Activated AMP-protein kinase (pAMPK) is overexpressed in human somatotroph pituitary adenomas.

INTRODUCTION: AMPK (AMP-activated protein kinase) is an enzyme that acts as a metabolic sensor and regulates multiple pathways via phosphorylating proteins in metabolic and proliferative pathways. The aim of this work was to study the activated cellular AMPK (phosphorylated-AMPK at Thr172, pAMPK) levels in pituitary tumor samples from patients with sporadic and familial acromegaly, as well as in samples from normal human pituitary gland. METHODS: We studied pituitary adenoma tissue from patients with sporadic somatotroph adenomas, familial acromegaly with heterozygote germline variants in the aryl hydrocarbon receptor interacting protein (AIP) gene (p.Q164*, p.R304* and p.F269_H275dup) and autopsy from normal pituitary glands without structural alterations. RESULTS: Cellular levels of pAMPK were significantly higher in patients with sporadic acromegaly compared to normal pituitary glands (p < 0.0001). Tissues samples from patients with germline AIP mutations also showed higher cellular levels of pAMPK compared to normal pituitary glands. We did not observe a significant difference in cellular levels of pAMPK according to the cytokeratin (CAM5.2) pattern (sparsely or densely granulated) for tumor samples of sporadic acromegaly. CONCLUSION: Our data show, for the first time in human cells, an increase of cellular levels of pAMPK in sporadic somatotropinomas, regardless of cytokeratin pattern, as well as in GH-secreting adenomas from patients with germline AIP mutations.

Psychopathological characteristics in patients with arginine vasopressin deficiency (central diabetes insipidus) and primary polydipsia compared to healthy controls.

OBJECTIVE: Distinguishing arginine vasopressin deficiency (AVP-D; central diabetes insipidus) from primary polydipsia (PP), commonly referred to as psychogenic polydipsia, is challenging. Psychopathologic findings, commonly used for PP diagnosis in clinical practice, are rarely evaluated in AVP-D patients, and no comparative data between the two conditions currently exist. DESIGN: Data from two studies involving 82 participants [39 AVP-D, 28 PP, and 15 healthy controls (HC)]. METHODS: Psychological evaluations were conducted using standardized questionnaires measuring anxiety [State-Trait Anxiety Inventory (STAI)], alexithymia [Toronto Alexithymia Scale (TAS-20)], depressive symptoms (Beck's Depression Inventory-II (BDI-II), and overall mental health [Short Form-36 Health Survey (SF-36)]. Higher STAI, TAS-20, and BDI-II scores suggest elevated anxiety, alexithymia, and depression, while higher SF-36 scores signify better overall mental health. RESULTS: Compared to HC, patients with AVP-D and PP showed higher levels of anxiety (HC 28 points [24-31] vs AVP-D 36 points [31-45]; vs PP 38 points [33-46], P < .01), alexithymia (HC 30 points [29-37] vs AVP-D 43 points [35-54]; vs PP 46 points [37-55], P < .01), and depression (HC 1 point [0-2] vs AVP-D 7 points [4-14]; vs PP 7 points [3-13], P < .01). Levels of anxiety, alexithymia, and depression showed no difference between both patient groups (P = .58, P = .90, P = .50, respectively). Compared to HC, patients with AVP-D and PP reported similarly reduced self-reported overall mental health scores (HC 84 [68-88] vs AVP-D 60 [52-80], P = .05; vs PP 60 [47-74], P < .01). CONCLUSION: This study reveals heightened anxiety, alexithymia, depression, and diminished overall mental health in patients with AVP-D and PP. The results emphasize the need for careful interpretation of psychopathological characteristics to differentiate between AVP-D and PP.

Arginine or Hypertonic Saline-Stimulated Copeptin to Diagnose AVP Deficiency.

