bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyponatremia as the Initial Presentation of Evolving Pituitary Apoplexy
Authors: Milosavljevic Jovan , Thomas Asha Mary
Published: May 2021

Pituitary apoplexy (PA) is a known, often under-recognized medical emergency and is characterized by ischemic or hemorrhagic necrosis of the pituitary gland. It is a rare clinical syndrome that occurs in 2-12% of pituitary tumors. Hyponatremia can occur secondary to hypocortisolism (12-40%) or, rarely, to the syndrome inappropriate antidiuretic hormone (ADH) secretion.

We present the case of a 69-year-old man who presented with altered mental status on post-operative day 3 from total knee replacement surgery. Initial testing revealed hyponatremia of 124 mmol/L, low serum osmolality of 266 mOsm/kg, and high urine osmolality of 664 mOsm/kg with urine sodium of 179 mmol/L. Head computerized tomography revealed a sellar mass of 1.8 x 2.4 cm. Initial testing revealed low prolactin (0.7 ng/mL), normal TSH (0.458 mcIU/mL) with borderline low free T4 of 0.72 ng/dL. Morning cortisol was 12.7 mcg/dL with ACTH of 8.5 pg/mL. Cosyntropin stimulation test was done revealing baseline cortisol of 5.8 mcg/dL (at midnight), increasing to 25.8 mcg/dL after 30 minutes and to 30.9 mcg/dL 60 minutes after cosyntropin administration. His sodium and mental status initially improved with fluid restriction and salt tablets, for the assumed syndrome of inappropriate ADH secretion. The patient remained hemodynamically stable. On the fourth day, however, his mental status deteriorated. Magnetic resonance imaging revealed expansion of sella with hyperintense mass 2.2 x 2.0 x 2.8 cm with compression of the optic chiasm. He was given stress dose hydrocortisone and levothyroxine and underwent emergency transsphenoidal resection. Biopsy revealed acute hemorrhage within infarcted adenoma. Postoperatively, both the patient’s sodium and mental status improved significantly and he was discharged to home on hydrocortisone and levothyroxine.

The main clinical concern in the management of PA remains under-diagnosis at presentation. Prognosis is dependent on management during the acute phase. PA can present as hyponatremia even in the absence of overt hypocortisolism, presumably due to inappropriate ADH secretion. Therefore, PA should be considered as one of the differential diagnoses in hemodynamically stable patients with altered mental status and hyponatremia.
Hypopituitarism as an Initial Presentation of Silent Squamous Cell Carcinoma of Lung
Authors: Zin Khin M , Meleis Mostafa , Purewal Tiffany , Holland Soemiwati W , Cheng Jennifer
Published: May 2021

Background: Symptomatic metastasis to the pituitary gland is a rare, life-threatening condition. A better understanding of its clinical presentation could lead to early diagnosis and also improve quality of life. In this unusual case, we present a patient with hypopituitarism as the first manifestation of undiagnosed squamous cell carcinoma of the lung. Clinical Case: A 56-year-old Caucasian female with past medical history of pre-diabetes, hypertension, hyperlipidemia, and a chronic smoker for 40 years presented with recent onset of headache for two weeks and diplopia for three days. Initial CT head was negative but MRI of brain pituitary scan revealed a large heterogeneously enhancing sellar/suprasellar mass (1.5 x 2.8 x 2.4 cm) extending into the prepontine cistern with probable bilateral cavernous sinus invasion and contacting the optic chiasm without significant compression. Physical examination showed left abducens nerve (CN VI) palsy. Lab results showed elevated prolactin at 67.4 ng/ml (normal postmenopausal: 1.8 – 20.3 ng/ml), normal IGF-1 at 136 ng/ml (normal 48- 235 ng/ml), low TSH at 0.129 µIU/ml (normal 0.3 – 4.5 µIU/ml), low normal Free T4 at 0.50 ng/dl (normal 0.5 – 1.26 ng/dl), low ACTH at 5.1 pg/ml (normal 7.2 – 63.3 pg/ml), low am cortisol at 2.6 mcg/dl (normal 8.7 – 22.4 mcg/dl), low FSH at 2.6 mIU/ml (normal postmenopausal 23.0-116.3 mIU/ml) and low LH at 0.2 mIU/ml (normal postmenopausal 15.9 - 54.0 mIU/ml). She subsequently began treatment for hypopituitarism. Given her smoking history and unusual presentation of cranial nerve palsy, a chest x-ray was ordered and revealed a left upper lobe mass. CT chest confirmed the left upper lobe mass (4.0 x 3.3 x 2.9 cm), and biopsy reported poorly differentiated squamous cell carcinoma. Decompression of the pituitary macroadenoma was performed for symptomatic improvement but was complicated with the development of central diabetes insipidus. Pathology report disclosed metastatic pituitary carcinoma, compatible with primary lung carcinoma. Following surgical resection and radiation therapy to the pituitary gland, the patient remains stable and is currently tolerating all treatment. Conclusion: In a patient with occult malignancy, pituitary metastasis is an exceedingly rare and challenging diagnosis that carries a poor prognosis. The purpose of this abstract is to raise clinical suspicion for sellar metastasis in a patient presenting with hypopituitarism and cranial nerve palsy.
Management of Persistent Cushing’s Disease Despite Prior Pituitary Adenoma Resection in a Pregnant Patient
Authors: Leiter Amanda , Shrivastava Raj , Pozharny Yevgeniya , Shah Nirali
Published: May 2021

