bluuebunny/crossref_metadata_2025 huggingface dataset:
Tissue-Specific Tumorigenesis in Multiple Endocrine Neoplasia Type I
Authors: Gardiner Juliet C
Published: May 2021

While a germline heterozygous mutation in the MEN1 gene predisposes tumor formation in the endocrine pancreas, parathyroid glands and anterior pituitary, this tissue-specific tumorigenesis is not dependent on MEN1 mutations alone. In fact, a homozygous deletion of Men1 in the entire pancreas of a mouse results in tumor formation only in the endocrine pancreas, not in the exocrine pancreas, suggesting an endocrine tissue-specific mechanism. The MEN1 gene encodes the menin protein, which interacts with chromatin associated protein complexes, therefore engaging in epigenetic control mechanisms. Recognizing menin’s participation in epigenetic regulation led to an investigation of whether the pathogenesis of MEN1 syndrome may be related to epigenetic changes in the affected endocrine tissues. Indeed, MEN1-associated endocrine cell types exhibit various menin-dependent epigenetic mechanisms. In fact, a significant increase in methylated DNA loci was observed in MEN1 human parathyroid tumors when compared to human parathyroid adenomas and carcinomas without known MEN1 mutations. Subsequent studies revealed that loss of menin results in increased activity of DNA methyltransferase 1 (Dnmt1). Our studies have shown that Dnmt1 is transcriptionally regulated by the menin-interacting protein Rbbp5. While menin normally functions to suppress Rbbp5 activity, loss of menin activates Rbbp5, thus upregulating Dnmt1 expression, causing global DNA hypermethylation and subsequent tumorigenesis in MEN1-target endocrine tissues. In order to assess the behavior of Rbbp5 in both MEN1-target tissues and non-target tissues, Rbbp5 protein expression was analyzed in both MEN1-target tissues (endocrine pancreas, anterior pituitary, parathyroid) and non-MEN1-target tissues (kidney, lung, liver, brain, heart) of wild-type (WT) mice. We confirmed that Rbbp5 protein expression is ubiquitous throughout all of these WT mouse tissues. Since Rbbp5 is a transcriptional activator responsible for enhanced Dnmt1 gene expression, and the loss of menin causes Dnmt1 overexpression solely in MEN1-target tissues, we assessed whether Rbbp5 binds preferentially in a tissue-specific manner to the Dnmt1 promoter. We determined the presence of Rbbp5 on the Dnmt1 promoter in MEN1-target tissues (WT mouse endocrine pancreas, normal human parathyroid, WT mouse pituitary) and the absence of Rbbp5 on the Dnmt1 promoter in non-MEN1-target tissues (WT mouse liver, WT mouse kidney, WT mouse lung). These results confirmed that Rbbp5 does exhibit MEN1-target-tissue-specific occupancy at the Dnmt1 promoter. This endocrine-specific localization of Rbbp5 to the Dnmt1 promoter suggests the presence of additional tissue-specific factors (with tissue-specific expression or interactions/activity) that must be validated and tested further.
GH1 C.291 + 34G>C in a Growth Hormone Deficient Pedigree
Authors: Vidal Katherine , Britt Allison D , George Anu , Ray Joseph , Lee Phillip D K
Published: May 2021

Background: Heterozygous loss of function mutations in GH1 are a cause of autosomal dominant isolated growth hormone deficiency (GHD) or IGHD type II. However, this condition is rare and a genotype/phenotype association is often based on single case or pedigree reports.

Clinical Case: The male proband was born at 38 weeks following an uncomplicated pregnancy, birthweight 2585 gm (˗1.3SD), length 43 cm (˗2.7SD). At 20 months old: length ˗3.2SD, weight/length 16%. Peak growth hormone (GH) levels 4.42 ng/mL and 3.2 ng/mL following clonidine and arginine stimulation, respectively; cortrosyn-stimulated cortisol was 41.4 mcg/dL. Prolactin was 61.2 ng/mL (reference range 2.6 to 13.1 ng/mL); T4 and TSH levels were normal. Magnetic resonance imaging showed a flattened anterior pituitary gland, consistent with empty sella, with normal bright spot. He has had an intermittent and variable response to GH treatment due to noncompliance; recent recorded height was ˗3.6SD at 13.9 and he was early pubertal. Father had a history of childhood growth hormone treatment and is 151 cm tall, 2 paternal aunts did not receive treatment and are 145 cm tall, 3 children of these aunts are diagnosed with GHD. There is no maternal family history of GHD; mother is 155 cm. Proband testing revealed heterozygous GH1 c.291 + 34G>C (EGL Genetics), classified as a variant of unknown significance; father was also found to have this variant, mother was negative. Genetic testing for of additional family members is under consideration.

Conclusion: Nine of 96 heterozygous GH1 variants are located in intron 3. Two have been classified as pathogenic and are predicted to cause exon skipping. Our proband’s variant cannot be considered a canonical splice site or in a mutational hot spot but has extremely low frequency in population databases. Functional studies clan clarify if our proband’s variant results in a 17.5 kDa GH isoform and dominant negative effect on full length GH production with potential detrimental effects on other anterior pituitary hormones. We present the second GHD pedigree with GH1 c.291 + 34G>C mutation. As in the previous report (1), no other hormone deficiencies are identified, despite the appearance of an empty sella for our proband.