BACKGROUND: Distinguishing between arginine vasopressin (AVP) deficiency and primary polydipsia is challenging. Hypertonic saline-stimulated copeptin has been used to diagnose AVP deficiency with high accuracy but requires close sodium monitoring. Arginine-stimulated copeptin has shown similar diagnostic accuracy but with a simpler test protocol. However, data are lacking from a head-to-head comparison between arginine-stimulated copeptin and hypertonic saline-stimulated copeptin in the diagnosis of AVP deficiency. METHODS: In this international, noninferiority trial, we assigned adult patients with polydipsia and hypotonic polyuria or a known diagnosis of AVP deficiency to undergo diagnostic evaluation with hypertonic-saline stimulation on one day and with arginine stimulation on another day. Two endocrinologists independently made the final diagnosis of AVP deficiency or primary polydipsia with use of clinical information, treatment response, and the hypertonic-saline test results. The primary outcome was the overall diagnostic accuracy according to prespecified copeptin cutoff values of 3.8 pmol per liter after 60 minutes for arginine and 4.9 pmol per liter once the sodium level was more than 149 mmol per liter for hypertonic saline. RESULTS: Of the 158 patients who underwent the two tests, 69 (44%) received the diagnosis of AVP deficiency and 89 (56%) received the diagnosis of primary polydipsia. The diagnostic accuracy was 74.4% (95% confidence interval [CI], 67.0 to 80.6) for arginine-stimulated copeptin and 95.6% (95% CI, 91.1 to 97.8) for hypertonic saline-stimulated copeptin (estimated difference, -21.2 percentage points; 95% CI, -28.7 to -14.3). Adverse events were generally mild with the two tests. A total of 72% of the patients preferred testing with arginine as compared with hypertonic saline. Arginine-stimulated copeptin at a value of 3.0 pmol per liter or less led to a diagnosis of AVP deficiency with a specificity of 90.9% (95% CI, 81.7 to 95.7), whereas levels of more than 5.2 pmol per liter led to a diagnosis of primary polydipsia with a specificity of 91.4% (95% CI, 83.7 to 95.6). CONCLUSIONS: Among adult patients with polyuria polydipsia syndrome, AVP deficiency was more accurately diagnosed with hypertonic saline-stimulated copeptin than with arginine-stimulated copeptin. (Funded by the Swiss National Science Foundation; CARGOx ClinicalTrials.gov number, NCT03572166.).

Changing the name of diabetes insipidus: a position statement of the working group to consider renaming diabetes insipidus

"What's in a name? That which we call a rose / By any other name would smell as sweet" (Juliet, from Romeo and Juliet by William Shakespeare). Shakespeare's implication is that a name is nothing but a word and it therefore represents a convention with no intrinsic meaning. Whilst this may be relevant to romantic literature, disease names do have real meanings, and consequences, in medicine. Hence, there must be a very good rational for changing the name of a disease that has a centuries-old historical context. A working group of representatives from national and international endocrinology and endocrine pediatric societies now proposes changing the name of "diabetes insipidus" to "Arginine Vasopressin Deficiency (AVP-D)" for central etiologies, and "Arginine Vasopressin Resistance (AVP-R)" for nephrogenic etiologies This editorial provides both the historical context and the rational for this proposed name change.

Changing the Name of Diabetes Insipidus: A Position Statement of the Working Group for Renaming Diabetes Insipidus.

Recent data show that patients with a diagnosis of diabetes insipidus (DI) are coming to harm. Here we give the rationale for a name change to arginine vasopressin deficiency and resistance for central and nephrogenic DI, respectively.

Changing the name of diabetes insipidus: a position statement of The Working Group for Renaming Diabetes Insipidus.

'What's in a name? That which we call a rose/By any other name would smell as sweet.' (Juliet, from Romeo and Juliet by William Shakespeare). Shakespeare's implication is that a name is nothing but a word and it therefore represents a convention with no intrinsic meaning. Whilst this may be relevant to romantic literature, disease names do have real meanings, and consequences, in medicine. Hence, there must be a very good rationale for changing the name of a disease that has a centuries-old historical context. A working group of representatives from national and international endocrinology, nephrology and pediatric societies now proposes changing the name of 'diabetes insipidus' to 'arginine vasopressin deficiency (AVP-D)' for central etiologies and 'arginine vasopressin resistance (AVP-R)' for nephrogenic etiologies. This editorial provides both the historical context and the rationale for this proposed name change.

Changing the name of diabetes insipidus: a position statement of The Working Group for Renaming Diabetes Insipidus.