Introduction: Cushing’s Disease (CD) in pregnancy is a rare, but serious disease that adversely impacts maternal and fetal outcomes. As the sole use of metyrapone in the management of CD has been rarely reported, we describe our experience using it to treat a pregnant patient with pre-existing CD. Clinical Case: The patient is a 29-year-old woman with a history of hypertension (HTN), who was diagnosed with CD a year prior to becoming pregnant based on elevated urinary free cortisol (UFC) 209 ug/24h (Reference Range (RR) 6 - 42), positive 1 mg dexamethasone suppression test, elevated ACTH 61 pg/mL (RR 0-46). and an 8 x 8 x 8 mm pituitary adenoma on magnetic resonance imaging (MRI). She underwent trans-sphenoidal adenoma resection 3 months prior to becoming pregnant; however, was found to have persistent disease based on a repeat MRI showing a residual 8 x 8 x 9 mm adenoma extending into the cavernous sinus and UFC 290 ug/24h. The patient discovered 6 weeks later that she was pregnant. She was referred to endocrinology at 12 weeks’ gestation, where she was experiencing easy bruising and taking labetalol 400 mg twice daily for HTN. UFC was 768 ug/24h and midnight salivary cortisols were 0.175 and 0.625 ug/dL (RR <0.010 - 0.090). Surgery was deemed to be high risk given the proximity of the tumor to the cavernous sinus and likelihood of residual disease. She was started on metyrapone 250 mg twice a day, and was uptitrated to 1000mg three times daily by the time of delivery with a UFC of 120 ug/24h (goal < 150 ug/24h). Her pregnancy was also complicated by diet-controlled gestational diabetes and cervical insufficiency requiring cerclage. Otherwise, her HTN was well controlled on labetolol and she remained normokalemic. The patient was induced at 37 weeks gestation and was given stress dose steroids along with metyrapone. She delivered a healthy baby boy without any complications. Discussion: CD during pregnancy is a rare disease, with the best outcomes in published cases seen with surgical intervention. This case highlights the use of metyrapone, a steroidogenesis inhibitor, as a sole therapy in cases where surgery is deemed to be high risk and unlikely curative due to location of the tumor. While it is effective in reducing cortisol levels, close surveillance of patients is required for worsening HTN, hypokalemia, and potential adrenal insufficiency. Though no fetal adverse events have been reported, the medication does cross the placenta and longterm effects are unknown.
Neuroinfundibulitis: Pituitary Stalk Thickening Presenting as Diabetes Insipidus
Authors: Patel Payal P , Samson Susan Leanne , Rao Sarika
Published: May 2021

Background: Isolated pituitary stalk thickening (PST) from neuroinfundibulitis is a rare entity that requires thorough evaluation of secondary causes and understanding of treatment options.

Clinical Case: A 55-year-old male presented with progressive polyuria and polydipsia over several months. He had no significant head injuries, headache, weight loss, fatigue or inability to exercise. His serum sodium level was 148 (135 - 145 mmol/L) with a serum osmolality 310 (275-305 mOsm/kg), and urine osmolality was 246 (40-1200 mOsm/kg) suggestive of partial diabetes insipidus (DI). A 24-hour urine collection had a volume of 9.2 liters. He had a normal hemoglobin A1c. Hormonal work-up was unremarkable with normal range his prolactin, IGF-1, and a.m. cortisol (19 mcg/dl). He was already on levothyroxine with normal thyroid function tests and negative thyroid antibodies. Water deprivation testing confirmed a diagnosis of central DI and he was started on desmopressin. Magnetic resonance imaging (MRI) of the pituitary demonstrated diffuse PST with T2 hyperintensity and loss of normal T1 hyperintensity (“bright spot”) of the posterior pituitary. Repeat imaging 3 months later showed progressive thickening. He underwent full body positron emission tomography-computerized tomography (PET-CT) which demonstrated increased metabolism of the pituitary stalk, but no other suspicious uptake in other areas. Chest X-ray, tuberculin screen, angiotensin converting enzyme, and calcium were all normal. Patient underwent transsphenoidal stalk biopsy. Pathology demonstrated fibrosis and chronic inflammation without malignancy but otherwise was nondiagnostic. Based on these findings, he was presumed to have neuroinfundibulitis and is being actively followed with MRIs and labs.

Conclusion: Isolated PST is exceedingly rare, especially in adults. The differential diagnosis includes neoplastic (germinomas, lymphoma, metastatic disease), autoimmune, and infiltrative disease (sarcoidosis, histiocytosis). One review of 38 adult patients with central DI and PST showed that almost half had neuroinfundibulitis. Of those, 4 were treated with corticosteroids and 7 were not. All patients showed reduction or resolution of PST on subsequent MRIs indicating that resolution of thickening can be spontaneous without steroid use, and can be followed by MRI and with hormone replacement for deficiencies (1). Because of the rarity of isolated neuroinfundibulitis, it is important that neoplastic and systemic diseases be ruled out in all patients with PST, as in the case of our patient.

1.Devuyst F, Kazakou P, Baleriaux D, Alexopoulou O, Burniat A, Salenave S, et al. Central diabetes insipidus and pituitary stalk thickening in adults: distinction of neoplastic from non-neoplastic lesions. European Journal of Endocrinology. 2020;183(1):95-105.
Olfactory Neuroblastoma: The Adjunctive Role of Somatostatin Agonists After Surgery
Authors: Toral Fernando Pazos , Martino Maria , Duro David Lobo , Rodriguez Isabel Martinez
Published: May 2021

