bluuebunny/crossref_metadata_2025 huggingface dataset:
Unmasking of Neurosarcoidosis
Authors: Venugopal Sharini , Neupane Binita , Nepal Mahesh , Chavez Luis F
Published: May 2021

Introduction: Central diabetes insipidus is a rare complication of neurosarcoidosis. In patients with concomitant adrenal insufficiency (AI), the symptoms of Diabetes Insipidus (DI) can be masked. Case: A 55-year-old female with past medical history of sarcoidosis presented to the hospital with hematemesis, nausea and dizziness. She has a past medical history of cardiac sarcoidosis that was revealed on a PET scan done before 10 years for which she was being treated with methotrexate and prednisone. She was off prednisone for a year prior to hospitalization. She underwent an upper endoscopy that showed diffusely erythematous gastric mucosa in the antrum. She was also hypotensive on admission, and she received packed red blood transfusions after which her sodium increased from 145mmol/L to 165mmol/L (Normal: 135-145mmol/L) in 48 hours. Further workup revealed persistent hypernatremia and urine osmolality was 75mOsm/kg H2O. (Normal: 50-1200mOsm/kg H2O). She was also hypoglycemic and hypotensive requiring multiple fluid boluses throughout her hospitalization. This prompted us to perform a random cortisol that came back at 2.1ug/dl (Normal: 3-23ug/dl) and 1.8ug/dl on two occasions. Cortisol Stimulation test was subsequently ordered, but was done only at 30 minutes, and Cortisol increased from 1.8ug/dl to 6.3ug/dl. Free thyroxine was 0.5 ng/dl (Normal: 0.9-1.8 ng/dl) and her TSH was 7.58uIU/ml (Normal: 0.55-4.78uIU/ml). MRI of the brain revealed extensive areas of extra-axial supra-sellar/infundibular nodular homogeneous intense enhancement that is most consistent with neuro-sarcoid. She was started on prednisone 40 mg daily, Desmopressin 0.05 mg twice daily, and levothyroxine as well. Her sodium level normalized and was 137mmol/L at discharge. She followed up later with outpatient Endocrinology and reported around 90lbs weight gain and no more episodes of nausea or vomiting or epistaxis or lightheadedness. Conclusion: The involvement of the hypothalamic-pituitary axis in sarcoidosis is extremely rare and attributes to < 1% of patients with a sellar mass. Small case series have shown that hypogonadism is the most common endocrine abnormality followed by DI. Our patient had a long-standing history of sarcoidosis with her pituitary dysfunction unmasked only on admission for other causes. She did not manifest any symptoms of DI or AI. There have been case reports where the symptoms of DI are masked due to underlying glucocorticoid deficiency. There have been theories that glucocorticoid deficiency impairs renal water excretion by both ADH (Anti-diuretic hormone) dependent and ADH independent pathways. Another notable feature in our case is that our patient presented with primary hypothyroidism. In fact, sarcoidosis has been commonly implicated in auto-immune polyglandular syndromes type 3, which can present with auto-immune thyroiditis more so in females.
Weiss-Kruszka Syndrome With Unreported Manifestations; Empty Sella Syndrome Associated With Growth Hormone Deficiency
Authors: Park Jisun , Kim Su Jin , Seo GoHun , Lee Ji-Eun
Published: May 2021

Objective: Weiss-Kruszka syndrome (WSKA; MIM#618,619) is a rare, autosomal dominant disorder associated with zinc finger protein 462 (ZNF462) gene variation or deletion of 9q31.2 involving ZNF462 and various congenital anomalies. Its specific clinical findings are abnormal facial shape, prominent forehead, high arched eyebrow, ptosis, delayed development of motor and language and mild global developmental delay. The prevalence of WSKA is only 25 individuals from literatures. Brain lesions related to WSKA are known as ventriculomegaly and middle line brain abnormalities like corpus callosum hypoplasia in about 25 percent of the patients. However, there have not been reported a patient who has structural malformation of pituitary gland with endocrine dysfunction. Here, we present a Korean boy molecularly confirmed as WSKA, having newly clinical manifestation of primary empty sella syndrome(ESS) associated with growth hormone deficiency(GHD).

Case Presentation: A 16-year-old boy visited to our hospital presented with severe short stature and delayed puberty. He also complained mild hypotonia, congenital both ptosis, mild intellectual disability. In the anterior pituitary combined test, GHD was diagnosed. In the brain magnetic resonance image, ESS was showed. With starting and continuing recombinant human growth hormone replacement therapy, to identify the underlying genetic cause, chromosomal microarray analysis and whole exome sequencing test were conducted. Finally, a heterozygous novel frameshift variant, c.4185del(p.Met1396Ter) in ZNF462 confirmed by Sanger sequencing, which had not been reported was identified

Conclusions: This is the first case of WSKA of an Asian with novel pathogenic variant of ZNF462 and new clinical features including primary ESS associated with GHD. This case could contribute to diagnosis of this syndrome, identify clinical features and provided novel insight into studies for the role of ZNF462 gene.
When One Autoimmune Condition Predisposes You to Another!
Authors: Panday Deepika , Jyothinagaram Sathya G , Guo Rong Rong , Correa Ricardo Rafael , Vinales Karyne Lima
Published: May 2021

Introduction: Lymphocytic hypophysitis (LYH) is an autoimmune condition in which pituitary gland is infiltrated by lymphocytes, plasma cells and macrophages. It is more common in pregnant and postpartum women, presenting with headache, visual field changes and one or more pituitary hormone impairment.