Reference: (1) Cho SY, Ki, CS, Park, HD, et al. Genetic investigation of patients with undetectable peaks of growth hormone after two provocation tests. Clin Endocrinol 2013; 78: 317-20.
A Case Of Panhypopituitarism, Resembling The Picture Of Syndrome Of Inappropriate Antidiuretic Hormone Secretion
Authors: Jung Andrew , Shahid Novera , Shaaban Noreen , Angueira-Serrano Eugenio
Published: May 2021

Background: Hyponatremia is a common medical condition in the elderly. When encountering hyponatremia in the clinical setting, it is important to start with a broad differential list, and then work through all the different possibilities before arriving at the correct diagnosis. Treatment guidelines recommend starting with broad differentials in order to avoid premature conclusions, reach the correct diagnosis, and avoid suboptimal treatment or inappropriate workup. Clinical Case: 86-year old female presented with one week of general weakness, decreased appetite, sleep, and polyuria. Initial serum sodium was 128 mmol/L (136-146), and plasma and urine osmolarities were 271mOsmol/kg (285-305) and 592 mOsmol/kg (50-1400), respectively. Her urine sodium was elevated at 126 mmol/L (n<20), suggestive of a clinical picture of a syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The patient did not respond to <1L/day fluid restriction alone. The initial dose of furosemide did not improve the sodium level; thus, the dosage was raised and salt tablets were added, which improved sodium level steadily. Meanwhile, her thyroid profile showed TSH 0.07uU/mL (0.3-4.2), free T4 0.9 ng/dL (0.8-1.8), demonstrating central hypothyroidism while taking levothyroxine as a home medication. Further pituitary workup revealed an abnormally low level of FSH 4.95mIU/mL (16.7-113.5) and LH 2.33mIU/mL (10.8-58.6), considering the post-menopausal state. Prolactin was elevated at 39ng/mL (3.3-26.7). The rest of the hormone labs including cortisol, ACTH, and GH were normal. Blood sugar and serum triglyceride levels were within the normal range. Per history and physical, the patient neither exhibited hypervolemic nor hypovolemic features. No home medications would have likely caused SIADH. Her MRI of the brain in 2016 reported a sellar mass uplifting the optic chiasm and its extension of the right cavernous sinus. Latest outpatient record from October 2020 documented pituitary macroadenoma with secondary hypothyroidism, secondary hypogonadism, and hyperprolactinemia due to the stalk effect. Finally, ADH returned as <0.8 pg/mL (0-4.7), ruling out SIADH as the most likely etiology. Conclusion: Treating hyponatremia in the elderly is a challenge. Starting with a broad differential list and effectively ruling out each diagnosis is critical to find the most likely etiology and prevent a premature diagnosis. Instances of such diagnoses and subsequent inappropriate treatments invariably lead to poor patient outcomes. It is, therefore, crucial to keep an open mind and consider all possibilities when approaching a hyponatremic elderly patient. References: Paul Grant, John Ayuk, Pierre-Marc Bouloux. The diagnosis and management of inpatient hyponatraemia and SIADH. Eur J Clin Invest 2015;45(8):888-894.
A Case of Unusual Initial Presentation of Panhypopituitarism From Metastatic Adenocarcinoma of Lungs
Authors: Ahmad Malik Waseem , Becker Susannah
Published: May 2021

Introduction: Metastatic disease of the pituitary gland account for about 1 to 2 percent of the sellar masses with suprasellar extension. Approximately 7 percent of the patients are symptomatic with varying symptoms based on the location and extent of metastases. We present you a case in which patient presented with features of Panhypopituitarism starting with severe hypothyroidism in a previously undiagnosed lung cancer. The Patient also suffered with some serious complications such as diabetes insipidus, adrenal insufficiency and complete vision loss. Clinical Case: A 60 y/o male with a past medical history of Hypertension, Chronic Obstructive Pulmonary Disease, smoking 2 packs of cigarettes per day for 40 years, second-degree heart block requiring a pacemaker, Chronic kidney disease 3b presented to the emergency department with complaints of left ankle pain, swelling, and syncope. The Patient was admitted for further workup and Endocrinology was consulted for concerns of hypothyroidism with severe myxedema and adrenal insufficiency. CT head was done, which showed sellar and suprasellar mass lesion measuring 1.8 x 2.2 x 3.0 cm. Finding were confirmed on MRI. Pertinent labs were PTH 57.7 pg/ml, TSH 0.33 uIU/ml, Free T4 0.4 ng/dl, ACTH 8 pg/ml, Cortisol 2.5 ug/dl, FSH 0.5 MIU/ml, LH 0.1 MIU/ml, testosterone 4 ng/dl, Prolactin 17.7 ng/ml, Insulin-like GFBP-3: 2.1 mg/L. The Patient was started on high dose Hydrocortisone, IV Levothyroxine T4 and desmopressin for Diabetes Insipidus. The Patient complained of peripheral vision loss. Neurosurgery partially resected the sellar mass through the transsphenoidal approach. Histopathology came back with Metastatic adenocarcinoma. Further clinical course was complicated by complete vision loss from increase in the sellar mass size after 8 weeks. Patient received radiation therapy but unfortunately there was no significant improvement in the vision. Conclusion: This case highlights some serious complication from metastatic disease of Pituitary gland from lung cancer. There is a need for continued annual screening for dysfunction of the hypothalamic-pituitary axis to monitor therapy. This case also highlights the importance of widespread screening of smokers in accordance with the standard lungs cancer screening recommendations. This can potentially prevent some of the serious complications of metastatic lung disease. Reference: Ross, D. Cooper, D. Mulder, J. (2020, September) Central Hypothyroidism. https://www.uptodate.com/contents/central-hypothyroidismSnyder, P. Cooper, D. Martin, K. (2020, September) Causes, presentation, and evaluation of sellar masses. https://www.uptodate.com/contents/causes-presentation-and-evaluation-of-sellar-masses
A Case With Adult GH Deficiency Complicated With Osteogenesis Imperfecta: Effect of GH Replacement on Bone Mineral Density
Authors: Taguchi Tomomi , Toki Takuya , Hayashi Akinori , Takano Koji
Published: May 2021

Background: Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with many phenotypic presentations. Bisphosphonates are the mainstay of pharmacologic fracture prevention therapy, although they aren’t officially approved for the treatment of OI.