Clinical Case: A 54 years old woman who had a right-sided nasal obstruction, rhinorrhea, and sometimes purulent discharge in 2016. In 2002 she had hyperthyroidism by Graves disease and treated for two years with remission after that. The examination of the nose revealed a dark red bleeding mass filling the area from the right nasal cavity to the nasopharynx. The biochemical and serum hormonal values were in a normal range. Urine 5 -HIIAA was 2,5 mg/24h. MRI T1 and T2-weighted images revealed a mass of 4,1 x 4,2 cm, slightly higher signal in T2 and isointense in T1, that extended into the right nasal cavity and ethmoidal sinus. A biopsy was performed, which revealed neuroendocrine characteristics. Octreotide scan with SPECT showed an intense nasal uptake. Right internal maxillary artery embolization was performed. In the next two days, the tumor was resected through a right lateral rhinotomy. Histopathological examination revealed olfactory neuroblastoma, score low grade, ki67<2%. Positive immunohistochemical staining to CD56, synaptophysin, NSE, GFAP, calretinin, S-100 and chromogranin A, and negative staining to cytokeratins (CKs) (CKAPM, CKBPM, CK8/18), CD99 and Bcl-2. The resection was almost total, with no octreotide scan uptake. The post-MRI revealed a minimal residual lesion. Lanreotide treatment was introduced after surgery; the dose was 120 mg every four weeks the first year and every 8 weeks after that. No secondary effects or biochemical alterations were observed. In 2020 the octreotide scan again revealed nasal uptake showing local recurrence. This local recurrence was treated with surgery, followed by lanreotide 120 mg every 4 weeks. No residual disease has been found afterward. Discussion: A limited number of cases have been reported, but none of them were treated with somatostatin agonists. As in our case, the majority of the ON is slow-progressive and non-secreting. The patients mainly complain of local symptoms such as nasal congestion. Surgery is considered to be the first-line treatment for localized disease. In the case of a close margin of the lesion or a residual tumor, the recommendation was radiotherapy or chemotherapy for more advanced disease. We confirmed that the tumor expressed somatostatin receptors. The octreotide scan has been found helpful in the diagnosis and follow-up. We treated the patient with lanreotide with no progression of the disease for three years. Local recurrence could be treated with surgery, following by lanreotide treatment, no residual disease has been found to date. The somatostatin analogs may be a useful adjuvant therapy for stable disease without evident residual disease after surgery.
Pituitary Apoplexy and Fulminant Liver Failure
Authors: Khan Mehvish , Elias Heather Lisa , Javeed Iqra
Published: May 2021

Pituitary apoplexy is a rare endocrine emergency due to acute infarction or hemorrhage of the pituitary gland. It most often involves an underlying adenoma. Precipitating factors include hypertension, major surgery, coagulopathy, or medications. Fulminant liver disease giving rise to a coagulopathy can lead to an increased risk of hemorrhage into the pituitary. A 20-year-old female was transferred from British Overseas Territory for evaluation of fulminant liver failure after presenting with worsening of longstanding abdominal pain and vomiting. She was taking ciprofloxacin and metronidazole for colitis and Tylenol for pain. She denied alcohol abuse, illicit drugs or herbal supplements. Her blood pressure was 107/72 mmHg and physical exam was notable for jaundice. Labs were significant for Alanine Aminotransferase (ALT) 10277 IU/L (n<35 IU/L), Aspartate aminotransferase (AST) 10886 IU/L (n<40 IU/L), total bilirubin 15 mg/dl (n<1.2 mg/dl), alkaline phosphatase 160 IU/L (n<115 IU/L) and INR 4.9 (n<1.3). She was given 100 mg of methylprednisolone. CT head without contrast (WO) completed prior to transfer showed no abnormal findings. The next day, she reported new onset severe headache and diplopia. Bilateral wrist asterixis and worsening lethargy was noted on exam. Ammonia was 278 umol/L (<n 42 umol/L). CT head WO showed a 0.6 x 0.9 x 1.0 cm hyperdense area in the posterior aspect of pituitary gland concerning for apoplexy. Additional labs showed cortisol 11 ug/dL (n<22 ug/dL), ACTH 2.9 pg/mL (n 7.2-63.3 pg/mL), TSH 0.04 uIU/mL (n 0.3-4.5 uIU/mL), free (F) T4 1.4 ng/dl (n 0.6-1.5 ng/dl), FT3 1.2 ng/dl (n 2.4-4.2 ng/dl), FSH 1.8 mIU/ml (n 3.5-12.5 mIU/ml), LH <0.1 mIU/mL (n 2.4-12.6 mIU/ml), prolactin 49 ng/mL (n 5-23 ng/mL), and IGF-1 141 ng/mL (n 109-372 ng/mL). She was managed conservatively with hydrocortisone for secondary adrenal insufficiency and hypopituitarism. With extensive work up, no underlying cause was found for her fulminant hepatic disease. She underwent a deceased donor liver transplant. Perioperatively, she was given 200 mg methylprednisolone which was subsequently tapered to 5 mg prednisone. Postoperative course was complicated by a new right parietal lobe hemorrhage. There was no change in pituitary hemorrhage size. As her FT4 trended down to 0.6 ng/dl, along with suppressed TSH, she was started on 50 mcg of levothyroxine. Upon discharge, she was advised to follow with an endocrinologist and have her hormones revaluated once the acute phase has resolved. Pituitary apoplexy as a consequence of coagulopathy caused by liver failure has not been described before. Although she was given methylprednisolone which can suppress ACTH for up to 48 hours, ACTH deficiency is the most critical endocrine dysfunction and is present in nearly 70% of cases of pituitary apoplexy. Therefore, urgent treatment of secondary adrenal insufficiency is warranted along with thyroid hormone replacement.
Pseudopheochromocytoma as a Presentation of Amyotrophic Lateral Sclerosis
Authors: Castellanos-Diaz Jessica , Edwards Catherine M , Ghayee Hans Kumar
Published: May 2021