Case Presentation: 32year-old female recently diagnosed with RA complicated by uveitis, presented to our facility with headache, shortness of breath, blurred vision and dysphagia. MRI head revealed a 1.9cm sellar mass with suprasellar extension displacing the optic chiasm. There was clear thickening of the pituitary stalk which raised suspicion for autoimmune hypophysitis. Exam in the ED revealed an anxious female wit hypertension, tachycardia and BMI 30. The rest of the physical exam was unremarkable. Her pituitary gonadal axis workup revealed panhypopituitarism with TSH 0.01uIU/ml, FSH <0.3Miu/ml, LH <0.3mIU/ml, ACTH <5pg/ml, IGF-1 31ng/ml and prolactin 14.4ng/ml. She was started on prednisone 50mg daily and on levothyroxine 150mcg daily. On day 2, she developed polyuria and the work up revealed a serum sodium of 146 meq/L, serum osmolality 315mOsm/kg, urine osmolality 281mOsm/kg and urine output 5.6L in 24hrs. The diagnosis of DI was made and she was started on desmopressin. On day 7, the serum sodium normalized and she did not require any other dose of desmopressin. On the day of discharge, a repeat MRI head was done which showed reduced enhancement of the pituitary which was reassuring.

Discussion: LYH is a neuroendocrine disorder characterized by autoimmune inflammation of the pituitary gland with various degrees of pituitary dysfunction. Associated autoimmune diseases are seen in 18%– 50% of cases of AH. The most commonly-associated disease is autoimmune thyroid disease (15%–25%), while concurrent autoimmune conditions including RA are reported as well. Homogenous symmetrical enlargement of the pituitary gland, a thickened non deviated stalk, and a prompt, intense and homogenous enhancement of the mass after gadolinium contrast are the characteristic findings on MRI. Spontaneous resolution is the usual course and surgery is indicated only when the symptoms of sellar compression are serious and progressive.

Conclusion: LYH is predominantly a disease of young females. We present this case in order to create awareness about the co-existence of LH with other autoimmune conditions and its usual course of regression with steroids.
Abnormal Sodium is a Predictor for Respiratory Failure and Mortality in Hospitalized Patients With COVID-19
Authors: Tzoulis Ploutarchos , Waung Julian , Bagkeris Emmanouil , Hussein Ziad , Biddanda Aiyappa , Cousins John , Dewsnip Alice , Falayi Kanoyin , McCaughran P W , Mullins Chloe , Naeem Ammara , Nwokolo Munachiso , Quah Helen , Bitat Syed Rabha , Deyab Eithar , Ponnampalam Swarupini , Bouloux Pierre-Marc Gilles , Montgomery Hugh , Baldeweg Stephanie
Published: May 2021

Background: Hypernatremia and hyponatremia (serum sodium > 145 mmol/L and < 135 mmol/L, respectively) are independent risk factors for excess mortality in patients with bacterial pneumonia. We sought, for the first time, an association of sodium [Na] abnormalities with mortality, need for advanced respiratory support and Acute Kidney Injury (AKI) in hospitalized patients with coronavirus disease 19 (COVID-19). Methods: This retrospective, longitudinal, cohort study included 488 adults, 277 males and 211 females, with a median age of 68 years, who were hospitalized with COVID-19 to two hospitals in London over an 8-week period (February to May 2020). Results: The in-hospital mortality rate was 31.1% with a medial length of stay of 8 days. High [Na] levels at any timepoint during hospital stay were associated with significantly increased mortality rate (56.6% vs 21.1% in patients who remained constantly normonatremic; odds ratio 3.05, 95% CI 1.69-5.49; p<0.0001). On day 3 and on day 6, high [Na] values predicted mortality with an estimated odds ratio of 2.34 (95% CI 1.08 – 5.05, p=0.0014) and 2.40 (95% CI 1.18 - 4.85, p=0.001), respectively. Non-survivors had a significantly higher 5-day rise in serum [Na] when compared to survivors (3.60 mmol/L vs 1.14 mmol/L respectively, p<0.05). Patients with low serum [Na] levels on admission had a 2.18-fold increase (95% CI 1.34-3.46, p=0.001) in the likelihood of needing advanced ventilatory support compared to those with normal [Na] (31.7% vs 17.5%, respectively). However, exposure to hyponatremia at any timepoint, including at presentation or on day 3 or day 5, was not associated with excess risk of

death. AKI affected 37.1% of patients (21.3%, 7.4% and 8.4% stages 1, 2 and 3 respectively) but was not related to serum sodium values. Conclusions: In hospitalized COVD-19 patients, hypernatremia at any timepoint was associated with excess mortality, suggesting that [Na] concentration may facilitate risk stratification. In addition, whilst our data cannot prove causality, these findings highlight the significance of judicious rehydration in such patients.
Acute and Chronic Posterior Pituitary Insufficiency Among Traumatic Brain Injury Patients at a Tertiary Care Center
Authors: Bhat Imtiyaz Ahmad , Bhat Moomin Hussain , Masoodi Shariq Rashid , Bhat Javid Ahmad , Shah Zafar A , Wani Arshad I , Sood Mona , Arif Sajad Hussain
Published: May 2021