"What's in a name? That which we call a rose/By any other name would smell as sweet." (Juliet, from Romeo and Juliet by William Shakespeare). Shakespeare's implication is that a name is nothing but a word and it therefore represents a convention with no intrinsic meaning. Whilst this may be relevant to romantic literature, disease names do have real meanings, and consequences, in medicine. Hence, there must be a very good rational for changing the name of a disease that has a centuries-old historical context. A working group of representatives from national and international endocrinology and pediatric endocrine societies now proposes changing the name of "diabetes insipidus" to "Arginine Vasopressin Deficiency (AVP-D)" for central etiologies, and "Arginine Vasopressin Resistance (AVP-R)" for nephrogenic etiologies. This editorial provides both the historical context and the rational for this proposed name change.

Changing the name of diabetes insipidus: a position statement of The Working Group for Renaming Diabetes Insipidus.

'What's in a name? That which we call a rose/By any other name would smell as sweet' (Juliet, from Romeo and Juliet by William Shakespeare). Shakespeare's implication is that a name is nothing but a word, and it therefore represents a convention with no intrinsic meaning. While this may be relevant to romantic literature, disease names do have real meanings, and consequences, in medicine. Hence, there must be a very good rationale for changing the name of a disease that has a centuries-old historical context. A working group of representatives from national and international endocrinology, and pediatric endocrine societies now proposes changing the name of 'diabetes insipidus' to 'arginine vasopressin deficiency (AVP-D)' for central etiologies, and 'arginine vasopressin resistance (AVP-R)' for nephrogenic etiologies. This article provides both the historical context and the rationale for this proposed name change.

Changing the name of diabetes insipidus: a position statement of the working group to consider renaming diabetes insipidus.

"What's in a name? That which we call a rose / By any other name would smell as sweet" (Juliet, from Romeo and Juliet by William Shakespeare). Shakespeare's implication is that a name is nothing but a word and it therefore represents a convention with no intrinsic meaning. Whilst this may be relevant to romantic literature, disease names do have real meanings, and consequences, in medicine. Hence, there must be a very good rational for changing the name of a disease that has a centuries-old historical context. A working group of representatives from national and international endocrinology and endocrine pediatric societies now proposes changing the name of "diabetes insipidus" to "Arginine Vasopressin Deficiency (AVP-D)" for central etiologies, and "Arginine Vasopressin Resistance (AVP-R)" for nephrogenic etiologies This editorial provides both the historical context and the rational for this proposed name change.

Nephrogenic diabetes insipidus: a comprehensive overview.

Nephrogenic diabetes insipidus (NDI) is characterized by the inability to concentrate urine that results in polyuria and polydipsia, despite having normal or elevated plasma concentrations of arginine vasopressin (AVP). In this study, we review the clinical aspects and diagnosis of NDI, the various etiologies, current treatment options and potential future developments. NDI has different clinical manifestations and approaches according to the etiology. Hereditary forms of NDI are mainly caused by mutations in the genes that encode key proteins in the AVP signaling pathway, while acquired causes are normally associated with specific drug exposure, especially lithium, and hydroelectrolytic disorders. Clinical manifestations of the disease vary according to the degree of dehydration and hyperosmolality, being worse when renal water losses cannot be properly compensated by fluid intake. Regarding the diagnosis of NDI, it is important to consider the symptoms of the patient and the diagnostic tests, including the water deprivation test and the baseline plasma copeptin measurement, a stable surrogate biomarker of AVP release. Without proper treatment, patients may developcomplications leading to high morbidity and mortality, such as severe dehydration and hypernatremia. In that sense, the treatment of NDI consists in decreasing the urine output, while allowing appropriate fluid balance, normonatremia, and ensuring an acceptable quality of life. Therefore, therapeutic options include nonpharmacological interventions, including sufficient water intake and a low-sodium diet, and pharmacological treatment. The main medications used for NDI are thiazide diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), and amiloride, used isolated or in combination.

"Subclinical atherosclerosis in acromegaly: Possible association with cardiovascular risk factors rather than disease activity".