Introduction: Pseudopheochromocytoma presents as paroxysmal events of hypertension and other noradrenergic symptoms similar to pheochromocytoma (PCC) but do not meet tumoral diagnosis. Case Report: A 70-year-old Caucasian male with history of gastroesophageal reflux disease (GERD) and Barrett’s esophagus presented to the Emergency Department with fatigue, shortness of breath, palpitations, and fasciculations in the anterior chest wall. He reported recent diagnosis of PCC. Patient had episodes of non-exertional palpitations, diaphoresis, dizziness, facial flushing, and facial involuntary movement along with self-monitored average blood pressure (ABP) of 160/100 mmHg and heart rate (HR) of 90 beats per minute (bpm). Spells occurred 2 to 3 times per month at first, later increased. Between episodes self-monitored ABP was 120/70 mmHg and HR of 50 bpm and asymptomatic. He reported unintentional weight loss of 40 pounds in the same interval and newly muscle weakness that he attributed to weight loss and malnutrition. Patient had no remarkable past medical history. Medications included coq10 enzyme, glucosamine, flax seed oil, primrose oil and recently added doxazosin 1 mg tab per day. Evaluation revealed a cachectic patient (body mass index 17.46 k/m2) with normal vital signs, otherwise unremarkable physical exam except for diffuse fasciculations in chest and upper extremities. Outpatient work up included normal complete blood count, comprehensive metabolic panel, drug screening, thyroid function test. He had elevated free plasma metanephrine (FPM) of 73 pg/mL (< 57 pg/mL), free plasma normetanephrine (FPN) of 487 pg/mL (<148 pg/mL), before doxazosin. Repeated FPM of 55 pg/mL (< 57 pg/mL), FPN of 347 pg/mL (<148 pg/mL). The 24-hour urine for metanephrine was normal with total metanephrine of 157 ug/d (55-320 ug/d) and normetanephrine 432 ug/d (114-865 ug/d) with a creatinine of 900 mg/dL (800-2100 mg/d). He also had outpatient computed tomography (CT) scan of thorax, abdomen, and pelvis that was normal. Positron emission tomography CT scan did not reveal any tumors. Our initial suspicion, later confirmed with electromyography, was a neurodegenerative disease with motor neuron dysfunction. Patient was diagnosed with Amyotrophic Lateral Sclerosis (ALS) and started in riluzole with improvement of spells. Since, his muscle weakness progressed, he now requires noninvasive ventilation. Discussion: Pseudopheochromocytoma is an idiopathic disease that mimics catecholamine-secreting PCC and needs adequate and complete evaluation. Catecholamine levels can be affected by illness, stress, medications, and sample collection. In the case presented, the patient’s muscular weakness and fasciculations was caused by ALS. Neurodegenerative diseases such as ALS can cause a central nervous system stress response, consequently causing elevated norepinephrine levels.
Recurrent Head and Neck Adenocarcinoma Presenting With a Pituitary Mass
Authors: Alpertugna Ipek , Safain Mina , Tracy Jeremiah , Tischler Arthur , Lechan Ronald M
Published: May 2021

Background: Metastasis to the pituitary gland is a rare condition. Only 1.8% of all surgically resected pituitary masses are metastases with the majority originating in the breast and lung (1). Salivary gland tumors rarely metastasize to the brain and only a few cases have been reported in the literature. Clinical Case: A 61 year-old woman presented to an outside emergency department with horizontal diplopia, blurry vision and left-sided sharp frontal headaches. MRI of the head showed a large, 2.0 x 4.6 x 1.8 cm sellar/suprasellar mass involving both cavernous sinuses, encasing the right internal carotid artery which was narrowed, and compressing the optic chiasm. Her past medical history was significant for adenocarcinoma of the left buccal mucosa and masseteric space, treated with resection in 2016, and a second resection in 2018 for recurrence followed by radiation therapy. Areas were identified where focal perineural invasion was present. She was referred to our institution for treatment recommendations for the sellar/suprasellar lesion. Laboratory testing revealed secondary hypothyroidism, adrenal insufficiency and partial diabetes insipidus, and she was started on replacement hormone therapy with levothyroxine and hydrocortisone. Neurosurgery and ENT evaluated patient and a surgical biopsy and subtotal resection via an endoscopic endonasal transsphenoidal approach was recommended for diagnosis and possible decompression of the optic chiasm. The final pathology was consistent with metastatic, high grade adenocarcinoma, supported by positive mucicarmine stain for mucin, positive immunohistochemical stain for CAM 5.2 and CK7 and negative immunohistochemical stains for the pituitary transcription factors, PIT-1 and SF-1. Conclusion: We report the second case in the literature of adenocarcinoma of the head and neck to the pituitary gland. In our case, radiological appearance of the tumor together with patient’s malignancy history led to the consideration of a pituitary metastasis. Tumors invading the cavernous sinus and causing internal carotid artery compression are rarely pituitary adenomas (2). Presence of these imaging features in patients with known risk factors for malignancy should raise suspicion for pituitary metastasis. The route of spread from the masseteric space to the sellar region remains unclear. Tumor metastasis can occur through direct invasion, hematogenous spread and perineural spread. Hematogenous spread and/or perineural spread along the trigeminal nerve are the most likely routes of metastasis in this case.

Reference: (1)Javanbakht A, D’Apuzzo M, Badie B, Salehian B. Pituitary metastasis: A rare condition. Endocr Connect 2018; 7(10):1049-1057. PMID: 30139817.

(2)Molitch ME et al (2012) Tumors invading the cavernous sinus that cause internal carotid artery compression are rarely pituitary adenomas. Pituitary 15(4):598–600
Early Follow-up of Atypical Thyroiditis Induced by SARS-CoV-2
Authors: Muller Ilaria , Cannavaro Daniele , Dazzi Davide , Mantovani Giovanna , Longari Virgilio , Cuzzocrea Marco , Re Tiziana E , Gori Andrea , Arosio Maura , Salvi Mario Giovanni
Published: May 2021

Background: In Spring 2020 the severe acute respiratory syndrome coronavirus 2 pandemic disease (Covid-19) badly affected Northern Italy. We have described for the first time the occurrence of thyrotoxicosis due to atypical subacute thyroiditis in 15% of patients hospitalised for Covid-19 pneumonia, compared with only 1% among patients hospitalised in the same wards during Spring 2019, thus before the Covid-19 pandemic. The whole group of Covid-19 patients also had median serum TSH concentrations significantly lower compared with the control group. The atypical thyroiditis induced by Covid-19 is not associated with neck pain, affects more men than women and especially those severely ill, thus coexists with non-thyroidal illness syndrome. Subacute thyroiditis is classically followed by subsequent occurrence of permanent thyroid dysfunction and autoimmunity, thus we have started a systematic follow-up program of these patients.