Background: Traumatic brain injury (TBI) is the leading cause of death and disability in young adults. Disorders of salt and water balance are the most commonly recognized medical complications in the immediate post-TBI period and contribute to early morbidity and mortality. Objective: We aimed to evaluate the prevalence of acute (during hospital stay) and chronic posterior pituitary dysfunction in patients of head injury admitted at our tertiary care hospital. Study Design: Prospective, Observational study. Participants: 136 patients, attending tertiary care in North India with TBI with radiological evidence of head injury. Methodology: The severity of brain injury was assessed by the Glasgow Coma Scale (GCS), and Modified Rankin Scale (MRS) score at the time of admission. Lab measurements, apart from routine CBC and biochemical tests, included tests of serum and urinary osmolality, serum sodium, cortisol, and thyroid function test during the hospital stay. All patients were monitored closely during the hospital stay. Surviving patients were evaluated at 3, 6, and 12 months of follow-up. Urinary output and water deprivation tests were done to determine chronic posterior pituitary dysfunction. The results were compared against normative data obtained from 25 matched, healthy controls. Serum & urinary osmolality was measure by the freezing point method. Diabetes insipidus (DI) and Syndrome of inappropriate ADH secretion (SIADH) were diagnosed according to standard criteria. Results: Of 136 patients admitted, 61 (44.85%) had a mild head injury (GCS, ≤8), 47 (35.55%) had a moderate injury (GCS, 9-12), and 27 (19.85%) had a severe injury (GCS, 13-15). DI occurred in 10 patients (7.4%), while SIADH was observed in 4 patients in the immediate TBI period. Risk factors for diabetes insipidus were GCS of ≤ 8 at admission, midline shift, and surgical intervention. DI was an independent risk factor for death. There was a negative correlation between the presence of DI and GCS score (r, -0.367). Most of the patients with DI (8 out of 10) died during the hospital stay. One patient persisted to have partial diabetes insipidus and another one SIADH at three months post-TBI; both patients had recovered at six months of follow-up. No new case of DI or SIADH occurred on the follow up to 12 months. Conclusion: The incidence of acute DI in severe head injury (GCS ≤ 8) could be an indicator of the severity of TBI, and associated with increased mortality as most of our patients died during the hospital stay.
Once-Weekly Exenatide Enhances Weight Loss Maintenance in Adolescents with Severe Obesity: A Randomized, Placebo-Controlled Trial
Authors: Fox Claudia K , Rudser Kyle , Clark Justin , Ryder Justin R , Gross Amy C , Nathan Brandon M , Sunni Muna , Dengel Donald R , Billington Charles John , Bensignor Megan O , Kelly Aaron S
Published: May 2021

Background: In adolescents with severe obesity, long-term weight loss maintenance using lifestyle therapy alone is hampered by numerous biological adaptations favoring weight regain such as increased appetite and sense of food palatability and decreased satiety and resting energy expenditure. Anti-obesity pharmacotherapy may have a role in mitigating some of these physiological adaptations, thereby enhancing weight loss maintenance. We conducted a randomized, double-blind, placebo-controlled clinical trial to evaluate the effect of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide extended release (XR) on the maintenance of BMI reduction and improvements in cardiometabolic risk factors induced by short-term meal replacement therapy (MRT) among adolescents with severe obesity. Methods: One-hundred adolescents ages 12 to <18 years with BMI ≥120% of the 95th percentile engaged in an MRT intervention consisting of pre-portioned meals averaging 1,400 kcals/day with a goal of reducing BMI by ≥5% within eight weeks. Participants achieving this goal were randomized 1:1 to either exenatide XR (2 mg/week subcutaneously) + lifestyle therapy or matching placebo + lifestyle therapy for a subsequent 52 weeks. The primary outcome was mean percent change in BMI from randomization (post-MRT) to 52 weeks. Secondary outcomes included changes in body fat (DXA) and cardiometabolic risk factors. Results: Sixty-six participants (mean age 16±1.5 years; 47% female; mean BMI 36.9±4.4 kg/m2) achieved ≥5% BMI reduction with MRT and were randomized; 56 (85%) completed the 52-week visit. From randomization (post-MRT) to 52-weeks, the exenatide and placebo group mean BMI increased 4.6% and 10.1%, respectively. The prespecified intention-to-treat, last observation carried forward primary analysis demonstrated a placebo-subtracted exenatide treatment effect of -4.1% (95% CI -8.6 to 0.5, p=0.078). The per-protocol analysis (excluding participants with major protocol deviations) demonstrated a placebo-subtracted exenatide treatment effect of -5.7% (95% CI -10.9 to -0.6, p=0.030). The placebo-subtracted exenatide treatment effect on total body fat was -3.0 kg (95% CI -6.7 to 0.7, p=0.108), systolic blood pressure -3.2 mmHg (95% CI -7.0 to 0.7, p=0.107), and triglycerides to HDL ratio -0.6 (95% CI -1.2 to 0.0, p=0.050). Exenatide was generally well-tolerated and the adverse event profile was similar to previous reports of GLP-1RAs. Conclusion: The steep trajectory of weight regain following short-term MRT, particularly in the placebo group, underscores the challenge many adolescents encounter in maintaining weight loss over time. GLP-1RA treatment with once-weekly exenatide appears to partly mitigate the propensity toward weight regain after initial dietary-induced weight loss among adolescents with severe obesity.
Resolution of Abnormal Gonadotropin Secretion After Surgical Cure in Men With ACTH-Dependent Cushing Syndrome
Authors: Shekhar Skand , Tonelu Joselyne Tessa , Cutler Gordon B , Nieman Lynnette K , Hall Janet Elizabeth
Published: May 2021

Background: Hypothalamic-pituitary-gonadal (HPG) dysfunction is known to occur in male patients with Cushing Syndrome (CS) but the underlying mechanisms of HPG dysfunction remain unclear. We performed frequent blood sampling and GnRH stimulation tests to assess gonadotropin secretion in males before and after surgical cure of CS. Methods: We evaluated eight males age 32.5±12 years (mean ± SD) enrolled for surgical cure of ACTH-dependent CS at a tertiary care research center. Urinary free cortisol (UFC) was measured before and after surgery. Blood was sampled every 20 minutes for 24-hours with measurement of LH and FSH, before and 2 weeks to 160 weeks (median 80 weeks) after surgery. Patients received 100 μg of gonadotropin releasing hormone (GnRH) iv with measurement of LH and FSH at 0, 10 and 20 min before and 15, 30, 45, 60, 120 and 180 min after administration. Non-normative data was log-transformed before analysis using paired two-tail t-tests. A p-value of <0.05 was considered significant. Gonadotropin values are expressed in U/L as equivalents of the 2nd International Preparation of human menopausal gonadotropins with normal adult male ranges of 6-26 and 5-25 IU/L for LH and FSH, respectively. Results: Mean UFC was elevated ~ 6 times above the upper normal limit before surgery and returned to the reference range after surgery. 24-hour LH rose from 7.82 ± 1.48 preoperatively to 13.07 ± 2.96 IU/L (mean ± sem) after surgery (p=0.026) while mean FSH was unchanged (8.48 ± 1.51 vs 6.92 ± 1.29, p=0.37). LH pulse frequency, a marker of pulsatile GnRH secretion, recovered from a subnormal value of 6.88 ± 0.55 pulses/24 hr before to 12.13 ± 0.72 pulses/24 hr after surgery (p<0.0001) while LH pulse amplitude did not change (6.47 ± 1.21 vs 4.76 ± 0.88 IU/L, p=0.21). In response to GnRH there was a robust increase in LH that was not affected by curative surgery for CS (27.0 ± 7.2 vs 21.2 ± 7.6 IU/L; p=0.14) as was also the case for FSH (3.7 ± 1.2 vs 2.3 ± 0.5 IU/L; p=0.48), consistent with the absence of an effect of CS on gonadotroph responsiveness to LHRH. Conclusion: In men with Cushing Syndrome, hypogonadism is associated with inhibition of endogenous GnRH secretion but preservation of the pituitary response to GnRH. Hypothalamic suppression of the HPG axis is reversible after cure of CS.
The Effect of Hypothalamic Involvement and Growth Hormone Treatment on Cardiovascular Risk Factors in Patients With Childhood-Onset Craniopharyngioma
Authors: Park Sang Hee , Jung Hae Woon , Lee Yun Jeong , Cheon Jung-Eun , Lee Young Ah , Shin Choong Ho
Published: May 2021