Clinical Case: The patient was born by breech delivery. After he had multiple fractures at the age of two years, he was diagnosed with osteogenesis imperfecta (OI) type I by genetic analysis (c.1299 + 1G> A mutation in the COL1A1 gene). On the growth curve, his height fell below -2SD at the age of six years. When he was 12 years old, he visited another hospital because of short stature (Hight 119 cm: -2.7SD). Pituitary MRI revealed pituitary stalk disruption and pituitary atrophy. Endocrinological examinations (ITT, TRH, LHRH, arginine stimulation tests) showed severe GH deficiency. Growth hormone replacement therapy was started. At the age of 16 years, he was diagnosed to have central hypothyroidism and central diabetes insipidus, and levothyroxine and DDAVP were started. His bone mineral density of the lumbar spine was 0.546 g/cm2, and alendronate was started. At the age of 17, central hypogonadism was diagnosed by LHRH stimulation test, and HCG injections were initiated. His bone mineral density continued to increase by GH replacement, HCG injections and bisphosphonate and reached 0.820 g/cm2 (Z-score: -0.27) by the age of 18 years. GH replacement was discontinued (final height 180 cm). At that age, his bone mineral density declined to 0.717 g/cm2 at the age of 25 years, although he stayed on an alendronate and HCG injections. At that time, total testosterone 890 ng/dL (142<n<923 ng/dL) was within normal range, but IGF-1 level was below the lower limit (44 ng/mL; -4.6SD, 225<n<337 ng/mL). He was referred to our hospital for transition to adult endocrine care. Endocrinologic evaluation revealed low serum cortisol level in the early morning (2.26 µg/dL, 7.07<n<19.6 μg/dL). GH-releasing peptide-2 stimulation test revealed severe GH deficiency (peak GH 0.18 ng/mL, n> 15 ng/mL (1)) and replacements with GH and hydrocortisone were initiated. After the GH replacement, the bone mineral density started to increase to 0.954 g/cm2 (Z-score: -0.5).

Conclusion: So far as we know, this is the first case report of OI with panhypopituitarism treated with GH and bisphosphonate. This case suggests that bisphosphonate alone is not sufficient to maintain bone mineral density complicated with both OI and severe GHD. GH replacement therapy was inevitable to increase bone mineral density in this patient.

Reference: (1) Kazuo Chihara et al. A simple diagnostic test using GH-releasing peptide-2 in adult GH deficiency. Eur J Endocrinol.2007;157;19-27.
A Rare Case of a Plurihormonal Pituitary Adenoma
Authors: Hossain Alisha , Skutnik Emily , Ahluwalia Arjan , Gelin Lindor , Singh Sonum , Perilli Gretchen , Koshy Sharmilia
Published: May 2021

Background: Pituitary adenomas are usually benign tumors that arise from adenophypophyseal cells and produce one or two types of hormones. Plurihormonal adenomas are a rare subtype that produce two or more hormones and represent less than 1% of all pituitary adenomas.

Clinical Presentation: A 76-year-old female presented for evaluation of abnormal thyroid function test results. She was found to have an elevated free T4 of 1.92 ng/dL and total T4 of 14.4 ug/dL with an inappropriately normal TSH of 2.11 uIU/mL. Physical examination was significant for tachycardia, tremors, diaphoresis, coarse facial features, and enlarged hands. Further biochemical evaluation of her pituitary hormone levels demonstrated an elevated prolactin (PRL) of 237.2 ng/mL, elevated insulin-like growth factor 1 (IGF-1) of 787 ng/mL, normal morning ACTH of 47 pg/mL, normal morning cortisol of 17.0 ug/dL, an inappropriately suppressed FSH of <5.0 mIU/mL, an elevated alpha subunit of pituitary glycoprotein hormones (PGH) of 6.9 ng/mL, and an elevated free T4 of 3.5 ng/dL by equilibrium dialysis. She underwent an MRI of the pituitary and brain which demonstrated a pituitary adenoma measuring 1.2 x 1.3 x 1.8 cm with a portion herniating into the sella turcica with no mass effect of the optic chiasm. A formal visual field examination was normal. The patient underwent workup for Cushing’s Disease with a low dose overnight dexamethasone suppression test, resulting in an appropriate response with an 8 AM cortisol of <1.0 ug/dL. Glucose suppression test confirmed the diagnosis of acromegaly with growth hormone at 120 minutes of 19.90 ng/mL. Neurosurgery performed a trans-sphenoidal pituitary adenoma resection. Thyroid function tests on post-operative day 4 demonstrated a suppressed TSH of 0.01 uIU/mL and an elevated free T4 of 2.30 ng/dL. Histological evaluation revealed dual expression of transcription factors pituitary-specific positive transcription factor 1 (PIT1) and steroidogenic factor 1 (SF1) as well as PRL, GH, TSH and FSH expression. Immunostaining for LH and ACTH were negative. Post-operative IGF-1 and GH levels were 106 ng/mL and 0.51 ng/mL at 17 weeks, respectively. Post-operative TSH normalized to 0.82 uIU/mL, free T4 normalized to 1.04 ng/dL, and PRL normalized to 8.1 ng/mL at 12 weeks. The patient remained symptom free after successful surgical resection.

