transgenic tilapia expressing GFP and RFP in LH or FSH cells, respectively, we identified genes specifically enriched in each cell type. Analysis of the RNA-seq discovered 4 types of SST-Rs: sstr2, sstr3, sstr5 and sstr5x3. The specific localization of each SST-R was identified by In Situ hybridization with specific probes for each of the SST-Rs. SST-R2 and SST-R5x3 were expressed on LH and FSH cells, while SST-R5 was exclusively expressed on LH cells. Interestingly, SST-R3, which was expressed on GH secreting cells, was also expressed on both gonadotropin-secreting cells. Transactivation assays, using COS7 cell line transfected with tilapia SST-Rs together with the reporter plasmid CRE-luc, demonstrated an effect through the cAMP/PKA pathway. Signal transduction analysis demonstrated that SST agonist (Octreotide; IC50 = 0.8-60nM) decreased the cAMP/PKA pathway, while an opposite effect was found when SST antagonist (Cyclosomatostatin; EC50 = 0.1 - 188 nM) was used. To understand the physiological effects of somatostatin on gonadotropins and GH release, we examined the effect of ip injection (100 μg/kg BW) of somatostatin agonist and antagonist on plasma FSH, LH and GH levels. SST agonist decreased plasma GH and FSH levels, as fast as two hours post injection and their levels remained low until the end of the experiment. On the other hand, SST antagonist increased LH and FSH levels two hours post injection, but while FSH levels remained high during the entire experiment, LH levels went back to basal levels afterwards. Our results show - for the first time in fish - a direct effect of SST on gonadotropin release, that could serve as a bridge between the GH-axis and the GTH-axis. The research was funded by the Israel Science Foundation (ISF) no. 1540/17.
Sirtuin 1 Regulates Synapsin 1 in POMC-Producing N43-5 Neurons via FOXO1
Authors: Teaney Nicole A , Cyr Nicole E
Published: May 2021

The nutrient-sensor protein Sirtuin 1 (Sirt1; silent mating type information regulation 2 homolog 1) has been shown to have significant and opposing effects on insulin resistance, leptin resistance, and body weight in the periphery and the brain. In the hypothalamic arcuate nucleus (ARC) of the brain, Sirt1 increases in the obese state and acts to promote weight gain as well as insulin and leptin resistance by increasing the orexigenic neuropeptides Agouti-related protein (AgRP) and neuropeptide Y (NPY), and in a distinct set of ARC neurons, by decreasing POMC and thus its anorexigenic derivative alpha-melanocyte stimulating hormone (alpha-MSH) (1). Sirt1’s actions on these neuropeptides are mediated at least in part by the deacetylation of the transcription factor forkhead box O1 (FOXO1). Another mechanism by which Sirt1 regulates body weight appears to be through mediating changes in the synapses of these neuropeptide-producing ARC neurons. For example, a previous study demonstrated that Sirt1 inhibition with the specific Sirt1 inhibitor, Ex-527, decreased AgRP-NPY inhibitory synaptic input on POMC neurons, which suggests that the obesity-induced increase in ARC Sirt1 would increase AgRP-NPY inhibition of POMC neurons thus promoting weight gain (2). The present study investigated how Sirt1 regulates synapses specifically in POMC-producing N43-5 neurons. Results reveal that inhibition of Sirt1 with Ex-527 significantly increased the presynaptic marker Synapsin 1 (Syn1) in N43-5 neurons. Furthermore, we investigated whether the Sirt1 target, FOXO1, mediates these synaptic changes. FOXO1 overexpression significantly decreased Syn1 and transfection of mutant FOXO1 significantly increased Syn1. Overall, our results suggest that Sirt1 regulates synapses of POMC neurons and does so in a manner that differs from Sirt1’s regulation of AgRP-NPY neuronal synapses. Future work will elucidate the mechanisms and consequences of Sirt1 and FOXO1 regulation of POMC neuron synapses under different nutritional conditions in vitro and in vivo.

(1) Cyr, N. E., Steger, J. S., Toorie, A. M., Yang, J. Z., Stuart, R., Nillni, E. A. (2014). Central Sirt1 Regulates Body Weight and Energy Expenditure Along With the POMC-Derived Peptide α-MSH and the Processing Enzyme CPE Production in Diet-Induced Obese Male Rats, Endocrinology, 155(7), 2423–2435.

(2) Dietrich, M. O., Antunes, C., Geliang, G., Liu, Z., Borok, E., Nie, Y., . . . Horvath, T. L. (2010). Agrp neurons mediate Sirt1’s action on the melanocortin system and energy balance: Roles for Sirt1 in neuronal firing and synaptic plasticity. The Journal of Neuroscience, 30(35), 11815–11825.
A Case of Pituitary Germinoma With Complete Recovery of Visual Field
Authors: Alameri Majid , Boharoon Hessa , Alnuaimi Abdulla Mohamed , Wernig Florian , Seckl Michael , Gonzales Michael
Published: May 2021

Central nervous system germ cell tumours (GCTs) are rare, accounting for 0.1-3.4% of all primary brain malignancies. Intracranial GCTs (ICGCTs) usually arise within the pineal recess (50-65%), sellar-suprasellar region (25-35%) and rarely in the basal ganglia-thalamus (5-10%). A peakonset occurs during the second decade of life with a median age at diagnosis between10-12 years and a male predominance. Histologically, ICGCTs are classified into germinomas accounting for two thirds of cases and non-germinomatous GCTs. ICGCTs present with clinical features dependent on their location and tumour size. Symptoms most often arise from compressed optic structures, increased intracranial pressure and central endocrine abnormalities, particularly diabetes insipidus (DI). Clinical findings combined with elevated tumour marker levels within the serum and/or cerebrospinal fluid (CSF) can be diagnostic.