Background: We evaluated cardiovascular risk factors at the time of growth hormone (GH) retesting after completion of linear growth in patients with childhood-onset craniopharyngioma (CP). We also investigated the effects of postoperative hypothalamic involvement (HI) and GH discontinuation during transition period on cardiovascular risk factors. Methods: Forty-two CP patients (24 males, mean age 17.7 years) who reached final adult height after GH therapy between 1995 and 2012 from a tertiary center were included. We measured anthropometric data and components of the metabolic syndrome at the time of GH retesting. The period of GH discontinuation was classified as < 6 months vs. ≥ 6 months. The extent of HI was categorized into “no”, “mild”, and “extensive” HI according to Puget grading system. Results: The mean age of initial operation after CP diagnosis was 7.5 ± 3.6 years, and 23 (54.8%) patients showed extensive HI. All patients were treated with GH during childhood for median 5.8 years (range 2.4-8.2years). Duration of GH discontinuation was median 1.5 years (range 0.5-3.2 years), and 32 (76.2%) had GH discontinuation ≥ 6 months. At the time of GH retesting, 13 (31.0%) were obese, and the proportion of patients with impaired fasting glucose (≥ 100 mg/dL), high triglycerides (≥ 150 mg/dL), low high-density lipoprotein (HDL) cholesterol (male, < 40 mg/dL; female, < 50 mg/dL), and hypertension (systolic blood pressure ≥ 130mmHg or diastolic blood pressure ≥ 85mmHg) was 5 (11.9%), 18 (42.9%), 24 (57.1%), and 5 (11.9%), respectively. When multivariate-adjusted models were constructed including age, sex, postoperative duration, extent of HI, duration of GH discontinuation, and family history of cardiovascular disease, the extent of HI was significantly predictive for increased body mass index z-score (β = 1.27, P = 0.017), fasting insulin levels (β = 7.1, P = 0.049), HOMA-IR (β = 1.61, P = 0.020), and decreased HDL cholesterol levels (β = -9.9, P = 0.012). GH discontinuation more than 6 months was significantly associated with decreased

HDL cholesterol levels (β = -10.23, P = 0.026). Conclusion: In this study, impaired fasting glucose or hypertension accounted for one-tenth, and dyslipidemia was detected in more than half of childhood-onset CP patients with GH deficiency at the time of GH retesting. The more extensive HI and the longer duration of GH discontinuation were associated with increased risk of metabolic disturbance during the transition period.
Clinical Outcomes in Patients With NFPAs Treated With Stereotactic Linear Accelerator Radiation Therapy
Authors: Ordaz-Candelario Karla Krystel , Godoy-Alonso Juan Pablo , Vázquez-Aguirre Marlon Vladimir , Gonzalez-De-la-Cruz German , Silva-Serrano Juanita , Gómez-Sámano Miguel Ángel , Gómez-Pérez Francisco Javier , Cuevas-Ramos Daniel
Published: May 2021

Background: Non-functioning pituitary adenoma (NFPAs) are benign tumors of the pituitary gland characterized by the absence of hormonal hypersecretion. Surgical treatment and fractionated stereotactic radiotherapy (FSRT) are necessary in majority of patients. NFPAs appear to cause higher mortality compared to the general population. Objective: To assess outcomes in patients with NFPAs treated with stereotactic linear accelerator radiation therapy. Material and Methods: Comparative, observational, longitudinal study, with prolective evaluation, from January 1987 to August 2019. Results: 264 patients (65.5% women and 34.5% men, mean age 43 ± 16 years) with a diagnosis of non-functional adenomas were evaluated. 30 patients received FSRT (14%), 93% were macroadenomas, and 80% of the cases were operated as a first line of treatment. The mean number of surgeries before radiotherapy was 1.2+-.847 (0-4). FSRT were used in 91.7% (n=21) because of post-surgical recurrence. Diabetes insipidus after surgery was transitory in 5.4%, and persistent in 4.0%. Hypopituitarism was identified in 59.4% before radiation (n=19), and in 13 patients (7.7%) after mean of 6.5+-5.5 years of FSRT. Dyslipidemia (62.0% vs. 45.9%), high blood pressure (16.5% vs. 23%), type 2 diabetes mellitus (10% vs. 77%) and heart failure (10% vs. 8.4%) were observed in the irradiated vs. non-irradiated groups, respectively (p<0.05). Conclusions: FSRT is a useful and safe strategy as an adjuvant treatment in patients with NFPA.
Giant Prolactinomas: An Experience From South India
Authors: S Vishwanath , George Belinda , Ayyar Vageesh , Bantwal Ganapathi , Appaiah Sonali
Published: May 2021