Methods: Longitudinal follow-up study of survived Covid-19 patients without previous known history of thyroid disorders and/or medications, assessing serum thyroid function and autoantibodies, C reactive protein (CRP), full blood count (FBC) and thyroid ultrasound (US) every 3 months. Patients showing baseline (at hospitalisation for Covid-19) thyroid dysfunction and/or focal hypoechoic areas suggestive for subacute thyroiditis at US performed 3 months post-infection, also underwent thyroid 99mTc or I123uptake.

Results: To date, 53 patients have been included in the follow-up study. At 3 months post-infection, all of them presented with increased median (IQR) serum TSH concentrations compared with baseline: 1.3 (0.9–2.0) mIU/L versus 0.9 (0.5–1.8) mIU/L (p=0.0001). Similarly, serum concentrations of free-thyroxine, free-triiodothyronine, CRP and FBC had normalised compared with baseline. All patients had negative autoantibodies to TSH receptor; autoantibodies to thyroglobulin and to thyroid peroxidase were positive in 6/53 (11%) and 5/53 (9%) of patients, respectively. The thyroid US showed the presence of focal hypoechoic areas of thyroiditis in 16/51 (32%) patients, with thyroid uptake normal in 6/16 (37%), focally reduced in 8/16 (50%) and diffusely reduced in 2/16 (12%).

Conclusions: At 3 months after Covid-19 disease all patients had a normalised thyroid function, however imaging findings suggestive for subacute thyroiditis were still present in about one third of cases. The thyroid dysfunction induced by Covid-19 seems not mediated by autoimmunity. It is important to continue to follow these patients since they might develop thyroid dysfunction during the following months.
Severe Symptomatic SIADH as a Sign of Unknow Hypopituitarism: A Case Report
Authors: Marques-Sá Juliana , Araújo Catarina Silva , Santos Maria Joana
Published: May 2021

Background: SIADH due to secondary adrenal insufficiency is a rare condition that can be life-threatening. Treatment with glucocorticoids is highly effective, but, as symptomatology of hypopituitarism can be mild and unspecific, a high level of clinical suspicion is necessary.

Clinical Case: A 64-year-old postmenopausal woman, with a previously diagnosed and treated hypothyroidism and depressive syndrome, presented at the emergency room with nausea, vomits, asthenia and recurrent syncopes over the past three weeks and weight loss in the last months. One week before, she had been admitted at other hospital due to the same complaints and a serum Na+ of 112mmol/L (N 135-145 mmol/L) was detected. One year earlier, she had reported the same symptomology and hyponatremia had also been found, but no etiologic study was performed. At admission, she was conscient, hydrated, pale, hemodynamically stable, with unremarkable cardiopulmonary auscultation. A severe hyponatremia was found (Na+ 111mmol/L), with low serum osmolarity (241mOsm/Kg, N 280-301mOsm/Kg), low urine osmolality (125mOsm/kg N 300-900 mOsm/Kg) and low urinary sodium (33mmol/24h, N 40-220mmol/24h). Treatment with saline fluids was initiated and the patient was admitted for etiological investigation, which showed a low morning serum cortisol (3.7 µg/dl)) with inappropriately low-normal ACTH level (12.2 pg/mL), low FSH (15.07 mUI/mL, N 23.0-116.3 mUI/mL) and LH (4.28 mUI/mL, N 15.9-54 mUI/mL), estradiol of 78.81 pmol/L (N <118.2 pmol/L), undetectable IGF-1 (<25 ng/mL, N 36-244 ng/mL) and PRL of 21.98 ng/mL (N 1.8-20.3 ng/mL). Under 50µg of levothyroxine, TSH was 2.5 µUI/mL (N 0.358-3.74 µUI/ml), and FT4 was 1.1 ng/dL (N 0.76-1.46 ng/dL). Anti-thyroglobulin and anti-TPO antibodies were negative. A pituitary MRI revealed an empty sella with arachnoidocele. Other differential diagnosis of SIADH were excluded. The patient was started on oral hydrocortisone 30 mg/day, with a remarkable recovery, with better mood, more energy and appetite, resolution of all symptoms and normalization of the natremia.

Conclusion: Hypopituitarism due to an empty sella is a relative rare disorder, whose etiology may be difficult to prove. It usually develops insidiously, with unspecific symptoms, which often delays the diagnosis. In our patient, this severe hyponatremia likely developed over a long time, allowing adaptation to such low levels of Na+. Moreover, the presence of a previously diagnosed hypothyroidism raises the suspicion if this wasn’t the first manifestation of the pituitary disease and if treatment of levothyroxine did not worsen an undetected secondary adrenal insufficiency.
Successful Pregnancies in an Acromegalic Woman After Non-Radical Pituitary Adenomectomy for Somatoprolactinoma
Authors: Gatzk Arruda Anna Catarina , Outuki Giovana , Dias Marcos Antonio , Carrilho Alexandre Jose Faria , Mazzuco Tania Longo
Published: May 2021

Background: Pregnancy is unusual in patients with acromegaly due to somatotropinomas or somatoprolactinomas. Fertility is impaired because of hormonal hypersecretion, pituitary damage by tumor compression or both. Managing somatoprolactinomas and fertility issues are often challenging.