Case: A 30-year-old lady who survived a childhood leukaemia presented as an emergency with a two-month history of headaches, dizziness and near-complete visual loss. Cranial MRI identified a large sellar mass with suprasellar extension compressing the optic chiasma and hypothalamus. Biochemical and endocrine profiles confirmed diabetes insipidus, hypocortisolaemia and hypothyroidism all requiring hormone replacement. Visual field examination revealed total left visual loss and a right temporal hemianopia. Cerebrospinal fluid analysis identified an elevated human chorionic gonadotropin (HCG) level at 16 IU/L (normal <2), with a normal alpha-fetoprotein (AFP) level. Both tumour markers were normal in the serum. Emergency Etoposide-Cisplatin (Em-EP) chemotherapy was initiated for a suprasellar GCT followed by the EPOMB-ITMTX regimen [Etoposide-Cisplatinwith intrathecal Methotrexate (ITMTX) alternating with Vincristine-Methotrexate-Bleomycin]. After four cycles EPOMB-ITMTX, the vision was fully restored, brain MRI demonstrated an excellent radiological response and the CSF HCG normalised. Our patient received volumetric-modulated arc cranial radiotherapy (VMAT) with a total 54 Gy in 16 fractions. She remains well without disease recurrence for 14 months. Tumour markers are normal with stable MRI brain and whole-spine. Endocrine follow-up confirms recovery in all pituitary axes except the gonadotrophins for which she remains on hormone replacement therapy. Conclusion: This case demonstrates an excellent outcome for a young adult diagnosed with a suprasellar GCT treated with chemotherapy followed by stereotactic radiotherapy. It highlights the importance in keeping a high clinical index of suspicion in young adults presenting with a midline intracranial tumour, visual dysfunction and an endocrinopathy. CSF analysis identified an elevated tumour marker level, which bypasses the need for a histological diagnosis.
Skeletal Muscle Stromal Cells Derived From MuRF1 Knockout Mice Are Resistant to Adipogenesis
Authors: Norman Jennifer Elise , Marshall Andrea Gail , Rutledge John C , Bodine Sue C
Published: May 2021

Background: Intramuscular adipose tissue has been found to contribute to muscle dysfunction and is associated with a sedentary lifestyle, aging, and glucocorticoid treatment. Muscle ring finger 1 knockout (MuRF1 KO) mice have been shown to be protected from muscle loss following disuse, aging, and glucocorticoid treatment. In this study we used in vitro techniques to determine if MuRF1 KO muscle stromal cells are resistant to adipogenesis. Methods: Stromal cells were isolated from skeletal muscle tissue of MuRF1 KO and wild type mice. These cells were expanded in culture until 70–90% confluent, then differentiated in either a myogenic media formulation (myogenic cultures) or an adipogenic media formulation (adipogenic cultures). Gene expression was analyzed by qRT-PCR, protein content was measured by bicinchoninic acid assay, and triglyceride content was analyzed by colorimetric assay. We also analyzed isolated stromal cells, which had not been expanded in culture, by flow cytometry to identify myogenic satellite cells (SCs) and fibro-adipogenic progenitors (FAPs). Results: Wild type adipogenic cultures had higher expression of Trim63, the gene encoding MuRF1, when compared to wild type myogenic cultures. Adipogenic cultures had higher expression of adipogenic programing and lipid handling genes than myogenic cultures. These adipogenic cultures also had higher triglyceride content than myogenic cultures. The expression of adipogenic programing genes and lipid handling genes were lower in cultures derived from MuRF1 KO mice compared to wild type derived cultures; however, there was no statistically significant difference in the triglyceride content between the two genotypes. Analysis of stromal cell populations by flow cytometry indicated no difference in the FAP:SC ratio between wild type and MuRF1 KO mice. Conclusions: These results indicate that although there are no differences in the ratio of FAPs to SCs in wild type and MuRF1 KO mice, the MuRF1 KO cultures appear to be resistant to adipogenesis. The mechanism behind this resistance to adipogenesis remains to be elucidated.
A Rare Case of Nephrogenic Diabetes Insipidus From Tenofovir
Authors: Vasim Izzah , Amoakohene Peggy Nana Ama , McMillan Janice , Hong Gregory
Published: May 2021