Giant prolactinomas are large lactotroph adenomas, defined as those with maximum dimension of >4cm. They constitute <5% of all prolactin secreting tumors, and are more frequently seen in men. They present with features of hyperprolactinemia and hypopitutarism and are responsive to dopamine agonist therapies. In the current study we have shared our experience on management of giant prolactinomas over the last 15 years. We collected clinical data retrospectively from medical records of patients with giant prolactinoma managed at our institute over the last 15 years. This study describes the symptomatology, tumor characteristics and response to therapy. Our study included 21 patients with 15 males and 6 females. The mean age of presentation was 32 ± 10.3 years, ranging between 10 to 53 years. Vision defect was the predominant complaint (57%, 12 patients), followed by headache (52%, 11 patients). Erectile dysfunction was a presenting feature in 13% of men (2 patients) and amenorrhea/galactorrhea in 33% of women (2 patients). Seizure was seen in 10% of the patients (2 patients) and 10% (2 patients) were diagnosed with giant prolactinoma on evaluation for primary infertility. Tumor associated pituitary dysfunction manifested as hypogonadism in 67%, 14 patients, central hypothyroidism in 38%, 8 patients, and hypocortisolism in 1 patient. The median maximum tumor dimension was 4.4 cm with median basal PRL of 7168 ng/ml. Five patients underwent debulking surgery (24% of the patients) prior to endocrinology referral for indications such as apoplexy/raised intracranial tension. All patients received cabergoline and a mean dose of 2.1 ± 1.7 mg/week (range, 1-7 mg/week) was prescribed to attain a median nadir prolactin level of 48 ng/ml over a median period of 4 months (range, 1-40 months). The follow-up MRI data was analysed for 13 patients. Tumor shrinkage of >50% from the baseline was seen in all but 1 patient (92%) and 2 patients had disappearance of radiologically detectable tumor. Although giant prolactinomas have a greater tumor burden than the more common macroprolactinomas, the responsiveness to dopamine agonist therapy is excellent and surgical therapy is reserved for any exceedingly large tumors to relieve compression on vital structures.
Increased Serum High-Sensitivity C-Reactive Protein in Growth Hormone-Deficient Patients With Non-Functioning Pituitary Tumors
Authors: Seki Yasufumi , Ichihara Atsuhiro
Published: May 2021

Introduction: Growth hormone (GH) deficiency, the most common hormone deficit complicated with pituitary tumors, is associated with higher mortality and cardiovascular events. Inflammation, as measured by high-sensitivity C-reactive protein (hs-CRP), has been reported to be associated with cardiovascular events. However, the association between hs-CRP and GH deficiency is still unknown. We retrospectively evaluated the association between serum hs-CRP levels and GH secretion in patients with non-functioning pituitary tumors (NFPTs). Methods: In this retrospective study, adult patients with non-functioning pituitary adenoma (NFPA) and Rathke’s cyst who received a GH-releasing pepitide-2 (GHRP-2) test from 2013 until 2016 were included. Patients with a history of pituitary surgery or radiation, or estimated GFR lower than 30 mL/min/1.73m2 were excluded. Results: Of 81 patients (70 NFPA and 11 Rathke’s cyst), 44% were diagnosed as severe GH deficiency by GHRP-2 test. Serum hs-CRP level was significantly higher in the male patients (P = 0.001) and the patients with regularly alcohol intake (P = 0.011) and was significantly correlated with BMI (r = 0.35, P = 0.002), creatinine (r = 0.41, P < 0.001), eGFR (r = -0.29, P = 0.009), peak GH response to GHRP-2 (r = -0.48, P < 0.001), AST (r = 0.32, P = 0.004), ALT (r = 0.34, P = 0.002), γGTP (r = 0.41, P < 0.001), HDL-cholesterol (r = -0.33, P = 0.003) and triglyceride (r = 0.25, P = 0.02). Smoking habit (P = 0.084), age (r = 0.18, P = 0.10), LDL-cholesterol (r = 0.16, P = 0.15), IGF-1 (r = -0.14, P = 0.23) and IGF-1 SD score (r = -0.11, P = 0.32) were not significantly correlated with serum hs-CRP level. Peak GH response to GHRP-2 (β = -0.24, P = 0.024) was a significant variable to determine serum hs-CRP level after adjustment for age, sex, BMI, regularly alcohol intake and serum creatinine, γGTP and HDL-cholesterol levels. Conclusion: Increased serum hs-CRP levels in the GH-deficient patients with NFPTs suggested the contribution of GH deficiency to pathogenesis of inflammation associated with cardiovascular diseases.
One Fourth of Adult Patients With Acromegaly Have Tall Stature With Similar Frequency in Males And Females
Authors: Bogusławska Anna , Gilis-Januszewska Aleksandra , Magdid Kesson , Godlewska Magdalena , Olszewska Marta , Nowak Andrzej Jerzy , Starzyk Jerzy , Korbonits Marta , Hubalewska-Dydejczyk Alicja
Published: May 2021

Introduction: Tall stature (TS) is a manifestation of growth hormone (GH) excess, with higher prevalence reported for males. The aim of this study was (i) to evaluate the relationship between height of patients with GH excess related to midparental height (MPH) and population mean height; (ii) to test whether TS patients with acromegaly come from tall families. Methods: Single-centre, observational study on 101 consecutive adult patients with acromegaly and no family history of pituitary adenoma. Patients were analysed in two subgroups depending on height using country-specific data: 1) normal stature and 2) TS group, defined as either height above gender-specific 97 percentile or as >1.5 country-specific standard deviation (SD) from MPH. Results: Twenty-four percent of acromegaly patients (13 females/11 males) met one or both of the TS criteria. TS patients were significantly younger at the diagnosis (mean±SD, 33.6±13.4 vs 50.6±12.3 years) and at first symptoms (median 27.5, range 23-42 vs 41 (33-54) years) with greater tumour size and higher basal GH concentration than normal stature patients (p<0.01). The TS criteria based on the 1.5 SD above MPH identified more TS patients than the above 97 percentile height (92% vs 38%) and especially increased the diagnosis of TS in women (92% vs 31%). There was no difference in height of family members of acromegaly patients with or without TS. Height of family members were not taller than the population mean. Conclusion: One fourth of adult patients with acromegaly have TS with similar frequency in males and females. Based on our data TS patients with acromegaly do not come from tall families.
Prevalence of Abnormal Glucose Metabolism in Acromegaly & Impact of Treatment Modalities on Glucose Metabolism
Authors: Khan Sajjad Ali , Ram Nanik , Masood Muhammad Qamar
Published: May 2021

Objective: To determine the frequency of diabetes mellitus impaired glucose tolerance and impaired fasting glucose in Pakistani patients with acromegaly and to establish the impact of the intervention (surgery/ medical) on glucose metabolism.