Clinical Case: A 20-year woman with primary amenorrhea and headache was diagnosed with hypogonadotrophic hypogonadism secondary to hyperprolactinemia (2500 µg/L, n<23 µg/L). No other abnormalities were found on the pituitary function screening tests. MRI revealed an intra and suprasellar adenoma (2.5x1.8x1.8 cm) with optic chiasm compression. The onset of menses occurred after 11 months under dopaminergic treatment, and tumor size diminished (1.9x1.5x1.5 cm), bringing on optic chiasm decompression. She remained under dopamine agonist treatment for 6 years, when she realized extremities enlargement and height increase by 3 cm. Acromegaly was confirmed by blood levels of IGF-1 (3.37xULN), GH (8 µg/L, n<8 µg/L), and GH nadir (4.3 µg/L, n<1 µg/L) during OGTT. Then, octreotide LAR was added to cabergoline treatment while waiting for elective surgical treatment. She underwent to transsphenoidal endonasal neurosurgical microscopy approach guided by neuronavigation, with the removal of a large portion of tumor. However, it was not possible to extract the part of invasive adenoma close to right carotid artery due to the risk of vascular and intracavernous cranial nerves injury. Immunohistochemistry analysis of the adenoma was positive only for GH cells with low Ki67 index (<1%). Due to the poor biochemical control (unsuppressed post-OGTT GH, IGF-1 1.66xULN and PRL 301 µg/L) and the presence of a small stable tumor residue, treatment with cabergoline and somatostatin analogues was maintained (3-year octreotide LAR, transitioned to lanreotide in an attempt to achieve a better biochemical response). After 14 years of the initial diagnosis and 5 years post-surgery, the patient expressed the desire to get pregnant and all medications in use were suspended. In the following 3 years, she had two uneventful gestation without complications or worsen of acromegaly; she only breastfed for few months after her first pregnancy. The second one was a twin pregnancy. After one year, the MRI revealed no increase of tumor mass (1.0x0.3x1.0 cm), and PRL levels withing normal range, IGF-1 slightly elevated, but GH not suppressed by OGTT. Cabergoline was reintroduced and the biochemical control of acromegaly was achieved.

Conclusion: We reported the very unusual spontaneous conception and normal course of pregnancies in a woman with acromegaly, who was submitted to successful transsphenoidal neurosurgical microscopy approach in which large part of the tumor was removed and the normal pituitary tissue was preserved, allowing fertility restoration.
Surgical Remission of Acromegaly Resolves Neuroglycopenia and Paradoxical Rise in GH after OGTT
Authors: Magar Maria , Carmichael John
Published: May 2021

Background: Acromegaly is known to cause insulin resistance through increased gluconeogenesis and reduction in peripheral glucose use; however, hypoglycemia related to acromegaly has not been reported.

Clinical Case: A 58-year old man presented for evaluation of several elevated serum IGF1 levels. The patient had reported years of increased body heat but no changes in his hands or feet and no voice deepening. He recently needed 15 dental crowns due to gaps in his teeth. He also had difficult to manage OSA and weight gain. The patient reported neuroglycopenia after a high glycemic meal or drink, although he was never able to objectively measure any low blood glucoses when they occurred; these symptoms improved but did not resolve despite adhering to a low carbohydrate diet. He also had decreased libido and erectile dysfunction. Exam was significant for coarse facial features. Prior testing revealed several elevated IGF1 serum levels, the last one being 227 ng/mL (54-194). One year prior, OGTT resulted in an initial GH level of 0.1 ng/mL with a decrease to <0.1 ng/mL after two hours. Repeat OGTT had an initial GH of 2.98 ng/mL which paradoxically rose to 12 ng/mL. Fasting BG was 90 mg/dL and peaked at 171 mg/dL. Pituitary MRI showed a 5 mm microadenoma, consistent with acromegaly from a GH secreting adenoma. He underwent a TSSC, and his heat intolerance, low libido, and symptom of hypoglycemia resolved completely. Subsequent IGF1 levels and MRI imaging normalized. Postoperatively OGTT showed a peak GH of 0.23 ng/mL with a peak glucose of 134 mg/dL. There was no paradoxical rise in GH.

Discussion: Acromegaly is commonly associated with insulin resistance in ~30% of cases; however, there are no reports of associated neuroglycopenia after a carbohydrate-rich meal or OGTT, which in our patient resolved after successful removal of the pituitary microadenoma. His low glucose symptoms could have been a result of reactive hypoglycemia, which is often seen in patients with diabetes or even prediabetes. However this patient had no history of either. He did not have evidence of any tumors causing hypoglycemia and no gastric surgery to suggest a related etiology (e.g, dumping syndrome or nesidioblastosis). Conversely since GH is normally anabolic and stimulates insulin release, the patient’s elevated GH may have caused an abnormal increase in insulin, leading to his hypoglycemia symptoms. Indeed GIP, which stimulates insulin, is thought to be the cause of the paradoxical rise in GH seen in 30% of acromegaly cases. Remarkably, the patient’s hypoglycemia symptoms disappeared after treatment of the acromegaly, which leads us to consider that excess GH was the culprit.
Characteristics of Pituitary Tumors Including Non-Functioning Tumors - a Tertiary Care Center Experience
Authors: Kumbar Lohit , Dharmalingam Mala
Published: May 2021