Introduction: Diabetes insipidus (DI) is a clinical condition which manifests as excessive urine output, either because of impaired or inadequate antidiuretic hormone (ADH) secretion, or an inability of the kidneys to respond to ADH. Nephrogenic DI is more often drug induced. Recent clinical reports have shown that medications like tenofovir may result in nephrogenic DI as well. Tenofovir is a well-known nucleoside reverse transcriptase inhibitor analog of adenosine used in the management of both human immunodeficiency virus (HIV) and chronic hepatitis B. With its increased use, reports of adverse outcomes have been documented, mainly its effect on renal function including nephrogenic DI, renal failure and Fanconi syndrome. We present a case of nephrogenic DI whilst on Biktarvy (a combination of bictegravir, emtricitabine and tenofovir alafenamide). Case: A 59-year-old African American female with a history of HIV on Biktarvy, T2DM, HLD, HTN, MI, CAD, COPD presented to our hospital with weakness and falls for 1-2 months associated with polydipsia and polyuria. She had started Biktarvy for HIV about 2 months ago after which her symptoms got worse. Labs showed a serum Na of 151, potassium of 3.2 on admission with serum osmolality of 323 and urine osmolality of 134. During hospitalization, she was challenged with 100ug oral Desmopressin. Urine labs failed to correct after Desmopressin administration which was highly indicative of severe nephrogenic DI. The challenge was repeated with 200ug oral Desmopressin with similar results. Pituitary DI was considered given the patient’s falls; however urine osmolality did not improve following desmopressin challenge. Furthermore, her serum Co-peptin level was elevated at 36.1 that ruled out central DI. The patient’s hypokalemia was believed to be driving her nephrogenic DI which has been reported in various case reports with patients on Tenofovir, but has never been reported in patients taking Biktarvy (which includes Tenofovir Alafenamide). She was subsequently placed on fluid restriction during which time the patient’s serum Na and Cr increased while urine osmolality did not correct. HCTZ was ultimately started as a treatment for nephrogenic DI and patient was transitioned of biktarvy to lamivudine and dolutegravir. Her polyuria and polydipsia improved, however she developed hyponatremia likely because of HCTZ. Patient concentrating ability improved off biktarvy and HCTZ was discontinued on the day prior to discharge without issue. Her subsequent serum sodium and potassium levels were normal. Conclusions: Our case highlights a rare incidence of tenofovir induced hypokalemia leading to nephrogenic DI. This case illustrates the importance of monitoring patients on tenofovir for signs of renal [tubular] dysfunction. In a polyuric patient on tenofovir, there should be a high index of suspicion for nephrogenic diabetes insipidus.
A Rare Case of Recurrent Lymphocytic Hypophysitis Spanning 8 Years
Authors: Prahdan Aprajita , Mishra Sunil Kumar , Kuchay M Shafi , Singh Varindera Paul , Kumar Modi Jayesh Ashok
Published: May 2021

Background: Lymphocytic Hypophysitis (LH) is predominantly a self-limiting condition. Reports of recurrent LH have been limited to case series, predominantly within first two years of initial presentation (1). There is paucity of data on long term follow up of these cases and late recurrence of LH is considered very rare (2). Clinical Case: We describe the clinical course of a 47-year female, who first presented to us, 8 years back, with headache, visual disturbance and secondary amenorrhea. Her MRI pituitary was suggestive of a pituitary mass, which was removed by trans-sphenoidal surgery. Histopathology of the mass was suggestive of LH. Patient had symptomatic improvement, and remained well on out-patient follow-up, on hormone replacement therapy. She took replacement dose of glucocorticoid for 4 years after the initial surgery and then it was discontinued. However, she re-presented to us with headache and visual disturbance this time associated with xerostomia and xerophthalmia. In this presentation, due to presence of sicca symptoms a suspicion of autoimmune aetiology was kept. Her lab parameters were consistent with pan hypopituitarism along with new appearance of anti-TPO antibodies. She underwent two consecutive trans-sphenoidal surgeries for relief of pressure symptoms, and has been started immunosuppressive doses of glucocorticoids along with methotrexate. Other causes of recurrent hyophysitis, as IgG4 related Hypophysitis, were excluded by immunohistochemistry and normal serum IgG4 level (0.72g/l). She has since been discharged, and remains well on outpatient follow-up with no mass effect. MRI pituitary done at 2 months follow up is not suggestive of residual regrowth or mass effect. Conclusion: This case highlights the importance of long term follow up of LH patients. Other autoimmune aetiology maybe considered in cases unresponsive to standard treatment, necessitating titration of additional immunosuppressive therapy. References: 1.M.N. Joshi et al, Hypophysitis: diagnosis and treatment, European Journal of Endocrinology 2018, 179, R151-R1632.Honegger et al, Treatment of Primary Hypophysitis in Germany: Journal Clinical Endocrinology and Metabolism, September 2015, 100(9):3460 –3469
A Rare Case of Sellar Mass Composed of Primary Leiomyosarcoma and Pituitary Adenoma
Authors: Kim Young Ki , Goak In Sun , Kim Yu Ji , Jin Heung Yong , Park Tae Sun , Lee Kyung Ae
Published: May 2021