Methods: Eighty-nine patients fulfilling the endocrine society criteria for acromegaly diagnosis were included. A data of baseline, growth hormone (GH), Insulin-like growth factor-1 (IGF-1) level, Hemoglobin A1C (HbA1C), fasting blood glucose (FBG), and random blood glucose (RBS) levels were reviewed before and after the intervention (surgery/medical therapy). Normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetes mellitus (DM) were defined based on the 2003 ADA criteria. Patients were grouped into normoglycemic (NGT) and dysglycemic (IFG, IGT, and DM) based on FBS, RBS, and HbA1C.

Results: Major risk factors for dysglycemia included age (15-45 years), male sex (33.70%), obesity (45.7%), and macroadenoma (76%). Both mean GH levels (58.29 vs. 54.36 ng/dl) and IGF-1 levels (862.98 vs. 824.32 ng/dl) were higher among the normoglycemic than dysglycemia. Pre-surgery, NGT, IFG, IGT, IFG, and IGT combined and DM were found in 48.31, 5.61, 1.1, 5.61, and 39.32 % of the subjects, respectively. Post-surgery, HbA1C improved in 79.5%, deteriorated in 6.8%, and remained the same in 13.6%. Similarly, it improved in 67.4.7% post-medical therapy. Both FBS and RBS improved post-surgery and medical therapy. Further, the number of anti-diabetic drugs used also decreased post-surgery.

Conclusion: Dysglycemia is more common among patients with acromegaly as compared to the general population and tends to be poorly controlled in untreated acromegaly. Glycemic control improves significantly after the surgery and medical therapy.

Keywords: Acromegaly, Diabetes Mellitus, Transsphenoidal surgery
Safety and Efficacy of Pegvisomant in Pediatric Growth Hormone Excess
Authors: Tatsi Christina , Wajnrajch Michael Paul , Camacho-Hubner Cecilia , Stratakis Constantine A
Published: May 2021

Objective: Pediatric growth hormone excess (GHE) and gigantism are mainly managed by pituitary surgery. However, a large percentage of patients require further medical management. Data for the pediatric population are scares and decisions are usually based on adult published data. We have initiated a study to investigate the efficacy and safety of pegvisomant in children and adolescents with GHE. MethodsThe study is registered in ClinicalTrials.gov (Identifier: NCT03882034, An open-label phase 3 study of the safety and efficacy of pegvisomant in children with growth hormone excess). Eligible patients must be children or adolescents (age: 24 months -18 years) with GHE with persistent disease after surgical or radiation therapy. The patients will receive pegvisomant via subcutaneous daily injection for one year and outcomes will be measured at baseline and at the end of the study. The main measure of efficacy is the change of IGF-1 from baseline to the end of the study. The main measure of safety is the description of side effects over the duration of the study. ConclusionsWe will collect data on the safety and efficacy of medical treatment for pediatric patients with GHE.
Somatotroph Adenomas have a Predilection to Invade the Cavernous Sinus and Resection of the Medial Wall of the Cavernous Sinus Offers the Highest Potential for Biochemical Remission in Acromegaly
Authors: Mohyeldin Ahmed , Katznelson Laurence , Fernandez-Miranda Juan
Published: May 2021

Recurrence and remission rates vary widely among different histological subtypes of pituitary adenoma. Invasion of the medial wall of the cavernous sinus is a known mechanism that may account for such failed clinical outcomes as its removal has long been considered unattainable. The use of modern endoscopic techniques allows for direct intraoperative evaluation of invasion and resection of the medial wall of the cavernous sinus with low morbidity when performed by highly experienced surgeons. In this retrospective study we evaluated 105 consecutive primary pituitary adenomas operated by a single surgeon including 28 corticotroph, 27 gonadotroph, 24 somatotroph, 15 lactotroph, 5 null-cell, 5 plurihormonal, and 1 dual adenoma; 53 caused hypersecretory syndromes, specifically acromegaly (30), hyperprolactinemia (15) and Cushing’s disease (8). In each case, we performed meticulous intraoperative inspection of the medial wall with its surgical removal when invasion was suspected, regardless of functional status. Medial wall resection was performed in 46% of pituitary adenomas, and 38/48 walls confirmed pathologic evidence of invasion rendering a positive predictive value of intraoperative evaluation of medial wall invasion of 79%. Furthermore, we show for the first time that the rate of medial wall invasion among pathological subtypes is dramatically different. Somatotroph tumors invaded the medial wall much more often than other adenoma subtypes, 83% intraoperatively and 71% histologically, followed by plurihormonal tumors (40%) and gonadotrophs (33%), both with intraoperative positive predictive value of 100%. The least likely to invade were corticotroph, at a rate of 32% intraoperatively and 21% histologically, and null-cell adenomas at 0%. Removal of the medial wall caused no permanent morbidity with no carotid artery injuries and 2 patients with transient diplopia. We report that resecting the medial wall of the cavernous sinus in acromegaly offers the highest potential for biochemical remission with average postoperative day 1 GH levels at 0.96 ug/l and early surgical remission rates at 90% (100% with adjuvant therapy) based on normalization of IGF-1 levels 3 to 6 months after surgery; these results are significantly better than previously reported but longer follow-up is required for definitive conclusions. Our findings may explain the failed biochemical remission rates seen in acromegaly and illustrate the relevance of advanced surgical techniques for successful outcomes in pituitary surgery.
The Pharmacological Burden of Comorbidities in Acromegaly
Authors: Fleseriu Maria , Barkan Ariel , Schneider Maria del Pilar , Darhi Yannis , de Pierrefeu Amicie , Munoz Kathryn , Ribeiro-Oliveira Antonio , Melmed Shlomo
Published: May 2021