Discussion: Our case demonstrates the clinical course of a unique patient with clinical and biochemical manifestations of thyroid dysfunction and acromegaly with a pituitary adenoma immunoreactive for GH, TSH, FSH, and PRL. The co-secretion of GH, TSH, PRL, and FSH as well as positivity for the alpha-subunit is extremely unusual. This case emphasizes the importance of considering pituitary abnormalities as a cause for abnormal thyroid function tests.
A Rare Case of Thyrotropin Secreting Pituitary Macroadenoma Primarily Treated With Somatostatin Analogue
Authors: Elsheikh Arwa Mahmoud , Vates G Edward , Shafiq Ismat
Published: May 2021

Introduction/Background: Thyrotropin secreting pituitary adenomas (TSH-oma) are a rare cause of hyperthyroidism. They account for <1% of the cases of hyperthyroidism with a reported incidence of 2.8 per 1 million in Sweden. Diagnosis is suspected by the presence of elevated T4 and T3 in the setting of an unsuppressed TSH level. The presence of large pituitary adenoma is highly suggestive of the diagnosis and can be differentiated from thyroid hormone resistance by elevated alpha subunit and SHBG levels. Trans-sphenoidal surgery is the definitive treatment. Peri-operative medical treatment with somatostatin analogues is indicated to achieve euthyroidism and prevent surgical risks and thyroid storm. The use of somatostatin analogues as a primary treatment for TSH-oma is still under investigation. We hereby report a rare case of TSH-oma where somatostatin analogues successfully resulted in normalization of thyroid function and tumor size reduction.

Clinical Case: A 61 years old gentleman with a history of hypothyroidism diagnosed three years before presentation to the Pituitary clinic. He was treated with Levothyroxine. On clinical examination, he had mild tremor and warm sweaty palms with no stigmata of Grave’s disease. The thyroid function test showed elevated free T4 of 3.6 ng/dl (0.9-1.7), elevated free T3 of 8.6 pg/ml (2.0-4.4), and a high TSH level of 9.10 μIU/ml (0.27-4.20). His prolactin level was mildly elevated at 24.8 ng/ml(4.0-15.2). Testosterone, IGF-1, and cortisol levels were normal. An MRI of his pituitary gland showed large pituitary macroadenoma with supra-sellar extension and mild compression of the optic nerve. He had an elevated alpha subunit of 5.6 ng/ml (<1.37) and a high SHBG level of 198 nmol/l(10-80). TSH adenoma was diagnosed and he was planned for trans-sphenoidal surgery. Pre-operative treatment with somatostatin analogue Lanerotide 90 mg monthly injection was initiated. Interestingly normal thyroid function was observed approximately 1 month after his first injection. Repeat MRI showed a considerable decrease in the size of the pituitary macroadenoma. The patient opted to hold on to surgery and to continue on medical treatment. His thyroid function remains normal 15 months after initiation of treatment and his MRI continues to show stable pituitary adenoma.

Conclusion: Somatostatin analogues can be used as a primary treatment for thyrotropin secreting pituitary adenomas when the patient is unable or unwilling to undergo surgery. It is use is associated with normalization of thyroid function and in some cases with a reduction in the adenoma size.
Spexin as a Satiety Factor in Mouse via Regulatory Actions Within the Hypothalamus
Authors: Wong Matthew K H , Chen Yuan , He Mulan , Lin Chengyuan , Bian Zhaoxiang , Wong Anderson On-Lam
Published: May 2021

Spexin (SPX) is a pleiotropic peptide with highly conserved protein sequence from fish to mammals and its biological actions are mediated by GalR2/GalR3 receptors expressed in target tissues. Recently, SPX was found to be a novel satiety factor in fish models but whether the peptide has a similar function in mammals is still unknown. Using the mouse as a model for mammalian species, the functional role of SPX in feeding control and the mechanisms involved were investigated. After food intake, serum SPX could be up-regulated in mice with parallel elevations of transcript expression and tissue content of SPX in the glandular stomach but not in other tissues examined. As revealed by immunostaining, food intake also intensified SPX signals in different cell types within the gastric mucosa of glandular stomach. Furthermore, IP injection of SPX was effective in reducing food consumption with parallel drops in transcript expression of NPY, AgRP, NPY type 5 receptor (NPY5R) and ghrelin receptor (GHSR) in the hypothalamus, and these inhibitory effects could be blocked by GalR3 but not GalR2 antagonism. In agreement with the central actions of SPX, similar inhibition on food intake and hypothalamic expression of NPY, AgRP, NPY5R and GHSR could be observed with ICV injection of SPX. In the same study, parallel rises of transcript expression of leptin receptor (LepR) and melanocortin 4 receptor (MC4R) were also observed in the hypothalamus. These findings, taken together, suggest that the role of SPX as a satiety factor is well-conserved in the mouse. Probably, food consumption can induce SPX production in glandular stomach and contribute to the postprandial rise of SPX in circulation. Through GalR3 activation, this SPX signal can act within the hypothalamus to trigger feedback inhibition on food intake by differential modulation of the feeding regulators (NPY & AgRP) and their receptors (NPY5R, GHSR, LepR & MC4R) involved in the feeding circuitry of the brain.
Acromegaly in a Young Women With Pituitary Hyperplasia Secondary to a Neuroendocrine Tumor
Authors: Bano Gul
Published: May 2021

Acromegaly is rarely due to an excess of the GH-releasing hormone (GHRH) and pituitary hyperplasia on histology should alert to its presence. Clinical Case: A 35-year-old was referred to surgery with a confirmed diagnosis of symptomatic acromegaly. Her GH failed to suppress during an oral glucose tolerance test (OGTT), her IGF-1 and prolactin was high. Her serum calcium was normal and her chromogranin B was high. MRI scan suggested microadenoma. Her surgery was deferred because of Covid 19, and she was treated with somatostatin analog (SSA). She finally had surgery in July. The histology and immunocytochemistry suggested pituitary hyperplasia with diffuse positivity for chromogranin and synaptophysin. GH was positive in the majority of the cells with many cells positive for Prolactin and ACTH. FSH and LH were positive in scattered cells with patchy positivity of TSH. A solitary nodule was noted in her neck during an examination. We arranged to look for conditions associated with pituitary hyperplasia resulting in GHRH production, including the genetic tests for inherited conditions. Her calcitonin level was normal. She had an ultrasound scan guided fine needle aspiration of the thyroid nodule, this showed Thy3f oncocytic nodule with no features of medullary thyroid carcinoma. She had an NMGa68DOTATATE whole body PET CTand the scan showed a large DOTATAE avid mass from the right adrenal gland compatible with Pheochromocytoma. Her 24 hours total urinary metadrenaline and normetadrenalin was high. Her genetic test for MEN1, CDKN1B, and MEN2 are negative. We have requested the GHRH measurement. After a pituitary surgery, her GH suppressed adequately on OGTT. Her IGF-1 and prolactin is low and her hypogonadism is resolved. Conclusion: Excess production GHRH can result from neuroendocrine tumors of the lung, pancreas, thyroid (medullary thyroid cancer), or pheochromocytomas and hypothalamic gangliocytomas.