Introduction: Pituitary tumors compromise 10-20% of intracranial tumors. Non-functioning pituitary adenomas (NFPAs) are benign neoplasms which constitutes about 1/3rd of the pituitary tumors. There is few data on the characteristics of non-functioning tumors comparing with functioning tumors. Wide spread availability of MRI has eased the diagnosis of non-functioning tumors and early diagnosis. Objectives: To study the characteristics of pituitary tumors and the incidence of non-functioning tumors and compare with functioning tumors presenting to a tertiary care center. MethodsA retrospective study including 146 individuals with pituitary tumor were included from 2014 to 2020. Results: The study included 62(42.5%) male and 84(57.5%) female. The mean age was 41.97 + 13.93 years in males and 39.88 + 16.12 years in females. The mean duration of symptoms prior to presentation was 7.52 + 7.12 months and 10.37 + 11.60 months in males and females respectively. Macroadenoma (size >1cm) incidence was more with 55(88.7%) in males and 58(69%) in females. More number of males (87.1%) underwent surgery when compared to females (64.3%)(p – 0.002). There was more number of suprasellar and invasion of pituitary tumors seen in males compared to females(P- <0.01). There was no significant difference between various parameters like TSH, T4, LH, FSH, prolactin, Electrolytes, cortisol, ACTH, GH and IGF1 between males and females(p- NS). Seventy percent (103) of them were non-functioning tumors. Functioning tumors included 7(4.8%) acromegaly, 8(5.5%) cushings disease, 2(1.4%) gonadotropinoma, 24(16.4%) prolactinoma and 2(1.4%) posterior fossa tumor. Mean age in non- functioning tumors was 43.74 + 15.5 years. Mean diameter of tumor in non-functioning tumors was 21.04 + 11.54 cm when compared to functioning tumors (17.03 + 10.33 cm)(p- 0.61). Most of the patients with non-functioning tumors who underwent surgery received post operatively hydrocortisone and levothyroxine when compared to patients with functioning tumors(p < 0.01). There was no significant difference in terms of gender, suprasellar extension, invasion and pituitary hormones(p-NS). ConclusionMost of the pituitary tumors in our study were macroadenomas with more number of males undergoing surgery as most of them had suprasellar extension and invasion. Non- functioning tumors should be followed up regularly as most of them required hydrocortisone and levothyroxine post-operatively.
Immunohistochemical Profile of Nonfunctioning Pituitary Adenomas
Authors: Solovey Mariana , Guk Mykola , Danevych Olena
Published: May 2021

Background: Nonfunctioning pituitary adenomas (NFPAs) are neuro-endocrine tumors without clinical and laboratory signs of anterior pituitary hormonal hypersecretion. The recent World Health Organization classification is based on the adenohypophyseal cell lineages and requires immunohistochemical evaluation of adenohypophyseal hormones and pituitary transcription factors. There are few data regarding the age and sex prevalence of different cell-types nonfunctioning adenomas and clinical data correlations. Objective: To discover the immunohistochemical profile of large cohort of NFPAs. Materials and Methods: The study includes 100 consecutive cases of endoscopically transsphenoidally removed nonfunctional pituitary adenomas, immunohistochemically assessed for anterior pituitary hormones and transcription factors. Clinical presentation, imaging, laboratory hormonal data and immunohistochemical staining features have been analyzed. All patients (64 women and 36 men) have been divided into four age groups: 20-34 (A) years old, 35-44 (B) years old, 45-59 (C) years old, 60-70 (D) years old. Peculiarities of immunohistochemical profile have been statistically analyzed in those age groups. Results: Most tumors (97%) were macroadenomas with mass effect symptoms. In the groups of silent corticotroph and Pit-1 adenomas most of the patients had subclinical symptoms of hormonal hypersecretion. The proportions of silent gonadotroph adenomas have appeared to be increased with age with predominant prevalence in group D (60%) in women and group C (78, 6%) in men. The proportions of silent Pit-1 adenomas decreased with age with maximum rate in group A (77,8%) in women and in group A (50%) in men. The incidence of silent corticotroph adenomas was different: increasing with age in women with maximum (36,8%) in group C and decreasing from young age (30%-0%) in men age groups B-D respectively. Plurihormonal pituitary adenomas from different cell lineages were found only in women, with maximum incidence rate (17,6%) in group B. The incidence of “null cell” adenomas didn’t differ in men and women in group B and C but was much more higher in men in groups A and D (16,7% vs 0% and 33% vs 6,6% respectively). Conclusions: The different age and sex prevalence of NFPAs, revealed in our study, may be helpful in diagnosing and optimal treatment of NFPAs.
New Transcriptional Insights into Silent and Active Corticotroph Pituitary Tumors at Single Cell Resolution
Authors: Zhang Dongyun , Hugo Willy , Bergsneider Marvin , Wang Marilene B , Kim Won , Vinters Harry , Heaney Anthony P
Published: May 2021

Silent pituitary corticotroph tumors derive from the Tpit (aka TBX19) pituitary lineage. Accounting for ~ 30% of corticotroph tumors, they are not infrequently clinically aggressive and invade locally into adjacent sellar structures, making complete surgical resection challenging and contributing to their higher recurrence rates. How silent and active corticotroph tumor subtypes differ is not clear although some studies reported that silent corticotroph tumors exhibit reduced PC1 expression causing impaired POMC processing. We used single cell RNAseq to compare the transcriptome between silent (n = 2) and active (n = 4) corticotroph tumors at the single cell level. We obtained an average of 265 million reads, and 24,682 genes per patient with an average of 1,240 genes expressed and 3,5442 unique molecular identifiers (UMIs) detected per cell. We further defined 5 distinct cell populations from a total of 23,269 cells, namely tumor cells (62%), stromal cells (25%), immune cells (7%), progenitor cells (5%), and a minor population of erythrocytes (1%). Tumor cells clustered in an origin-dependent manner and all expressed POMC and TBX19. However, the gene signatures of silent and active corticotroph tumors differed in 3 major aspects. Firstly, and supporting prior studies, a series of hormone processing peptidase genes, including PC1 (aka PCSK1), PDIA3, SEC11C, SPCS1 and CTSB, were reduced in silent corticotroph tumors (p=5.54e-5) compared to active corticotroph tumors. Secondly, genes involved in organization of secretory vesicles such as SCG5, TIMP1, VGF, SYT17, LGALS3 and CALY were also reduced in silent corticotroph tumors, which could further compound their inability to secrete ACTH. Thirdly, the silent corticotroph tumors exhibited several features of endothelial-to-mesenchymal transition (EMT), including increased expression of the mesenchymal genes CDH2 (aka NCAD), COL1A1, PCDH9, FGF5, ID2 (p=8.4e-3), and loss of EPCAM, which regulate cell migration and movement. Upstream analysis suggested that aberrant STAT3 activation may be related to these changes. Consequently, we noted that the stromal content was higher in silent corticotroph tumors (47.5% vs. 18.13%), concordant with the observed EMT de-differentiation of tumor cells. In summary, our scRNAseq analysis provides an unprecedented precise investigation of the transcriptomic features of thousands of heterogenous corticotroph tumor cells simultaneously. We demonstrate that although silent corticotroph tumor cells still express the pituitary lineage markers PITX1 and TBX19, they exhibit EMT, potentially affording increased migratory capacity at the cost of reduced neuroendocrine function with inability to produce and secrete mature ACTH. Our findings provide novel insights into the pathogenesis of silent versus active corticotroph tumor, but may reveal novel molecular targets for treatment of these challenging tumors.
The Secret Behind Anemia in Patients With Acromegaly
Authors: Firlatan Busra , Sendur Suleyman Nahit , Oguz Seda Hanife , Dagdelen Selcuk , Erbas Tomris A
Published: May 2021