Background: Nonfunctioning pituitary adenomas (NFPAs) are most common pituitary tumors, and primary pituitary gland malignancies are extremely rare. Most malignant pituitary gland lesions metastasize from other sites. Primary malignant lesions, such as sarcomas, usually develop after radiotherapy or chemotherapy for other diseases. We report a rare case of primary sellar leiomyosarcoma (LMS) without prior therapy that arose concurrently with a pituitary adenoma. Clinical Case: A 56-year-old woman with ptosis of the right eye, headache, and progressive visual deficits visited our neurosurgery department. She had no medical history besides hypertension. Twelve months ago, she was referred to us because of decreased visual acuity and a 3.5×3.6-cm-sized pituitary mass detected on brain MRI. Normal pituitary functions with mild hyperprolactinemia suggested a nonfunctioning pituitary mass with stalk compression. After transsphenoidal surgery, histopathology revealed a pituitary adenoma; MRI immediately post-surgery revealed no grossly remnant lesion. However, during the current visit, sellar MRI revealed a re-growing mass in the pituitary fossa extending to the sphenoid sinus and compressing the optic chiasm with a suprasellar extension. Functional endoscopic sinus surgery was performed, and histopathology revealed a composite tumor, i.e., a mesenchymal tumor with a pituitary adenoma. On immunohistochemical staining, smooth muscle actin, synaptophysin, and chromagranin were positive; tumor cell mitosis was observed at 7/10 high-power fields. Finally, a composite tumor of myxoid leiomyosarcoma and pituitary adenoma was diagnosed. Hence, systemic chemotherapy with radiotherapy was planned for the remnant lesion. Hormonal replacement therapy with hydrocortisone and thyroxine was also started for subsequent hypopituitarism. Conclusion: NFPA is benign and has good prognosis if it is not grow in size or is completely resected. Conversely, primary sarcomas, such as LMS, show rapid extension and aggressive local invasion. Although their incidence is extremely rare, few primary pituitary sarcoma cases with or without pituitary adenoma have been reported. In the former case, initial diagnosis of pituitary adenoma may lead to delayed diagnosis of combined malignant lesions. Thus, clinicians should consider this possibility and high index of suspicion is required when diagnosing a pituitary mass.
A Rare Case of Sellar Metastastic Renal Cell Carcinoma Mimicking Pituitary Adenoma - a Case Report
Authors: Tambovtseva Anastasia , Gandhi Rima , Abdelmasih Randa , Monsour Elio Paul , Hamza Alan
Published: May 2021

Introduction: Metastatic sellar masses are very contributing to 2% of all sellar masses, and up to 0.87% of all metastases to the brain. Breast and lung cancer contribute for up to 60% of all sellar metastases but it is important to recognize other cancers that can also metastasize to pituitary gland. Renal Cell carcinoma (RCC) is number nine on that list. Here we present a case of rare RCC metastasis to pituitary which was mistaken as pituitary adenoma to emphasize early recognition and management of pituitary metastases which may result in better patient’s outcomes and prognosis. Case Presentation: 7 2 year-old male with a remote history of left sided RCC presented with worsening diplopia, blurry vision and headaches for 2 months. Physical exam was remarkable for right sided ptosis with right oculomotor, trochlear and abducens palsy. Computed Tomography Imaging (CT) of the brain showed hyperdense sellar/suprasellar fullness. Magnetic Resonance Imaging (MRI) with and without contrast of the brain showed 2.2 x 1.7 cm enhancing mass in the right cerebellopontine angle with local mass effect concerning for a pituitary tumor. Laboratory work-up was remarkable for hyperprolactinemia 36.5 ng/mL, low TSH <0.015 mU/L, and normal ACTH, FSH and LH levels. Patient underwent endoscopic trans-nasal resection of pituitary tumor. Surgical pathology of the tumor was consistent with metastatic renal cell carcinoma. He was discharged with appropriate multidisciplinary outpatient follow up with endocrinology, oncology and radiology. Discussion: Pituitary metastasis is very rare and often mistaken for pituitary adenoma. Only 7% of Pitutary metastases are symptomatic. Symptom presentation depends on the location of metastases. They include diabetes insipidus (45.2%), visual field defects (27.9%), hypopituitarism (23.6%), ophthalmoplegia (21%), headache (15.8%) and hyperprolactinemia (6.3%). Although, there is no gold standard imaging for sellar masses, both thin-section CT and MRI are beneficial. CT is used for visualizing bony destruction and calcification, on the other hand MRI demarcates lesions in that area. Due to its rarity, there is no standardized guideline therapy for pituitary metastasis and it should be individualized based on patient’s presentation, but it should be multidisciplinary approach of surgical resection, postoperative stereotactic radiosurgery, chemotherapy, and hormone replacement therapy. Prognosis of metastases to pituitary is very poor, with reported six to twenty-two months post resection survival. Factors contributing to prolonged survival are younger age, single/small metastases, and locally guided radiation therapy. Conclusion: This case is to shed light on early recognition of sellar metastasis as a challenging diagnosis especially in patients with rapidly growing pituitary mass and neurological symptoms with history of malignancy for better outcomes.
Analysis of Treatment Outcomes of Patients With Cystic Prolactinomas: Report of Four Cases
Authors: Erdi Zuleyha Can , Ozkan Cigdem
Published: May 2021

Background: Prolactinomas are the most common functional pituitary adenomas. Treatment with dopamine agonists is considered as first-line therapy. Cystic prolactinoma is a variant prolactinoma. . It was assumed that since cystic area does not contain dopamine receptors, cystic prolactinomas would not respond to medical treatment. However, in recent years, it has been shown that cystic prolactinomas can also be treated with dopamine agonists, and medical treatment has become more preferred than surgical treatment. In this report, we aimed to evaluate the treatment effectiveness of patients with cystic prolactinomas who treated medically in our clinic. Materials and methods: Twenty-nine prolactinoma patients who were followed up in our hospital between 2019-2020 were evaluated retrospectively. Four patients (13%) were being followed up for cystic prolactinoma. Radiological images, laboratory findings, patients records were reviewed. Results: Four patients were being followed up for cystic prolactinoma and all were women. The average age of the patients followed up for cystic prolactinoma was 36 years. 3 patients (75%) had menstrual irregularity, 2 (50%) patients had galactorrhea, and 1 patient (25%) had headache at the time of admission. Tumor size regressed with medical treatment in two patients and the tumor disappeared completely in one patient. Although the symptomatic improvement and normalization of prolactin was achieved in one of our patients, the lesion did not shrink. We continued with medical treatment in this patient since there was no indication for surgery. Discussion: There was conflicting results in the literature regarding the management of cystic prolactinomas. Recently, dopamin agonist therapy is suggested as first- line treatment option in cystic prolactinomas. A study reported male predominance for cyst formation but we observed female predominance in our report. Faje et al. also reported female predominance in their study. Presentation of our patients were not different from solid prolactinomas. And although we evaluated very limited number of patients in our report, all of our patients respond to medical treatment which was consistent with recent literature.
Anterior Pituitary Failure in Patients with Granulomatous Inflammation
Authors: Narula Kavita , Esdaile Harriet , Martineau Marcus , Alegre Javier
Published: May 2021

