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.

"Micromegaly": Acromegaly with apparently normal GH, an entity on its own?

A small proportion of the patients with acromegaly present with apparently normal basal GH levels and suppressible GH levels despite increased IGF-1 levels, a pattern called micromegaly by some authors. Whether this pattern represents a distinct entity or is just an expression of acromegaly in its early stages is still a matter of debate. Nevertheless, these patients have some peculiar characteristics such as being more likely older and male, mostly harbour microadenomas or small macroadenomas, and have lower IGF-1 and postglucose GH levels. Even though, the frequency and severity of clinical signs and comorbidities are similar to those of patients with classic acromegaly. In conclusion, micromegaly seems to be a distinct clinical entity with a different biological behavior characterized by a low GH output.

Treatment Patterns, Adherence, Persistence, and Health Care Resource Utilization in Acromegaly: A Real-World Analysis.

Context: Treatment of acromegaly is multimodal for many patients, and medical treatments include somatostatin receptor ligands (SRLs), dopamine agonists (DAs), and growth hormone receptor antagonists (GHRAs). However, recent real-world evidence on treatment patterns for patients with acromegaly is limited. Objective: This study evaluated medication usage, treatment changes, adherence, persistence, comorbidities, and health care resource utilization using deidentified data from MarketScan, a US claims database. Methods: Eligible patients (n = 882) were those receiving monotherapy or combination therapy for ≥90 days without treatment gaps. Results: Mean age at diagnosis was 48.6 years; 50.1% of patients were female. Over half (59.4%) had 1 line of treatment (LOT); 23.1% had 2 LOTs; 17.5% had at least 3 LOTs. Most patients (94.6%) initiated treatment with monotherapies. The most common first-line monotherapy treatments were cabergoline (DA, 36.8%), octreotide long-acting release (first-generation SRL, 29.5%), and lanreotide depot (first-generation SRL, 22.5%). Adherence for first-line treatments (proportion of days covered) was higher for first-generation SRLs (lanreotide depot: 0.8) compared with DAs (0.7). Treatment persistence (time between the first treatment record and a change in LOT/censoring) in LOT 1 was higher for GHRAs (24.8 months) and first-generation SRLs (20.0 months) compared with DAs (14.4 months). Female patients and those diagnosed at a younger age were more likely to have shorter treatment persistence. The most prevalent comorbidities were hyperlipidemia, essential hypertension, and sleep apnea. Conclusion: Patients with more comorbidities had more health care visits during the first year after diagnosis, suggesting increased disease burden. Real-world evidence on treatment patterns provides insights into recommendations for individualized therapy.

PRESTO 2: An International Survey to Evaluate Patients' Injection Experiences with the Latest Devices/Formulations of Long-Acting Somatostatin Analog Therapies for Neuroendocrine Tumors or Acromegaly.

INTRODUCTION: Real-world data evaluating patients' injection experiences using the latest devices/formulations of the long-acting (LA) somatostatin analogs (SSAs) lanreotide Autogel/Depot (LAN; Somatuline®) and octreotide LA release (OCT; Sandostatin®) are limited. METHODS: PRESTO 2 was a 2020/2021 e-survey comparing injection experience of adults with neuroendocrine tumors (NETs) or acromegaly treated with LAN prefilled syringe versus OCT syringe for > 3 months in Canada, Ireland, the UK and the USA (planned sample size, 304). PRIMARY ENDPOINT: the proportion of patients with injection-site pain lasting > 2 days after their most recent injection, analyzed using a multivariate logistic regression model. Secondary endpoints included interference with daily life due to injection-site pain and technical injection problems in patients with current SSA use for ≥ 6 months. RESULTS: There were 304 respondents (acromegaly, n = 85; NETs, n = 219; LAN, n = 168; OCT, n = 136; 69.2% female; mean age, 59.6 years). Fewer patients had injection-site pain lasting > 2 days after the most recent injection with LAN (6.0%) than OCT (22.8%); the odds of pain lasting > 2 days were significantly lower for LAN than OCT, adjusted for disease subgroup and occurrence of injection-site reactions (odds ratio [95% confidence interval]: 0.13 [0.06-0.30]; p < 0.0001). Injection-site pain interfered with daily life "a little bit" or "quite a bit" in 37.2% and 3.8% (LAN) versus 52.5% and 7.5% (OCT) of patients, respectively. Among patients with ≥ 6 months' experience with current SSA (92.4% of patients), technical injection problems never occurred in 76.8% (LAN) and 42.9% (OCT) of patients. CONCLUSIONS: Compared with OCT, significantly fewer patients using LAN had injection-site pain lasting > 2 days after their most recent injection. Also, fewer LAN-treated patients experienced technical problems during injection. These findings demonstrate the importance of injection modality for overall LA SSA injection experience for patients with acromegaly or NETs.