Background: Acromegaly is characterized by excess GH and elevated IGF-I often treated by surgery, pharmacotherapy (somatostatin analogs, GH receptor antagonists, dopamine agonists) and/or radiotherapy.1 Common associated comorbidities include cardiovascular disorders and hypopituitarism, often requiring additional pharmacotherapy.2 We therefore assessed the most common comorbidities and related pharmacological burden in patients with acromegaly in a real-world clinical setting.

Methods: The MarketScan database was examined for medical claims from Jan 2010 to Jan 2020. We defined 2 groups: Group 1 - patients with acromegaly (2 diagnoses [ICD-9-CM/ICD-10-CM] on dates within >30 days) who had ≥1 medication for acromegaly since diagnosis, with ≥3 months coverage prior to index date (diagnosis date or first treatment available); Group 2 - a matched cohort (MC) with no acromegaly-related medical claims; direct matching (1:5 based on age, sex and follow-up duration) was performed. Group proportions and quantitative differences were compared by chi-squared tests and t-tests, respectively (unpaired due to different cohort sizes).

Results: 1,175 patients with and 5,875 without acromegaly were analyzed. Across both groups, median (95% CI) age was 50 (49, 51) years, 50% were female, median (95% CI) follow-up was 751 (702, 805) days. Comorbidities reported in ≥20% patients with acromegaly vs the MC were cardiovascular system disorders (68% vs 48%), hypopituitarism/hypothalamic disorders (26% vs 0%), sleep apnea (25% vs 8%), malignant neoplasms (23% vs 9%), arthritis and muscular skeletal disorders (20% vs 13%); frequencies were significantly higher in patients with acromegaly vs the MC (all p<0.0001). Thyroid replacement, lipid modifying and renin-angiotensin system agents were the most common treatments related to these comorbidities, all used more frequently in acromegaly (35%, 34% and 34%, respectively) vs the MC (9%, 26% and 25%, respectively; all p<0.0001). Overall in patients with acromegaly vs the MC, mean (SD) number of different oral medications used was 12.01 (10.49) vs 7.21 (7.99); 5% vs 20% and 79% vs 58% took 0 and ≥3 oral medications, respectively (all comparisons p<0.0001). Significantly more patients with acromegaly vs the MC took medications typically taken while fasting e.g. levothyroxine (34% vs 9%) and omeprazole (14% vs 9%), both p<0.01.

Conclusions: In this real-world analysis, patients with acromegaly had more comorbidities, compared with a matched population and required many concomitant medications. Oral medication use with or without fasting was higher in patients with acromegaly. These findings elucidate further physician understanding of the pharmacological burden of acromegaly comorbidities.

Funding: This ongoing study is sponsored by Ipsen.

1.Katznelson L J Clin Endocrinol Metab 2014:99:3933-51

2.Gadelha M Endocr Rev 2019:40:268-332
The Musashi1 RNA-Binding Protein Functions as a Leptin-Regulated Enforcer of Pituitary Cell Fate and Hormone Production
Authors: Banik* Jewel , Lim* Juchan , Linda Hardy L , Odle Angela Katherine , Childs Gwen V , MacNicol Melanie C , MacNicol Angus M
Published: May 2021

The pituitary gland is the major endocrine organ that produces and secretes hormones in response to hypothalamic signals to regulate important processes like growth, reproduction, and stress. The anterior pituitary adapts to metabolic and reproductive needs by exhibiting cellular plasticity, resulting in altered hormone production and secretion. The adipokine, leptin, serves a critical role to couple energy status to pituitary function. We have recently reported that the cell fate determinant, Musashi, functions as a post-transcriptional regulator of target mRNA translation in the mouse pituitary and have speculated that Musashi may modulate pituitary cell plasticity. However, the underlying mechanisms governing such pituitary plasticity are not fully understood. Musashi is an mRNA binding protein that is required for self-renewal, proliferation, and to control the differentiation of stem and progenitor cells. We have recently shown that Musashi is expressed in Sox2+ pituitary stem cells and surprisingly, we also found Musashi expression in all differentiated hormone expressing cell lineages in the adult anterior pituitary. The role of Musashi in these mature differentiated cells is unknown. We have observed that a range of critical pituitary mRNAs, including the lineage specification transcription factors Prop1 and Pou1f1, as well as hormone mRNAs including Tshb, Prl, and Gnrhr, all contain consensus Musashi binding elements (MBEs) in their 3’ untranslated regions (3’ UTRs). Using RNA electrophoretic mobility shift assays (EMSAs) and luciferase mRNA translation reporter assays we show that Musashi binds to these mRNAs and exerts inhibitory control of mRNA translation. Moreover, we determined that leptin stimulation opposes the ability of Musashi to exert translational repression of the Pou1f1 and Gnrhr 3’ UTRs. This de-repression does not require regulatory phosphorylation of Musashi on two conserved C-terminal serine residues. Interestingly in the same cell assay system, Musashi exerts translational activation of the Prop1 3’ UTR. We observed that this translational activation requires Musashi phosphorylation on the two regulatory C-terminal serine residues, consistent with the requirement for regulatory phosphorylation to drive translational activation of Musashi target mRNAs during Xenopus oocyte cell maturation. The distinction between MBEs in 3’ UTRs that exert repression (Pou1f1, Prl, Tshb, and Gnrhr) and the Prop1 3’ UTR that directs translational activation is under investigation. We propose that Musashi acts as a bifunctional regulator of pituitary hormone production and lineage specification and may function to maintain pituitary hormone plasticity in response to changing organismal needs.
Features of Slowly Progressive Type 1 Diabetes Mellitus in Overweight Adolescents
Authors: Romanenkova Elizaveta , Eremina Irina , Zilberman Lubov , Laptev Dmitry , Kuraeva Tamara , Bezlepkina Olga , Peterkova Valentina
Published: May 2021