OBJECTIVE: Cardiovascular (CV) disease is still a major cause of excessive morbidity and mortality in patients with active acromegaly, which may be attributed to a high prevalence of associated pro-atherosclerotic risk factors. However, a direct effect of GH/IGF-1 excess on the vasculature has been previously suggested, warranting further investigation. The present study was designed to investigate whether chronic GH/IGF-1 excess is associated with an increased prevalence of subclinical atherosclerosis in patients with acromegaly. DESIGN: We measured carotid intima-media thickness (cIMT) and assessed carotid plaques by ultrasonography along with classical CV risk factors in 54 acromegaly patients (34 females, 50 ± 12 years and compared those with 62 (42 females, 53 ± 13 years) age-, sex- and CV risk factors- matched controls. In order to compare cIMT measurements between patients and controls we analyzed common carotid artery far wall data as well as a combined measurement result, which consisted of the mean value of the six different measurements, three at each side. RESULTS: mean ± SD serum GH and IGF-1 levels were 2.76 ± 4.65 ng/mL and 1.7 ± 1.25 x ULN, respectively, in all acromegaly patients. Age, body mass index, blood pressure, lipid levels, fasting glucose and Framingham's global cardiovascular risk score classification were similar comparing patients and controls. Combined median [IQR] cIMT measurements were similar in acromegaly patients and matched controls (0.59 [0.52-0.66] mm vs. 0.59 [0.52-0.69] mm; P = 0.872) as well as in acromegaly patients with active and controlled disease (0.59 [0.51-0.68] mm vs. 0.60 [0.54-0.68] mm; P = 0.385). No significant correlations were observed between cIMT measurements and GH (Spearman r = 0.1, P = 0.49) or IGF-1 (Spearman r = 0.13, P = 0.37) levels in patients with acromegaly. Carotid atherosclerotic plaques prevalence was similar in patients and controls (26% vs. 32%; P = 0.54) as well as in patients with active and controlled acromegaly (22% vs. 30%; P = 0.537). CONCLUSIONS: Our data suggest that GH/IGF-1 excess itself is not one of the main drivers of subclinical morphological atherosclerosis changes in patients with acromegaly and that optimal control of acromegaly-associated CV risk factors may preserve vasculature structure even when strict biochemical control is not achieved.

The usefulness of copeptin for the diagnosis of nephrogenic diabetes insipidus in infancy: a case report.

OBJECTIVES: We report a case of an infant with nephrogenic diabetes insipidus (NDI) diagnosed by the measurement of serum copeptin. There is only one study that previously evaluated the use of copeptin measurement in a pediatric patient. CASE PRESENTATION: We present a 10-month-old child with polyuria-polydipsia syndrome (PPS) and hypernatremia that could not support water restriction due to increased risk of dehydration and worsening of his condition. Therefore, plasma measurement of copeptin allowed the diagnosis of NDI. CONCLUSIONS: The water deprivation test (WDT) is considered the gold standard for diagnosis in PPS. However, WDT has serious limitations regarding its interpretation. Furthermore, the WDT can cause dehydration and hypernatremia, especially in young children. Therefore, the measurement of plasma copeptin seems to be a promising method to perform an earlier, safer, and accurate investigation of PPS. Up to now, our study is the second to report the usefulness of copeptin in children.

Effects of oral macimorelin on copeptin and anterior pituitary hormones in healthy volunteers.