Introduction: Langerhan cell histiocytosis (LCH) is a rare cause of eosinophilic granulomatous inflammation that can affect multiple organ systems, mainly diagnosed in children. Hypothalamic-pituitary axis involvement is well established and is the characteristic intracranial manifestation of LCH. Patients can present with several presentations including anterior pituitary axis failure; however, the most common presentation is Diabetes Insipidus (DI). Here, we present a rare case of isolated pituitary LHC in male adult. Clinical Case: 47 years old gentleman presented with 4 week history of insidious headaches associated with persistent nausea. He also noticed drooping of his left eyelid and presented to hospital with complete ptosis. His CT head did not show any abnormalities. However finding on his MRI brain were consistent with a central skull base inflammatory process centred on the pituitary, extending cranially to the chiasm and third ventricular floor as well as laterally to the cavernous sinuses. His anterior pituitary profile was as follow: LH - 0.7 U/L (1.2-8.6 U/L), FSH - 4.2 U/L (1.3-19.3 U/L), Testosterone - <0.3 nmol/L (6.1 - 27.1 nmol/L), IGF-1 - 9.8 (8.8-31), Prolactin - 197 mIU/L (56-278 mIU/L), TSH - 1.18 mU/L (0.38 - 5.33 mU/L), FT4 - 4.4 pmol/L (8.4 - 19.1 pmol/L). He underwent a Short Synacthen test with a baseline cortisol of 19 nmol/L, rising to 100 nmol/L at 30 minutes and 130 nmol/l at 60 minutes. Following initiation of high dose steroid replacement (Prednisolone 15 mg daily), Levothyroxine and Testosterone, his Prednisolone was slowly weaned to 4 mg once a day in line with an improvement in his ptosis & left temporal hemianopia. His pituitary biopsy showed infiltrates of abundant histiocytes and inflammatory cells (lymphocytes). Histiocytes were organised in a granulomatous fashion with multinucleated giant cells and eosinophils (CD 68 staining positive). Langerin stain (positive) / S100 stain (some) / CD1a (few) - cells positive, confirming a diagnosis of LCH. Additional CT (chest/abdomen/pelvis) and PET imaging confirmed no additional organ involvement. Conclusion: LCH is a rare cause of anterior pituitary failure. Limited information regarding treatment for isolated pituitary LCH is available. This case suggests that a conservative approach to successful treatment with steroids can be considered.
Spexin Friend or Foe? Novel Role of Spexin During Thermogenesis of White Adipose Tissue
Authors: Gambaro Sabrina E , Zubiria Guillermina Maria , Giordano Alejandra P , Harnichar Ezequiel A , Portales Andrea E , Giovambattista Andrés
Published: May 2021

Spexin (SPX) is a novel adipokine playing an emerging role in metabolic diseases due to its involvement in carbohydrate homeostasis, weight loss, appetite control, gastrointestinal movement, among others. Moreover, plasma levels are reduced in obese and type II diabetic patients. In vitro, SPX favors lipolysis in adipocytes and hepatocytes and inhibits white adipogenesis. Therefore, the aim of this study was to evaluate the role of SPX in white adipose tissue (AT) thermogenesis. C57BL/6J male mice were treated or not with SPX for ten days (ip. 29 µg/kg/day; CTR and SPX). At day 3 mice were randomly divided: a group was kept at room temperature (RT) and the other at 4°C to stimulate thermogenesis (CTR-C and SPX-C). Caloric intake and body weight was daily recorded. At the end of the protocol plasma, Brown AT (BAT), abdominal AT (Epidydimal, EAT) and subcutaneous AT (Inguinal, IAT) depots were collected for several measurements. We found that caloric intake was increased when animals were exposed to cold (P<0.001). Body weight change revealed a differential effect of SPX depending on temperature (interaction SPX x Cold, P<0.05): SPX animals weighted less than CTR at RT, but upon cold stimulation there was no difference. No changes were observed for plasma glucose levels, however plasma triglycerides (Tg) levels decreased after cold exposure regardless SPX treatment (Cold P<0.01). Liver Tg content showed a SPX x Cold interaction effect (P<0.0001), where, upon cold stimulation, CTR-C animals increased their levels, but on the contrary SPX-C mice decreased it. EAT, IAT and BAT relative mass showed an interaction effect of variables (SPX x Cold P<0.05). When compared upon cold, SPX-C mice had less AT mass compared to CTR-C mice. IAT and EAT mRNA expression of UCP1 and Cox8b showed SPX x Cold interaction (P<0.05), with a tendency of reduction or no difference in SPX at RT, but with a significant decrease in SPX-C compared to CTR-C mice upon cold exposure. PGC1a expression was increased in EAT from cold exposed-mice and in IAT only in CTR-C mice. UCP1 protein levels showed different results depending on the AT depot. For IAT SPX x Cold interaction (P<0.05) was observed, where SPX inhibited UCP1 stimulation only upon cold exposure. On the contrary, for EAT UCP1 levels decreased in SPX-treated mice, regardless cold exposure (SPX P<0.05). In conclusion, SPX treatment in vivo reduced the thermogenic process in subcutaneous and abdominal AT, being more evident upon cold stimulation. PICT2017-2038, PICT2017-2314.
Are High Doses of Corticosteroids Protective in COVID-19 Patient With Panhypopituitarism?
Authors: Kurir Tina Ticinovic , Mizdrak Maja , Krnić Mladen
Published: May 2021