Several familial syndromes, multiple endocrine neoplasia type 1 (MEN1) and 4 (MEN4), familial isolated pituitary adenoma (FIPA), Carney complex, and sporadic germline mosaic disorder McCune-Albright disease predispose to pituitary hyperplasia. GHRH acromegaly should be suspected in a patient with biochemical/clinical features of acromegaly in the presence of co-existing neuroendocrine tumors when there is diffuse pituitary enlargement on imaging or resolution of acromegaly after the surgical resection of the primary neuroendocrine tumour or persistent acromegaly after surgery if there is histological evidence of somatotroph hyperplasia. References: Akirov A, ASA SL, AMER L Shimon I and Ezzat S. The clinicopathological spectrum of acromegaly. J. Clin. Med. 8(11), 1962 (2019) J. Clin. Med. 2019; 8: 11, 1962
Acute Ischaemic Stroke With Hyperprolactinemia:A Case Report
Authors: Wan Zain Wan Mohd Saifuhisam , Omar Julia , Ismail Tuan Salwani Tuan , Che Soh Noor Azlin Azraini
Published: May 2021

Background: Macroincidentalomas were reported in 0.2% of patient underwent imaging (CT scans) for central nervous symptoms (1). In acute ischaemic stroke with hyperprolactinemia, the diagnosis of a double pathology of ischemic stroke and sellar tumour especially prolactinoma need to be considered. Hyperprolactinemia itself may be considered as a risk factor for ischemic stroke due to its thrombogenic effect (3).

Clinical Case: A 47-year old man underlying hypertension and diabetes mellitus for 5 years presented with sudden onset of right sided body weakness associated with facial asymmetry and aphasia. No history of fever or trauma. Asymptomatic of hyperprolactinemia previously. On general examinations Glasgow Coma Scale 11/15 Eye 4 Verbal 1 Motor 6, blood pressure was unstable with readings of systolic 244mmHg and diastolic 142mmHg. Neurological examinations showed expressive aphasia, right hemianopia, right facial nerve palsy and absence of gag reflex. Cerebellar signs were negative. Motor function examinations of right upper and lower limbs showed hypertonia, reduce power of 2/5, normal reflexes and up going plantar response. Sensory functions of right upper and lower limbs were reduced. Clinically diagnosed as stroke with hypertensive emergency. CT brain showed multiple hypodensities due to recent infarct and incidental finding of an aggressive sellar mass. MRI brain showed left Middle Cerebral Artery territory infarct and an aggressive sphenoid sinus mass with suprasellar and bilateral cavernous sinus extension possibility of a macroadenoma. Serum prolactin level showed markedly hyperprolactinemia (21146 ng/ml, n 4.04 – 15.2 ng/ml) which level of 500ng/ml or greater is diagnostic of a macroprolactinoma (2). FSH level (0.929 IU/L, n 1.5-12.4 IU/L) and LH level (1.11 IU/L, n 1.7-8.6 IU/L) were low in this patient due to suppression of GnRH secretion from hypothalamus by prolactin. Testosterone level (0.15 nmol/L, n 8.64-29.0 nmol/L) was low secondary to low LH. Serum cortisol, growth hormone and TSH were normal. Platelet count and coagulation profiles were normal. The patient was treated conservatively in ward for acute ischaemic stroke and later was started on dopamine agonist cabergoline for hyperprolactinemia.

Conclusion: This is a case report of acute ischaemic stroke with markedly hyperprolactinemia secondary to incidentaloma macroprolactinoma.

Reference: (1)Freda PU, Beckers AM, Katznelson L, et al. Pituitary incidentaloma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96 (4): 894-904.(2)Abha Majumdar and Nisha Sharma Mangal. Hyperprolactinemia. J Hum Reprod Sci. 2013 Jul-Sep; 6(3): 168–175.(3)Sankalp Kumar Tripathi, Pallavi Kamble, M.G. Muddeshwar. Serum Prolactin Level in Patients of Ischemic stroke. International Journal of Contemporary Medical Research 2016; 3(12): 3459-3460.
Can Long-Standing GnRH Therapy Cause a Pituitary Prolactinoma?
Authors: Nandu Nitish Singh , Dawahir Wafa , Paduri Swetha , Gilden Janice L , Citrin Dennis L
Published: May 2021