Patients with neuroendocrine tumors or acromegaly often receive long-term monthly treatment with somatostatin analogs. These injectable drugs stop the body from making an excess of certain hormones. Understanding patients' experiences of these injections helps to provide better care. The PRESTO 2 online study surveyed 304 patients in Canada, Ireland, the UK and the USA with neuroendocrine tumors or acromegaly who were being treated with a somatostatin analog, either lanreotide Autogel/Depot (LAN) or octreotide long-acting release (OCT). The survey asked about injection experience, including injection-site pain lasting > 2 days and how it affected patients' lives, anxiety before injections and technical problems during injections (like syringe blockages). The survey showed fewer patients receiving LAN than OCT had injection-site pain that lasted > 2 days, and fewer said that the pain interfered with their daily lives. There were fewer technical injection problems with LAN than with OCT. However, more patients receiving LAN than OCT felt anxious before their injection. In some countries (including Canada, Ireland and the UK, but not the USA), the patient (or family member/friend) can inject LAN if they are on a stable dose, their doctor agrees, and they received training. A nurse/doctor must inject OCT. In PRESTO 2, about 40% of non-US patients who were eligible injected themselves (or were helped by a family member/friend). This may explain why more patients reported anxiety in the LAN group. PRESTO 2 provides important insights into patients' experiences of receiving somatostatin analogs and helps identify areas for improving patient care.

Evaluating home injection compared with healthcare-setting injection of somatostatin analogs: a systematic literature review.

PURPOSE: A systematic literature review was conducted to assess the use of home injections (self/partner/healthcare provider [HCP]-administered) of somatostatin analogs (SSAs) as an alternative to healthcare-setting injections in patients with acromegaly and neuroendocrine tumors (NETs). METHODS: MEDLINE/Embase/the Cochrane Library (2001-September 2021), key congresses (2019-2021), and bibliographies of relevant systematic reviews were searched. Eligible studies reported on efficacy/effectiveness, safety, adherence, patient-reported outcomes (PROs), and economic outcomes in populations receiving home injections of SSAs. RESULTS: Overall, 12 studies were included, all reporting on SSAs (lanreotide Autogel/Depot or octreotide long-acting release) in acromegaly or NETs. Across four studies, home injection was associated with similar disease control in patients with acromegaly/NETs compared with healthcare-setting administration. High rates of treatment adherence were shown in two studies of patients with acromegaly receiving lanreotide injections at home. Two studies reported non-serious adverse events; incidence of adverse reactions was similar in both the home and healthcare administration settings. Preference for injection setting varied between studies and indications; nonetheless, higher satisfaction/convenience (>75% patients) was reported for home injections. Self- or partner-injection was associated with economic savings compared with administration in the healthcare setting across five studies. CONCLUSION: Efficacy/effectiveness, adherence, and safety outcomes of SSAs in the home injection setting were similar to those in the healthcare setting, with high reported satisfaction and convenience. Self/partner injection also resulted in cost savings. These findings provide a basis to understand outcomes related to home injection and encourage healthcare providers to discuss optimal treatment choices with their patients.

Prevalence of comorbidities and concomitant medication use in acromegaly: analysis of real-world data from the United States.

PURPOSE: Patients receiving treatment for acromegaly often experience significant associated comorbidities for which they are prescribed additional medications. We aimed to determine the real-world prevalence of comorbidities and concomitant medications in patients with acromegaly, and to investigate the association between frequency of comorbidities and number of concomitantly prescribed medications. METHODS: Administrative claims data were obtained from the IBM® MarketScan® database for a cohort of patients with acromegaly, identified by relevant diagnosis codes and acromegaly treatments, and a matched control cohort of patients without acromegaly from January 2010 through April 2020. Comorbidities were identified based on relevant claims and assessed for both cohorts. RESULTS: Overall, 1175 patients with acromegaly and 5875 matched patients without acromegaly were included. Patients with acromegaly had significantly more comorbidities and were prescribed concomitant medications more so than patients without acromegaly. In the acromegaly and control cohorts, respectively, 67.6% and 48.4% of patients had cardiovascular disorders, the most prevalent comorbidities, and 89.0% and 68.3% were prescribed > 3 concomitant medications (p < 0.0001). Hypopituitarism and hypothalamic disorders, sleep apnea, malignant neoplasms and cancer, and arthritis and musculoskeletal disorders were also highly prevalent in the acromegaly cohort. A moderate, positive correlation (Spearman correlation coefficient 0.60) was found between number of comorbidities and number of concomitant medications in the acromegaly cohort. CONCLUSION: Compared with patients without acromegaly, patients with acromegaly have significantly more comorbidities and are prescribed significantly more concomitant medications. Physicians should consider the number and type of ongoing medications for individual patients before prescribing additional acromegaly treatments.