Introduction: Clinical course of COVID-19 infection is diverse and the best therapeutical guidelines are still lacking. Case Presentation: We present a case of 73 year old male COVID-19 positive patient. In 2017 transnasal hypophysectomy was performed due to prolactinoma. He receives therapy (hydrocortisone 20 + 10 mg/day, levothyroxine 75/50 µg/day, bromocriptine 2.5 mg twice/day). He suffers also from arterial hypertension. Present illness started with intensive dry cough, fever (37.5◦C), diarrhoea and loss of smell. On the first day patient was febrile up to 38.4◦C and later afebrile. Laboratory parameters showed abnormalities in several parameters: D-dimers 13.45 (RR:< 0.50) mg/L, creatinine 110 (49-90) µmol/L, ALT 73 (12-28) U/L, LDH 531 (25-241) U/L, creatine kinase 549 (<177) U/L, GGT 277 (9-35) U/L, CRP 38 (<5 mg/L), sedimentation rate 40 (5-28) mm/3.6ks, procalcitonine 0.07 (<0.05) ng/ml, sodium 128 (137-146) mmol/L, hs-TroponinT 18 (< 14) ng/L, neutrophils 8.56 (2.06-6.49 x109/L), lymphocytes 0.52 (1.19-3.35 x109/L) and pO2 6.1 (11.0-14.4) kPa. At the admission X-ray showed normal presentation, while four days later on the right side pneumonia was noticed as spotty inhomogeneous shading. He was treated with azithromycin, hydrocortisone (50 mg twice/day) and oxygen supplementation. At the beginning of hospitalization he was addicted to O2 10-12 L/min. After 22 days of hospitalization he was discharged without any symptom but with still positive SARS-CoV2 swabs. After a 30 days of follow-up, his swabs are now negative with no laboratory abnormalities. In the meantime, his two brothers, born in 1945 and 1940 died due to COVID-19 infection. They did not receive substitutional corticosteroid therapy. Conclusion: The main pathophysiological mechanism of infection is explained by cytokine storm. Hypercytokinemia causes myelosuppression and vascular endothelium damage. Corticosteroids are potent anti-inflammatory agents. High-doses of corticosteroids might beneficially modulate the host immune response to SARS-CoV2 virus and have protective role in this patient.
Central Diabetes Insipidus Due to Acute Myeloid Leukemia
Authors: Boston Dakota J , Levine Steven N , Yatavelli Rajini Kanth Reddy
Published: May 2021

Central diabetes insipidus (CDI) is a condition characterized by decreased secretion of antidiuretic hormone (ADH) and is commonly seen with pathology involving the hypothalamic/pituitary area. Common etiologies include congenital disorders, neurosurgery or trauma, infiltrative disorders, primary or secondary cancers, and idiopathic causes. CDI associated with acute myeloid leukemia (AML) is extremely rare, with about 100 published case reports, and typically occurs in patients with chromosome 3 or 7 abnormalities.

A 49-year-old woman was admitted to the inpatient oncology service for chemotherapy with gemtuzumab with a goal of inducing remission of her AML prior to allogeneic hematopoietic cell transplantation. She had been diagnosed with AML 7 months prior to this admission and was considered high risk for poor clinical outcome due to cytogenetics demonstrating deletion of chromosome 7 and inversion of chromosome 3. She was noted to have increasing serum sodium and endocrine was consulted for evaluation of hypernatremia.

Patient had a peak sodium of 154 meq/L which improved with free water replacement. She reported excessive thirst with associated polyuria and nocturia. Laboratory tests demonstrated inappropriately dilute urine for the degree of serum osmolality, consistent with a low ADH tone. A water deprivation test was performed which resulted in plasma and urine osmolalities of 311 mosm/kg and 103 mosm/kg, respectively. After the administration of desmopressin the Uosm increased to 345 mosm/kg at 2 hours and 484 mosm/kg at 5 hours, confirming a diagnosis of Central DI.

Evaluation of other pituitary axes showed normal TSH and FT4 with a normal cortisol response on a cosyntropin stimulation test. She had low-normal LH and FSH plus a mildly elevated prolactin level (38.7 ng/mL) which were attributed to stress. An MRI of the brain done to rule out any hypothalamic/pituitary metastasis or hypophysitis was normal.

AML associated with Central DI occurs rarely, is associated with a poor prognosis, and the pathogenesis is unclear. The most commonly reported cytogenetic aberrations in patients with AML and CDI are monosomy 7 and 3q alterations. Our patient had monosomy 7 and chromosome 3 inversion. Proposed pathogenic mechanisms include leukemic infiltration of the pituitary, overexpression of ectopic virus integration (EVI-1) site interfering with hypothalamic neuroendocrine secretion, and abnormal thrombopoiesis interfering with ADH levels in blood.