PURPOSE: The test with the highest diagnostic accuracy for diabetes insipidus is copeptin measurement after hypertonic saline infusion. However, the procedure is cumbersome and unpleasant due to rapid sodium increase. An oral stimulation test would be highly desirable. Macimorelin, an oral ghrelin agonist, is a newly approved diagnostic test for growth hormone (GH) deficiency, but its effects on copeptin/vasopressin are unknown and the effects on other pituitary hormones only scarcely investigated. METHODS: In this prospective, interventional, proof-of-concept study Copeptin and anterior pituitary hormones were measured in 28 healthy volunteers on two test days at baseline, 30, 45, 60, 90 and 120 min after a single dose of macimorelin (first visit: 0.5 mg/kg, second visit: 0.75 mg/kg). RESULTS: Baseline copeptin levels were 5.26 pmol/L [1.57, 6.81] and did not change after macimorelin intake (0.5 mg/kg: maximal median change 0.40 [- 0.49, 0.65] pmol/L, p = 0.442; 0.75 mg/kg: - 0.13 [- 0.45, 0.17] pmol/L, p = 0.442. Median GH levels increased from 3.67 mU/L with a maximal median change of 94.66 [IQR 56.5; 110.96] mU/L, p < 0.001. No effect was seen on cortisol, ACTH, LH and FSH levels. Prolactin (max. median change 100 [2.5; 146.5] mU/L, p = 0.004) and free thyroxine (fT4) (0.5 [0.2; 0.8] pmol/L, p < 0.001) increased, whereas TSH decreased (- 0.18 [- 0.22, - 0.09] mU/L, p < 0.001). CONCLUSION: We confirm an increase of GH upon macimorelin in healthy volunteers. However, macimorelin did not stimulate copeptin and therefore does not provide an oral test alternative for the diagnosis of diabetes insipidus. Additionally, a stimulatory effect was seen for prolactin and fT4, but not for ACTH and gonadotropic hormones. REGISTRATION: The trial was registered on ClinicalTrials.gov (NCT03844217) on February 18, 2019.

Interleukin-6 response to insulin-induced hypoglycemia is associated with hypothalamic-pituitary-adrenal axis activation.

Increased plasma levels of interleukin-6 (IL-6) in response to acute hypoglycemia have been well documented. Aiming to study the interaction between IL-6 and counter-regulatory hormones during hypoglycemic stress we conducted an exploratory single center study involving 26 adult patients undergoing insulin tolerance test. Insulin-induced hypoglycemia elicited a significant dynamic response of IL-6, adrenaline, noradrenaline, GH, prolactin, ACTH and serum and salivary cortisol (P < 0.001 for all variables). Patients with insufficient HPA axis response had lower hypoglycemia-induced IL-6 increase (median: 0.88 pg/mL) compared with individuals with intact HPA axis response (2.03 pg/mL, P = 0.007). IL-6 maximal increase correlated with the maximal increase of serum cortisol (rs = 0.48; P = 0.013), salivary cortisol (rs = 0.66; P = 0.012), plasma ACTH (rs = 0.48; P = 0.013) and with the increase in procedure-related symptoms of anxiety and hypoglycemia (rs = 0.57; P = 0.003). In conclusion, hypoglycemic stress-induced IL-6 increase is associated with activation of the HPA axis, suggesting that IL-6 response to hypoglycemic stress may be regarded as part of the counter-regulatory response, possibly contributing to the maintenance of glucose homeostasis.

Copeptin response to hypoglycemic stress is linked to prolactin activation in children.

PURPOSE: The physiological role of arginine vasopressin (AVP) in the acute stress response in humans and especially in children is unclear. The aim of this study was to explore the interaction between copeptin, a well-established surrogate marker of AVP release, and anterior pituitary hormone activation in response to acute hypoglycemic stress in children and adolescents. METHODS: We conducted an exploratory single center study involving 77 children and adolescents undergoing insulin-induced hypoglycemia. Blood levels of copeptin, ACTH, cortisol, GH, prolactin, interleukin-6 (IL-6), adrenaline and noradrenaline were determined at baseline and after insulin-induced hypoglycemia. RESULTS: Basal plasma levels of copeptin (median: 5.2 pmol/L) increased significantly after hypoglycemia (median 9.7 pmol/L; P < 0.0001). Subjects with insufficient HPA axis response or severe GH deficiency had lower hypoglycemia-induced copeptin increase (median: 2.3 pmol/L) compared with individuals with intact pituitary response (median: 5.2 pmol/L, P = 0.02). Copeptin increase correlated significantly with the maximal increase of ACTH (rs = 0.30; P = 0.010), cortisol (rs = 0.33; P = 0.003), prolactin (rs = 0.25; P = 0.03), IL-6 (rs = 0.35; P = 0.008) and with BMI-SDS (rs = - 0.28, P = 0.01). In multivariate regression analysis, prolactin increase was the only independent variable associated with copeptin increase (P = 0.0004). CONCLUSION: Our data indicate that: (1) hypoglycemic stress elicits a marked copeptin response in children and adolescents, pointing out its role as an acute stress marker in this population; (2) stress-induced AVP/copeptin release is associated with anterior pituitary activation, mainly a prolactin response.