Background: Pituitary adenoma (PA) is the most common cause of sellar masses and accounts for about 10% of all intracranial tumors. Several physiological, pathological, drugs, and rare causes like hypothyroidism can cause PA. We describe a case of long-standing treatment with GnRH analogues possibly contributing to development of PA. Clinical Case: An 86-year-old man with a history of prostate cancer (PC) treated with medical therapy, presented to the hospital with progressively worsening loss of vision in his right eye associated with low-grade headaches over the past few years. Fifteen years prior to presentation, the patient was diagnosed with Gleason 6 (3 + 3) localized PC. He had refused surgical intervention and hence was treated with flutamide, then leuprolide. Labs were significant for an elevated prolactin 34.2 ng/mL [n= 2.5 -17.4], low LH 0.7 mIU/mL [n=1.2-10.6], with normal FSH, TSH, ACTH, IGF, Cortisol, and PTH. CT head and MRI brain identified a 2.7cm x 2.6.3 cm X 1.7 cm mass in the suprasellar region involving the left cavernous sinus and right optic chiasm. These findings were consistent with a diagnosis of Prolactinoma. Patient refused surgery and hence was started on bromocriptine. The findings were suspected to be secondary to long-standing GnRH agonist therapy, and leuprolide was discontinued. DEXA scan confirmed osteoporosis with a T score of --2.5, which was treated with denosumab. Subsequently his vision improved. The patient continues to follow with endocrinology for the management of osteoporosis and prolactinoma. Conclusion: Primary hypothyroidism predisposes to PA due to loss of thyroxine feedback inhibition to hypothalamus with overproduction of TRH with hyperplasia of lactotrophs. We speculate that constant stimulation of the pituitary by GnRH analogues can also lead to enlargement of the anterior pituitary in a similar fashion, and can lead to the development of prolactinoma. LHRH agonists such as Leuprolide, as palliative treatment for advanced prostate cancer, causes desensitization of the anterior pituitary and decreases the production of LH and FSH, which ultimately leads to decreased testosterone in males. Although not standard of care for treatment of locally advance tumors, medical therapy was chosen in this patient’s case due to refusal of surgical intervention. He then developed a clinically significant pituitary adenoma years after the therapy. We suggest that constant stimulation of the pituitary by GnRH analogues can lead to enlargement of the anterior pituitary in a similar fashion, resulting in the development of the prolactinoma.

Reference(1) Du J, Ji H, Jin J, Gao S, Yan X, Hu S. Pituitary adenoma secondary to primary hypothyroidism: Two case reports. Medicine (Baltimore). 2020;99(8). https://journals.lww.com/md-journal/Fulltext/2020/02210/Pituitary_adenoma_secondary_to_primary.47.aspx
Case of a Giant Prolactinoma Measuring Greater Than 10 CM in a Post-Menopausal Woman
Authors: Imamudeen Nasvin , Zafar Aiman , Bettadahalli Shankar
Published: May 2021

Prolactinomas are the most common type of pituitary adenomas. Macroprolactinoma is the name used for tumors when their size exceeds 1 cm and giant prolactinomas are those that exceeds 4 cm. Females are more commonly reported to have microprolactinomas with female-to-male ratio of 20:1, on the contrary macroprolactinomas are usually diagnosed in men aged 20-50 years with a reported male-to-female ratio of 9:1. We are presenting the case of a 63-year-old female with history of cataracts and hypertension who presented with complaints of progressive decrease in vision in both of her eyes (right greater than left) for several months and declining night vision without headache. Her only other symptoms were tiredness and cold intolerance. A detailed visual exam led to the findings of bitemporal hemianopsia and possible right optic neuropathy. Her neurological exam otherwise was intact. Subsequently contrast magnetic resonance imaging (MRI) of the brain showed a large sellar and suprasellar mass measuring greater than 10 cm x 6 cm in size invading right cavernous sinus, surrounding vessels and compressing optic chiasm with extension into the right temporal lobe, left frontal lobe and subfalcine shift to the right. Laboratory studies indicated elevated prolactin level of 4932 ng/mL (2.8 - 29.2 ng/mL) consistent with prolactinoma. Pituitary hormone function testing revealed suppressed gonadotropins, subnormal ACTH stimulation test and central hypothyroidism. She was started on medical therapy with cabergoline. At one month follow-up, serum prolactin level significantly decreased to 136.2 ng/mL but the size of the mass did not significantly decrease on follow up brain MRI. Patient currently wants to try medical management alone.

Conclusion: Macroprolactinomas measuring >4 cm are rare, accounting for only 1–5% of all prolactinomas and are more commonly seen in men, however they can be seen in postmenopausal women as well. Headaches and visual field disturbances are common presenting symptoms due to compressive effect and warrant further investigation with MRI of the brain. Medical therapy alone can sometimes suffice and surgery is a second line option as it confers morbidity risks.
COVID-19 and Cushing Disease: A Protective or a Deadly Combination?
Authors: Mehfooz Ayesha , Araki Takako , Burmeister Lynn Ann
Published: May 2021

Background: Manifestations of Cushing disease, including diabetes mellitus, hypertension, and obesity are risk factors for severe novel coronavirus disease 2019 (COVID-19) disease. A potential for severe COVID-19 disease might be hypothesized in Cushing disease patients. We present a finding of asymptomatic COVID-19 positive nasopharyngeal PCR test in an untreated Cushing disease patient. Case: A 19 year old female presented in January 2020 reporting amenorrhea and cushingoid facies. Her last menstrual period was two years ago. Low energy, fatigue, easy bruising and dark stretch marks on her legs, axillae and flanks were reported. Physical exam showed blood pressure 123/83 mmHg, pulse 89 bpm, BMI 20.80 kg/m². She had a cushingoid appearance with fullness in the face, neck and supraclavicular area, mild proptosis, pink cheeks and a few faint lavender striae on the inner thighs and flanks. Test results relevant to or supporting a diagnosis of Cushing disease included the following: 1 mg overnight dexamethasone suppression test: AM cortisol 23.9 ug/dl (6.7-22.6 ug/dl). Random 1019 hrs AM ACTH was 32 pg/ml (<47 pg/ml), cortisol 6.5 ug/dl (4-22ug/dl). Repeat 1 mg overnight dexamethasone suppression test: AM cortisol was 36.5 ug/dl (4-22 ug/dl), Dexamethasone 249.2 ng/dl (140-295 expected post 1 mg DXA the night before). 24 hr urine free cortisol was 391.4 (<=45.0 ug/d). Other endocrine labs were within normal limits. Left sided hypoenhancing lesion (2mmx2mmx2mm) consistent with pituitary microadenoma was seen on pituitary MRI. Inferior petrosal sinus sampling supported the presence of central disease and left pituitary location, concordant with the MRI. The time course from first clinical presentation to surgery was impacted by the COVID 19 pandemic temporarily halting elective surgical treatments and her access to care. At August, 2020 pre-op evaluation, the COVID-19 nasopharyngeal PCR was positive. Surgery was rescheduled. She denied symptoms of COVID-19 but recalled community exposure, including known COVID-19 positive contacts, while working as a waitress. Discussion: Increased susceptibility to and increased severity of COVID-19 manifestations might be feared in Cushing disease patients due to Cushing disease-associated immunosuppression, hyperglycemia, hypertension, obesity and venous thromboembolism. In contrast, randomized control trials have shown glucocorticoids, at doses sufficient to produce iatrogenic Cushing syndrome, may improve mortality in COVID-19 patients. Although asymptomatic COVID-19 infection is known to occur in young adults, the finding of asymptomatic COVID-19 positive test in a young woman with untreated Cushing disease also raises the possibility that endogenous hypercortisolism confers a similar benefit against severe manifestations of COVID-19 infection.
Cushing’s Disease (CD) Due to ACTH-Secreting Pituitary Microadenoma Incidentally Discovered on a Sestamibi Scan for Primary Hyperparathyroidism
Authors: Mehmood Hassan , Gordon Murray B
Published: May 2021