Background: he obesity epidemic has led to an increase in the incidence of type 1 diabetes mellitus (T1DM) on the background of overweight. The combination of T1DM and obesity can lead to an erroneous diagnosis of type 2 diabetes (T2DM). Methods: The study included 35 adolescents with T1DM. Inclusion criteria were obesity at onset, high titer of diabetes-associated autoantibodies, and insulin requirement less than 0.5 U/kg with a diabetes duration of more than 6 months. We assessed the level of HbA1c, fasting level of insulin and c-peptide, and level during the Mixed-Meal Tolerance Test, the immunological status of GADA, IA-2, ZnT8, ICA. Results: The age of onset was 12.7 years [10.6; 14.5], the tanner stage of puberty was 4 [3; 5]. Sex distribution: boys (n = 25) - 71.5%, girls (n = 10) - 28.5%. HbA1c at the time of onset equaled 8,9% [7.4; 10.45]. Ketosis/diabetic ketoacidosis was registered in 47.8%. The duration of the diabetes was 1.7 years at the moment of examination [0.7; 2.9]. The fasting level of C-peptide - 1.37 mμg/ml [1.0.9; 2.19], insulin level (n = 26) - 13.93 uU/ml [9.57; 19.77]. The maximum level of stimulated secretion of C-peptide (n = 21) - 5.13 mμg/ml [3.05; 6.07], of insulin secretion (n = 21) - 58.59 uU/ml [31.02; 79.74]. Higher HOMA of insulin resistance (n = 25) was detected in 72% of the examined patients. In the study of pancreatic autoantibodies, an increase in ICA was detected in 57% (median of titer 1.68 [0.28;11.7]), IA-2 - 67% (192.8 ME/ml [65; 310.1]), GAD - 59% (90.25 ME/ml [32.27; 214.6]), ZnT8 - 82% (350.5 [90.4; 506.05]). The presence of 2 or more autoantibodies is found in 94% of cases. Dyslipidemia was observed in 34.8%, arterial hypertension was identified in 23% of patients. Received therapy: insulin 82%; metformin 0.02%; metformin + insulin 5.7%. Median daily dose per patient was 0.3 U/kg [0.2; 0.5]. Conclusion: T1DM in adolescents with obesity and overweight has a similar clinical picture both with T1DM (insulin dependence, high titer of autoantibodies, ketosis) and T2DM (slow progression of the disease, low insulin requirement, preserved secretion of c-peptide, and insulin for more than 1.5 years). We hypothesize that obesity and insulin resistance may contribute to DM onset at an earlier date, even if a satisfactory function of pancreatic beta-cells is still preserved. Given that the onset of the disease in our group falls on adolescence it seems that pubertal insulin resistance also contributes to the features of the course of the disease. Understanding the role of obesity in the progression of disorders of carbohydrate metabolism will allow postponing the acute manifestation of the disease and initiation of insulin therapy through lifestyle modifications in patients at risk. A long period of preserved insulin secretion opens up the possibility of new personalized therapies.
Sphingosine 1- Phosphate Lyase Insufficiency Syndrome (SPLIS); A Role in Multiple Endocrinopathies
Authors: Wai Kwong Ruth Ming , Maharaj Avinaash Vickram , Metherell Louise , Prasad Rathi
Published: May 2021

Sphingosine 1-phosphate lyase insufficiency syndrome (SPLIS) was described in 2017 as a novel condition affecting sphingolipid metabolism. There is a multisystemic phenotype including nephrotic syndrome and primary adrenal insufficiency (PAI) and to a lesser extent ichthyosis, neurological disease and lymphopenia. A proportion of patients also presented with hypothyroidism and hypogonadism. To interrogate the endocrine aspect of the syndrome we reviewed clinical data within our patient cohort with SPLIS and those within the wider literature. To date there have been 45 patients identified with SPLIS with significant associated mortality (n=23/45, 51%; 4 of these in utero). There is no clear genotype-phenotype correlation. Whilst nephrotic syndrome is most prevalent (n=34/45; 76%), a significant proportion of patients (n=27/45, 60%) also presented with glucocorticoid deficiency, some with additional mineralocorticoid deficiency (n=7/27). Five further patients were noted to have adrenal calcifications though biochemistry was not undertaken. Most patients presented with PAI in the first 2 years of life (n=21/27), with the oldest presentation being 11 years of age. Adrenal calcifications are a common finding in those who had documented imaging (n=13/15, 87%). Primary gonadal failure has been reported in 8 male cases, all with concomitant PAI. Presenting features included microphallus (n=7/8) and cryptorchidism (n=8/8), indicating reduced in utero androgen exposure. All who had biochemical evaluation demonstrated raised basal LH and FSH/ exaggerated response to LHRH stimulation, a lack of testosterone response to HCG stimulation and low antimullerian hormone (AMH) levels. To date there are no reports of pubertal delay in female patients, and those of age within our cohort have normal ovarian reserve as evidenced by AMH levels (n=2). Primary hypothyroidism, with mildly raised TSH and low Free T4 is reported in 12 patients. Most did not have goiters and had concomitant PAI and nephrotic syndrome (n=11/12). SPLIS is unique amongst sphingolipid disorders in presenting with significant endocrinopathy. This may be the consequence of the particular sphingolipid signature of the disease and the pathogenic mechanisms need to be explored further. It is clear that endocrine dysfunction needs to be considered at diagnosis and surveillance undertaken to detect evolving disease which could have a significant impact on morbidity and mortality.