"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.

Economic and clinical burden of comorbidities among patients with acromegaly.

OBJECTIVE: Acromegaly is a rare, pituitary hormonal disorder that requires improved awareness worldwide. The objective of this analysis was to quantify the clinical and economic burden of comorbidities for patients with acromegaly and examine the influence of biochemical control on these outcomes. STUDY DESIGN: Markov cohort decision analytic model consisting of two states, including alive (with and without comorbidity) and dead. METHODS: A cohort of patients with acromegaly who had achieved biochemical control, a cohort of patients with acromegaly who had not achieved biochemical control, and a cohort of individuals from the general US population were tracked over a lifetime time horizon. The model tracked the proportion of the alive population that had each comorbidity based on age, sex, presence of acromegaly, and biochemical control status. The proportion of patients with each acromegaly-associated comorbidity were assigned comorbidity-associated costs, disutilities, and increased risk of mortality. RESULTS: Compared with the general population, controlled acromegaly resulted in $192,000 additional comorbidity-related costs, 0.7 fewer years of life, 2.9 fewer quality-adjusted life years, and 1.1 more comorbidities across the remaining lifespan. Compared with the general population, uncontrolled acromegaly resulted in $285,000 additional comorbidity-related costs, 0.9 fewer years of life, 4.2 fewer quality-adjusted life years, and 1.6 more comorbidities across the remaining lifespan. CONCLUSIONS: Achieving biochemical control is associated with improvements in cost, quality of life, and mortality, albeit not to the level of the general population. A multimodal treatment strategy including biochemical control and management of comorbidities is necessary to improve patient outcomes.

Health Benefit Costs and Absenteeism Among Employed Patients With Acromegaly.

OBJECTIVE: Acromegaly is associated with increased morbidity and mortality. Limited data are available on these patients' utilization and costs of health care. This study assessed the impact of acromegaly on employees' health benefit (direct and indirect) costs and absenteeism. METHODS: A retrospective analysis was conducted of drug and medical claims and employer data (from January 2010 to April 2019) of patients with an acromegaly diagnosis and matched controls from a U.S. employee database. Patient claims were tracked for 12 months postdiagnosis (or matched) date. Outcomes were analyzed using separate 2-part regression models, controlling for clinical, demographic, and job-related variables. RESULTS: Forty-seven patients with acromegaly and 940 controls were identified. Cohorts were similar in most demographic and job-related variables. Patients with acromegaly had a significantly higher Charlson comorbidity index score and higher incidence of claims for several comorbidities. Acromegaly drugs represented 16.3% of the acromegaly cohort's total costs. Total health benefit costs were $54 821 higher (P < .05) for patients compared with controls, with direct costs representing 79.8% of the difference. Total indirect costs were higher for patients with acromegaly, with short-term and long-term disability comprising most of the difference between the acromegaly and control groups. Patients with acromegaly had significantly more short-term disability days than controls, but total sick days were similar for the 2 groups. CONCLUSION: The presence of acromegaly was associated with increased direct and indirect employee health benefit costs and increased work absenteeism.

Soluble Alpha Klotho in Acromegaly: Comparison With Traditional Markers of Disease Activity.

CONTEXT: Soluble alpha klotho (sαKL) has been linked to growth hormone (GH) action, but systematic evaluation and comparisons with traditional biomarkers in acromegaly are lacking. OBJECTIVE: To evaluate the potential of sαKL to aid classification of disease activity. METHODS: This retrospective study at 2 academic centers included acromegaly patients before surgery (A, n = 29); after surgery (controlled, discordant, or uncontrolled) without (B1, B2, B3, n = 28, 11, 8); or with somatostatin analogue treatment (C1, C2, C3, n = 17, 11, 5); nonfunctioning pituitary adenomas (n = 20); and healthy controls (n = 31). sαKL was measured by immunoassay and compared with traditional biomarkers (random and nadir GH, insulin-like growth factor I [IGF-I], IGF binding protein 3). Associations with disease activity were assessed. RESULTS: sαKL was correlated to traditional biomarkers, particularly IGF-I (rs=0.80, P <0.0001). High concentrations before treatment (A, median, interquartile range: 4.04 × upper limit of normal [2.26-8.08]) dropped to normal after treatment in controlled and in most discordant patients. A cutoff of 1548 pg/mL for sαKL discriminated controlled (B1, C1) and uncontrolled (B3, C3) patients with 97.8% (88.4%-99.9%) sensitivity and 100% (77.1%-100%) specificity. sαKL was below the cutoff in 84% of the discordant subjects. In the remaining 16%, elevated sαKL and IGF-I persisted, despite normal random GH. Sex, age, body mass index, and markers of bone and calcium metabolism did not significantly affect sαKL concentrations. CONCLUSION: Our data support sαKL as a biomarker to assess disease activity in acromegaly. sαKL exhibits close association with GH secretory status, large dynamic range, and robustness toward biological confounders. Its measurement could be helpful particularly when GH and IGF-I provide discrepant information.