This case illustrates a lesser-known cause for central diabetes insipidus. While other more common etiologies of CDI should still be considered first, recognition of this association can provide clarity to the origin of DI in select patients.
Change in Character of Headache in a Young Female Patient With Prolactin Secreting Pituitary Adenoma Complicated With Mild Hemorrhage
Authors: Soe Yuzana Myint , Ghani Marium , Siroya Pushplata
Published: May 2021

Background: Prolactin (PRL) secreting tumors are the most common functional neoplasms of the pituitary and are commonly subdivided into microprolactinomas (<10 mm) and macroprolactinomas (≥10 mm) according to their baseline diameter. The diagnosis of macroadenomas is usually straightforward and these large tumors may be associated with mass effects such as severe headache, nerve palsies or visual changes. Hyperprolactinemia can be due to other causes like pregnancy, drugs, hypothyroidism, and pituitary stalk effect should be considered in the differential.

Clinical Case: A 30 year female having symptoms of prolactinoma showing amenorrhea of 3 years, galactorrhea, decrease libido who presented to the clinic for headache recently associated with anxiety. Headache initially frequently with 2-3 times in a week, moderate intensity lasting few hours, on one side of head and sometimes on the forehead, associated with blurry vision. Patient was on oral contraception taking on and off, but not on any medication currently. Initial work up consistent with hyperprolactinemia: elevated prolactin level 737.6 ng/ml (n 3.0-30 ng/ml), however other pituitary hormones are within normal limit, ACTH 32 pg/ml (n 6-50 pg/ml),FSH 3.2 mid/ml, LH 0.3miu/ml, total testosterone 13 ng/dl (n 2-35 ng/dl),TSH 1.6 mid/l (N 0.35-3.7 mid/l), FT4 0.92 ng/dl (N 0.76-1.46 ng/dl), human growth hormone <0.1ng/ml (N <=7.1 ng/dl), random cortisol 14.6 ug/dl (N 4.3-22.4 ug/dl). Pregnancy test is also negative. MRI Brain with and without contrast revealed a mass within the pituitary fossa producing smooth depression of the floor and suprasellar extension just the right of midline producing mild impingement on the undersurface of the optic chiasm, craniocaudal dimension of the tumor approximately 1.85 cm by 1.8 cm mediolateral by 1.4 cm anteroposterior without encasement or diminution of carotid arteries flow. Within the sella there is a spherical collection of T1 high signal displaying a fluid level strongly concerning for hemorrhage within the pre-existing tumor. There is no prior CT Head or MRI Brain available. Ophthalmology evaluation showed normal dilated retinal exam and no visual field defects. Medical treatment with Cabergoline 0.25 mg PO twice weekly was given on the visit, however patient did not start it yet and repeat prolactin level with 629 ng/ml. Patient endorsed that headache is better with less frequent about once in two weeks but still with absence of menstruation.

Conclusion: This is the case of prolactin secreting pituitary macroadenoma with the change in character of headache due to hemorrhage in the tumor, having gradual improvement of headache which may be due to spontaneous resolving of hemorrhage from the pre-existing pituitary mass. It is very important to inform the patient with pituitary tumor go to ED if there is change in headache or vision.​
Deep Venous Thrombosis in a Patient With Cushing’s Syndrome
Authors: Rana Sanah , Brutsaert Erika
Published: May 2021

Introduction: Cushing’s syndrome (CS) is associated with a prothrombotic state due to increased activation of several clotting factors. As such, patients are more susceptible to development of post-operative venous thrombosis. We present the case of a patient who underwent pituitary surgery for CS and subsequently developed acute lower extremity deep venous thrombosis (DVT) after stopping anticoagulation upon discharge. Case Report: A 57-year-old female presented with abdominal pain 1 month after gastric bypass surgery. She was found to have intra-abdominal abscesses and started on IV antibiotics. Upon further questioning, she endorsed 2-week history of coarse hair over chin, difficulty climbing stairs, and easy bruising. She had type 2 diabetes and hypertension, both diagnosed 2 years prior. Blood pressure was 169/88 on admission. On exam she had coarse hair on chin, central obesity, scattered ecchymoses, proximal muscle weakness, and no abdominal striae. Labs revealed potassium level of 1.9 mmol/L despite supplementation with 60 meq/day of potassium chloride. Workup showed random cortisol 45 mcg/dl, ACTH 114 pg/ml, elevated urinary free cortisol to 898.6 ug/24 hours, unsuppressed cortisol to 30.6 mcg/dL with low-dose dexamethasone and partial cortisol suppression to 11 mcg/dl with high-dose dexamethasone. MRI brain showed pituitary adenoma measuring 6 x 9 x 2 mm. CRH stimulation test showed rise of ACTH to 302 pg/ml and cortisol to 81.5 mcg/dl consistent with ACTH-dependent hypercortisolism from pituitary tumor. While hospitalized, the patient received thromboprophylaxis with SQ enoxaparin 40 mg daily. Patient was started on ketoconazole and subsequently underwent transsphenoidal resection to remove the pituitary tumor, which effectively reduced her serum cortisol levels. She was started on hydrocortisone replacement. She was discharged to a skilled nursing facility 2 weeks later. However, she did not receive thromboprophylaxis at the facility and was diagnosed with acute lower extremity DVT soon after hospital discharge. Discussion: CS is associated with increased risk of thromboembolic events. Although our patient received DVT prophylaxis in the hospital until discharge 2 weeks after surgery, she developed DVT soon after discharge. This emphasizes the increased susceptibility to development of venous thrombosis even after normalization of cortisol levels following pituitary surgery. A recent retrospective study showed that patients with CS are at higher risk of thromboembolism for approximately 30 to 60 days during the postoperative period. This case highlights that the clotting risk remains elevated in patients with CS for an extended period after successful surgery. In conclusion, patients with CS are at high risk of thromboembolism even after surgery and extended thromboprophylaxis should be considered.
Hypopituitarism as the Initial Presentation of Pituitary Metastasis From Lung Cancer
Authors: Ayesh Hazem , Burmeister Cameron , Abdelrahman Ahmed , Beran Azizullah
Published: May 2021

Introduction: The annual incidence of hypopituitarism 4.2 cases of 100,000. Causes include primary tumor, metastasis, and non-tumor causes such as radiation therapy, infiltrative lesions, infection, and traumatic brain injury. Metastatic pituitary tumors constitute about 7-9% of the cases, with lung and breast cancers are the most common primary tumors.