Introduction: MIBI scintigraphy is commonly being used for the preoperative localization of parathyroid adenomas. Multiple studies showed MIBI uptake in pituitary adenomas are likely due to higher metabolic activity. When hyperfunctioning pituitary adenomas were reported, both had CD [1,2]. We present the third case of increased pituitary uptake on a MIBI scan later confirmed as CD. CaseA 64-year-old Caucasian female s/p renal transplantation for RPGN who presented for evaluation of hypercalcemia. Evaluation confirmed primary hyperparathyroidism with persistently elevated PTH levels 74-108 pg/ml (11-68), serum calcium levels 10.0-10.4 mg/dl (8.4-10.3), albumin 4.1-4.3 g/dl (3.6-5.1), phosphorus 3.0-3.2 mg/dl (2.5-4.5), creatinine 0.94-1.07 mg/dl. 24-hour urine calcium 60 mg/day (35-250). Vitamin D-25 OH level was 37 ng/dL (30-100). A sestamibi scan showed uptake in the right lower parathyroid, the midsternal chest region and the pituitary gland. MRI of the pituitary revealed a 7mm cystic pituitary microadenoma in the right posterior pituitary. CD was confirmed by the findings of persistently elevated 8 AM serum cortisol levels of 28.4 and 24.2 mcg/dl (4-22), ACTH levels of 59 and 39 pg/ml (10-48), and an elevated plasma free cortisol of 1.43 mcg/dl (0.07-0.93). CT of the abdomen showed L adrenal thickening suggesting adrenal hyperplasia from CD. Plasma cortisol suppressed to 1.2 mg/dl following 1 mg of dexamethasone. 24 urine for free cortisol 26.7 mcg/day (4-50). The patient had no proximal muscle weakness, striae or Cushingoid facial features. She had no hyperglycemia or hypertension. Patient was diagnosed with an ACTH secreting pituitary microadenoma with mild CD and adrenal hyperplasia. Her DXA scan showed osteoporosis. Genetic testing for MEN1 mutation was negative. Patient did not wish surgery for either her hyperparathyroidism or her CD and is being evaluated for medical treatment of hypercortisolism. Conclusion: There are two prior case reports of an incidentally discovered pituitary adenoma on sestamibi scan later diagnosed as CD [1,2]. Corticotrophs may have a strong affinity for sestamibi. Our case is the first, to our knowledge, of pituitary MRI confirmation of the ACTH secreting pituitary incidentaloma initially suspected by pituitary uptake on a sestamibi scan in a patient with hyperparathyroidism. Reference1. Kuhadiya ND et al. Incidentally Discovered ACTH-Secreting Pituitary Adenoma on a Sestamibi Scan in a Patient With Hyperparathyroidism. AACE Clinical Case Reports. 2015;1(3):e152-5. 2. Gierach M et al. The case of Cushing’s disease imaging by SPECT examination without manifestation of pituitary adenoma in MRI examination. Nuclear Medicine Review. 2005;8(2):137-9.
Cushing’s Disease: Not Always Black and White
Authors: Shah Kajal , Chang Alan , Jarahzadeh Natalie
Published: May 2021

Cushing’s Disease is a well known entity but the difficulty of diagnosis is often underappreciated. Given the wide spectrum of clinical presentation and pitfalls with each diagnostic evaluation, diagnosis of Cushing’s Disease (CD) is often difficult in clinical practice, even with pathological analysis. A 37 year old female with a history of Cushing’s Disease presented for her third transphenoidal resection to our institution. She was diagnosed with a pituitary microadenoma 16 years ago based on MRI, as she had persistent headaches and vision abnormalities. The patient also reported unexplained weight gain, “buffalo hump”, and moon facies at the time. She was diagnosed with CD due to an abnormal 1 mg overnight dexamethasone suppression test (DST) with AM cortisol of 3.03 ug/dl (normal <1.8 microgram/dl). She was on an oral contraceptive pill (OCP) at the time. The patient underwent her first pituitary transsphenoidal resection and was symptom free for about 10 years, after which she had a recurrence of her initial symptoms. She had another abnormal DST while on an OCP and pituitary MRI revealed growth of the pituitary adenoma. Patient underwent a second pituitary surgery with benign postoperative course with a recurrence about 5 years later. The workup prior to her third surgery revealed an abnormal DST while on OC pills with the 8am cortisol being 3.36 ug/dl (<1.8ug/dl), urinary free cortisol 35.4 mcg/24 hour (4-50 mcg/24 hour). 8am ACTH done on a separate day was 48 pg/ml (6-50 pg/ml) with a cortisol of 14.5 ug/dl. Midnight salivary cortisol was not performed. Interval history was still positive for weight gain and headaches, hence she was referred for her third pituitary surgery. Post surgery, the patient was on a short taper of hydrocortisone and 8am cortisol was 32 ug/dl the next day. After a discussion with the pathologist, it was determined that the pathology was suggestive of a corticotroph adenoma with moderate ACTH staining and patchy nuclear staining for TPIT, although the pathologist stated that it was difficult to be certain due to the small tissue size. From the current literature, this patient had an incomplete and equivocal biochemical work up while on OCPs but still had tissue diagnosis supporting CD. Whether this was a recurrence of Cushing’s disease, silent corticotroph adenoma, or non-functioning pituitary adenoma is unclear. This case illustrates the multiple challenges in the diagnosis of Cushing’s disease that may be encountered. 1.Braun LT et al. Recurrence after pituitary surgery in adult Cushing’s disease: a systematic review on diagnosis and treatment. Endocrine. 2020;70(2):218-231.
Diverse Manifestation of Acromegaly With Suspicion of Ectopic GHRH Secretion. Report of Two Cases
Authors: Godlewska Magdalena , Nowak Andrzej Jerzy , Boguslawska Anna , Kluczynski Lukasz , Grochowska Anna , Hubalewska-Dydejczyk Alicja , Gilis-Januszewska Aleksandra
Published: May 2021