Introduction: The GH/IGF-1 axis has regulatory effects on erythropoiesis. GH deficiency is associated with normocytic anemia in adults, and hemoglobin (Hb) concentrations are normalized after GH replacement. Little is known about the significance of anemia in acromegalic patients. The aim of this study is to evaluate the factors associated with anemia in patients with acromegaly.

Methods: A single-center retrospective cohort study was conducted. A total of 381 acromegalic patients who admitted to the University Hospital from 1980 to 2018 were included. Information regarding the demographic features, the pre-operative and follow-up hormone levels, radiological features of adenoma, treatment modalities, comorbidities, presence of cancer, colonoscopy results, medication history, presence and type of anemia together with the CBC, iron parameters, 25(OH)D, and vitamin B12 levels at the time of anemia detected were retrieved from the patient record system. Anemia was defined as Hb levels <12.0 g/dL in women and <13.0 g/dL in men.

Results: Of 381 acromegalic patients (120F/98M, age: 44±13yr/45±12 yr); 218 cases (57.2%) were diagnosed with anemia (67% normocytic, 33% microcytic) at a median duration of 6 months after the diagnosis of acromegaly. Hb values were 11.1±0.9 g/dL in women and 12.1±1.0 g/dL in men. Serum levels of ferritin and transferrin saturation were lower in anemic patients (p<0.001). The levels of 25(OH)D and vitamin B12 were lower in the anemic group, but the differences were not statistically significant. Anemia was detected more likely in patients who had macroadenoma (p=0.001), suprasellar extension (p=0.001), and cavernous sinus invasion (p<0.001) on pre-op MRI and residue tumor (p<0.001) on post-op MRI. Patients with anemia had higher GH, IGF-1 and PRL levels (p<0.01), and there was a significant difference related to the use of octreotide (p<0.001). Anemia was observed more frequently in patients with a history of radiotherapy (29% vs. 10%, p<0.001). Hypopituitarism was seen in 63 (29%) patients in the anemic group and 21 (13%) patients in the non-anemic group (p<0.001). Cancer prevalence in the study population was 14.2%, and the most commonly diagnosed cancers were thyroid, bladder, prostate, and breast. Although not statistically significant, the prevalence of cancer was higher in anemic patients compared to non-anemic patients (17% vs. 10%). There was no significant difference regarding the presence of colorectal polyps between groups, and only two anemic patients were diagnosed with colon cancer.

Conclusion: This is the first study highlighting that anemia is a common comorbidity in patients with acromegaly, and that anemia can be related to characteristics of the tumor, hormonal status, type of treatment, and the presence of cancer in addition to nutritional factors. Therefore, a comprehensive evaluation is required for anemia in acromegalic patients.
Transcription Factor Immunohistochemistry in the Diagnosis of Pituitary Tumors
Authors: Lenders Nele F , Wilkinson Adam C , Wong Stephen J , Shein Tint T , Harvey Richard J , Inder Warrick J , Earls Peter E , McCormack Ann I
Published: May 2021

Objective: The clinical utility and prognostic value of WHO 2017 lineage-based classification of pituitary tumors have not been assessed. This study aimed to (1) To determine the clinical utility of transcription factor analysis for classification of pituitary tumors and (2) To determine the prognostic value of improved lineage-based classification of pituitary tumors. Methods: This was a retrospective evaluation of patients who underwent surgical resection of pituitary tumors at a tertiary referral centre between 1990 and 2016. Included patients were at least 18 years of age and had complete histopathological data, forming the “histological cohort”. Patients with at least 12 months of post-surgical follow up were included in the subgroup “clinical cohort”. The diagnostic efficacy of transcription factor immunohistochemistry in conjunction with hormone immunohistochemistry was compared with hormone immunohistochemistry alone. The prognostic value of identifying “higher risk” histological subtypes was assessed. Results: There were 172 patient tumor samples analyzed in the histological cohort. Of these, there were 96 patients forming the clinical cohort. Subtype diagnosis was changed in 24/172 (14%) of tumors. Within the clinical cohort, there were 21/96 (22%) patients identified with higher risk histological subtype tumors. These were associated with tumor invasiveness (p=0.032), early recurrence (12-24 months, p=0.016), shorter median time to recurrence (38 [IQR 20-68.5] v 15 [IQR 12-27.25] months, p=0.02) and reduced recurrence-free survival (p=0.023). Conclusions: Application of transcription factor analysis, in addition to hormone IHC, is associated with improved diagnostic information.