Case Presentation: 48-year-old Caucasian female patient with 30 pack-year smoking history presented to the emergency department with abdominal pain, diarrhea, fatigue, and headache. Review of systems was significant for loss of appetite, left eye visual field defect, anorexia, cold intolerance, and shortness of breath. Physical examination was remarkable for decreased visual acuity. Vital signs notable for hypotension BP 92/63. Notable labs include glucose of 53 mg/dL, TSH 0.50 [0.49 - 4.67 uIU/mL], low free T4 0.52 ng/dL, low FSH 1.3 mIU/ml, low LH <0.2 mIU/ml, low ACTH 1.4 pg/mL, low morning cortisol 2.2 ug/dL, low DHEA-SO4 3ug/dL, low IGF-1 16 ng/ml. She was diagnosed with hypopituitarism and started on IV hydrocortisone 50 mg every 6 hours with 75 mcg levothyroxine daily. MRI brain showed interval growth of pituitary lesion into the suprasellar cistern with a mass-effect on the optic chiasm measuring 2.4 X1.6X 1.9 cm with a lesion in the right cerebellar hemisphere. Vertebral MRI showed multiple metastatic lesions in cervical/thoracic/lumbar vertebral bodies. On day two of hospital stay, she developed hypertonic hyponatremia (sodium 156 mmol/L, urine osmolarity 81 mOsm/kg, plasma osmolarity 328 mOsm/kg), and she was started on desmopressin 2 mg IV for diabetes insipidus. CT chest showed spiculated left upper lobe mass consistent with primary malignancy, and biopsy showed metastatic poorly differentiated epithelial malignancy likely from lung primary. Patient was discharged on desmopressin 100 mcg nightly, hydrocortisone 20 mg morning with 10 mg evening, levothyroxine 100 mcg daily with plans for further oncologic workup.

Discussion: Patient’s 2011 MRI brain showed a mildly enlarged pituitary gland. MRI brain two months before admission showed a pituitary gland diameter of 1.6 cm, while an MRI at presentation showed a pituitary

gland size of 2.4 cm with a new cerebellar lesion. She reported symptoms of nausea, vomiting, and weakness for more than one year ago but biochemical testing was not performed. The fact that the patient had pituitary enlargement eight years ago likely delayed the diagnosis of pituitary metastasis. Patient age precluded lung cancer screening despite smoking history and family history of lung cancer.

Conclusion: Symptomatic patients with pituitary enlargement on brain imaging may benefit from a close follow-up and biochemical testing for early diagnosis and treatment, especially if they have risk factors for malignancy.
The Pesticide Chlorpyrifos Promotes Obesity by Inhibiting Diet-Induced Thermogenesis
Authors: Wang Bo , Zhang Shuman , Llanos Andrea , Tsakiridis Evangelia E , Desjardins Eric M , Yabut Julian M , Green Alexander E , Day Emily A , Smith Brennan K , Lally James S V , Raphenya Amogelang R , Srinivasan Krishna A , McArthur Andrew G , Kajimura Shingo , Patel Jagdish Suresh , Wade Michael Gordon , Morrison Katherine Mary , Holloway Alison , Steinberg Gregory R
Published: May 2021

Obesity is a major risk factor for type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease that arises from a caloric surplus of as little as 10–30 kcal per day. And while increased consumption of energy dense foods and reduced physical activity are commonly thought to be the major contributors to this caloric imbalance, diet-induced thermogenesis is a quantitatively important component of the energy balance equation. In adult humans, recent studies have indicated that diet-induced thermogenesis requires the activation of brown adipose tissue (BAT), however, the determinants regulating this process and why they may differ between individuals are not fully understood. We hypothesized that environmental toxicants commonly used as food additives or pesticides might reduce diet-induced thermogenesis through suppression of uncoupling protein 1, the defining protein of human BAT thermogenesis. Through a screening approach of pesticides/toxicants chosen from the Toxcast chem Library, we discovered that the organophosphate insecticide chlorpyrifos potently suppressed the expression of uncoupling protein 1 (UCP1) and mitochondrial respiration in brown adipocytes at concentrations as low as 1 pM. Chloropyrifos-induced suppression of brown adipocyte thermogenesis was also observed in mice fed a diet high in fat and housed at thermoneutrality where it promoted greater obesity, non-alcoholic fatty liver disease and insulin resistance. Reductions in thermogenesis by chlorpyrifos were associated with impaired activation of the β3-adrenergic receptor and protein kinases critical for regulating UCP1 and mitophagy. These data indicate that the commonly used pesticide chlorpyrifos, at doses found within the food supply, suppresses the activation of brown adipose tissue, suggesting that its use may contribute to the obesity epidemic.