Clinical and Pathological Aspects of Silent Pituitary Adenomas.

CONTEXT: Silent pituitary adenomas are anterior pituitary tumors with hormone synthesis but without signs or symptoms of hormone hypersecretion. They have been increasingly recognized and represent challenging diagnostic issues. EVIDENCE ACQUISITION: A comprehensive literature search was performed using MEDLINE and EMBASE databases from January 2000 to March 2018 with the following key words: (i) pituitary adenoma/tumor and nonfunctioning; or (ii) pituitary adenoma/tumor and silent. All titles and abstracts of the retrieved articles were reviewed, and recent advances in the field of silent pituitary adenomas were summarized. EVIDENCE SYNTHESIS: The clinical and biochemical picture of pituitary adenomas reflects a continuum between functional and silent adenomas. Although some adenomas are truly silent, others will show some evidence of biochemical hypersecretion or could have subtle clinical signs and, therefore, can be referred to as clinically silent or "whispering" adenomas. Silent tumors seem to be more aggressive than their secreting counterparts, with a greater recurrence rate. Transcription factors for pituitary cell lineages have been introduced into the 2017 World Health Organization guidelines: steroidogenic factor 1 staining for gonadotroph lineage; PIT1 (pituitary-specific positive transcription factor 1) for growth hormone, prolactin, and TSH lineage, and TPIT for the corticotroph lineage. Prospective studies applying these criteria will establish the value of the new classification. CONCLUSIONS: A concise review of the clinical and pathological aspects of silent pituitary adenomas was conducted in view of the new World Health Organization classification of pituitary adenomas. New classifications, novel prognostics markers, and emerging imaging and therapeutic approaches need to be evaluated to better serve this unique group of patients.

A Copeptin-Based Approach in the Diagnosis of Diabetes Insipidus.

BACKGROUND: The indirect water-deprivation test is the current reference standard for the diagnosis of diabetes insipidus. However, it is technically cumbersome to administer, and the results are often inaccurate. The current study compared the indirect water-deprivation test with direct detection of plasma copeptin, a precursor-derived surrogate of arginine vasopressin. METHODS: From 2013 to 2017, we recruited 156 patients with hypotonic polyuria at 11 medical centers to undergo both water-deprivation and hypertonic saline infusion tests. In the latter test, plasma copeptin was measured when the plasma sodium level had increased to at least 150 mmol per liter after infusion of hypertonic saline. The primary outcome was the overall diagnostic accuracy of each test as compared with the final reference diagnosis, which was determined on the basis of medical history, test results, and treatment response, with copeptin levels masked. RESULTS: A total of 144 patients underwent both tests. The final diagnosis was primary polydipsia in 82 patients (57%), central diabetes insipidus in 59 (41%), and nephrogenic diabetes insipidus in 3 (2%). Overall, among the 141 patients included in the analysis, the indirect water-deprivation test determined the correct diagnosis in 108 patients (diagnostic accuracy, 76.6%; 95% confidence interval [CI], 68.9 to 83.2), and the hypertonic saline infusion test (with a copeptin cutoff level of >4.9 pmol per liter) determined the correct diagnosis in 136 patients (96.5%; 95% CI, 92.1 to 98.6; P<0.001). The indirect water-deprivation test correctly distinguished primary polydipsia from partial central diabetes insipidus in 77 of 105 patients (73.3%; 95% CI, 63.9 to 81.2), and the hypertonic saline infusion test distinguished between the two conditions in 99 of 104 patients (95.2%; 95% CI, 89.4 to 98.1; adjusted P<0.001). One serious adverse event (desmopressin-induced hyponatremia that resulted in hospitalization) occurred during the water-deprivation test. CONCLUSIONS: The direct measurement of hypertonic saline-stimulated plasma copeptin had greater diagnostic accuracy than the water-deprivation test in patients with hypotonic polyuria. (Funded by the Swiss National Foundation and others; ClinicalTrials.gov number, NCT01940614 .).