Introduction: Acromegaly can rarely be caused by an ectopic production of GH or GHRH by various neoplasms, most commonly neuroendocrine tumors of pancreatic or pulmonary origin. Squamous cell carcinoma of the lung has not been associated with ectopic GHRH secretion yet. The authors present two cases of acromegaly with suspicion of GHRH ectopy. Presentation of the Cases: Case 1. A male born in 1945 presenting with typical morphologic features of acromegaly. Pituitary MRI revealed a cuneatic-shaped, hypointense focal lesion (8x7x6 mm) in the right posterior part of the anterior pituitary lobe, radiologically interpreted as either hyperplasia of the intermediate lobe or atypical adenoma in a normal-sized pituitary. IGF-1 and no suppression of GH secretion after oral glucose load were observed. Furthermore, a polycyclic tumor in the 2nd segment of the right lung with pathological metabolic activity in 18FDG- PET/CT was discovered. Ga68- DOTA TATE PET/CT revealed no pathological accumulation of the tracer. After upper right lobectomy, squamous cell carcinoma, non-keratinizing, G3, with a negative immunohistochemical reaction for GH was confirmed. IHC for GHRH and serum GHRH have been scheduled. After surgery and chemotherapy, no biochemical remission of acromegaly was observed and the pituitary MRI showed stable radiological image of the pituitary tumor, suggesting rather a possible metastasis to the pituitary. Due to unfavorable prognosis, the patient was disqualified from neurosurgical resection of the pituitary tumor. Case 2. a male born in 1948 with typical symptoms of acromegaly, elevation of IGF-1 and no suppression of GH in OGTT. Due to MRI contraindications, only CT of the head was performed- it revealed partially empty sella, compressed pituitary with maximal diameter 3 mm and no focal lesions. Treatment with somatostatin analogue was introduced, however, only partial biochemical control was achieved. Ga68- DOTA TATE PET/CT performed after 8 years showed pathological expression of somatostatin receptors in the pancreatic tail. Abdominal CT confirmed a focal lesion in this location, 14x9 mm, with a strong enhancement after contrast administration, suggesting a neuroendocrine tumor. The patient refused to undergo any invasive procedures and remains treated with SRL. Serum GHRH has been scheduled. Conclusion: The authors report two cases of ectopic acromegaly suspicion, with an ambiguous clinical and radiological presentation. In unclear cases of acromegaly, ectopic production of GHRH should be taken into consideration.
The Effects of Diet Induced Obesity (DIO) on Skeletal Muscle Transcription in MuRF1 KO Mice
Authors: Marshall Andrea Gail , Norman Jennifer E , Chementi Michael S , Rutledge John C , Bodine Sue C
Published: May 2021

Background: As obesity and Type II Diabetes rise globally, it is important to understand the similarities and differences in the response of metabolic tissues between males and females. We wanted to evaluate the impact of prolonged diet induced obesity (DIO) on the skeletal muscle transcriptome of our MuRF1 KO (KO) mice. Methods: RNA was isolated from the gastrocnemius muscle of male and female WT and KO mice that were fed either standard chow (Envigo 2918) or a 45% HFD (Research Diets D12451) for 22 weeks (n = 4). RNA was enriched for mRNA prior to library preparation. RNA sequencing was performed using 150 bp paired-end reads (~ 31.6 M reads per sample). Differentially expressed genes (DEGs) were identified using DESeq2 with an FDR set to 5%. Results: At baseline (chow diet), both male and female KO mice had DEGs compared to their WT counterparts (male, 1174; female, 105). Most DEGs were found to be unique by sex (male, 1151; female, 82), though 23 genes were found to be changed in common. After obesity was induced by 22 weeks of 45% HFD feeding, KO animals showed a greater transcriptional response than their WT counterparts. Males had 1821 DEGs (v. 179 in WT) while females had 4425 DEGs (v. 2090 in WT). In males, 78 genes were changed in common between WT and KO in response to DIO, with 76 of those genes changing in the same direction (Slc282a and Gm15427 did not). In females, 1445 genes were changed in common between WT and KO, with all but 2 genes (Pla2g7 and Zfp385b) changing in the same direction. In both male and female KO animals, oxidative phosphorylation and ribosomal pathways were most significant, though the direction of change in the DEGs was opposite. Conclusion: In skeletal muscle, sex highly influences the genes and pathways changed in response to DIO. Even among common pathways identified, the response between males and females differed. Loss of MuRF1 results in common and unique transcript changes in and between males and females under normal conditions and in DIO.