Machine Learning-based Prediction Model for Treatment of Acromegaly With First-generation Somatostatin Receptor Ligands.

CONTEXT: Artificial intelligence (AI), in particular machine learning (ML), may be used to deeply analyze biomarkers of response to first-generation somatostatin receptor ligands (fg-SRLs) in the treatment of acromegaly. OBJECTIVE: To develop a prediction model of therapeutic response of acromegaly to fg-SRL. METHODS: Patients with acromegaly not cured by primary surgical treatment and who had adjuvant therapy with fg-SRL for at least 6 months after surgery were included. Patients were considered controlled if they presented growth hormone (GH) <1.0 ng/mL and normal age-adjusted insulin-like growth factor (IGF)-I levels. Six AI models were evaluated: logistic regression, k-nearest neighbor classifier, support vector machine, gradient-boosted classifier, random forest, and multilayer perceptron. The features included in the analysis were age at diagnosis, sex, GH, and IGF-I levels at diagnosis and at pretreatment, somatostatin receptor subtype 2 and 5 (SST2 and SST5) protein expression and cytokeratin granulation pattern (GP). RESULTS: A total of 153 patients were analyzed. Controlled patients were older (P = .002), had lower GH at diagnosis (P = .01), had lower pretreatment GH and IGF-I (P < .001), and more frequently harbored tumors that were densely granulated (P = .014) or highly expressed SST2 (P < .001). The model that performed best was the support vector machine with the features SST2, SST5, GP, sex, age, and pretreatment GH and IGF-I levels. It had an accuracy of 86.3%, positive predictive value of 83.3% and negative predictive value of 87.5%. CONCLUSION: We developed a ML-based prediction model with high accuracy that has the potential to improve medical management of acromegaly, optimize biochemical control, decrease long-term morbidities and mortality, and reduce health services costs.

Burden of acromegaly in the United States: increased health services utilization, location of care, and costs of care.

BACKGROUND: Limited information is available on the utilization and healthcare costs among patients with acromegaly. The purpose of this study was to assess the impact of acromegaly on healthcare utilization and costs by locations of care (LoC). METHODS: Patients with acromegaly and controls were identified from an analysis of drug and medical claims filed from January 2010 to April 2019 from a US employer database. Each patient with acromegaly was matched with 20 random controls (without acromegaly) selected from the database. Claims were tracked for 12 months postdiagnosis (or matched date for controls). Outcomes by LoC, including costs, services, and likelihood of use, were compared using two-stage regression models or logistic regression models, controlling for demographic and job-related variables, and Charlson comorbidity index scores. RESULTS: Claims from 60 patients with acromegaly and 1,200 controls were analyzed. Compared with the control group, patients with acromegaly had significantly higher likelihoods of receiving care in a physician's office [odds ratio > 1,000], inpatient [OR = 8.010], outpatient [OR = 12.656], laboratory [OR = 3.681], and 'other' locations [OR = 4.033] (all p < .001), except in an emergency department (ED). Significantly more services were performed at each LoC for those with acromegaly (p < .01) but not in an ED. Total costs were more than 5-fold higher for the acromegaly cohort compared with controls (p < .05). Costs by LoC were consistently higher (p < .001) for patients with acromegaly vs. controls, with mean annual cost differences greatest in outpatient hospital/clinic ($9,611 vs $1,355), inpatient ($8,646 vs $739), physicians' office ($4,762 vs $1,301), other ($2,001 vs $367), and laboratory ($508 vs $66). ED-related treatment costs were not significantly different between cohorts. CONCLUSIONS: Compared with matched controls, patients with acromegaly were more likely to utilize healthcare services in nearly all LoCs and accrue higher expenditures at each LoC, with the exception of ED services.

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.

Comparative study of complications after primary and revision transsphenoidal endoscopic surgeries.

A preferred treatment for residual/recurrent pituitary adenomas has not been established. The existence of higher complication rates for revision surgeries remains under debate. This study aimed to compare complication rates of primary and revision transsphenoidal endoscopic surgeries and to identify risk factors for complications. Data from 144 primary and 39 revision surgeries were analysed. The surgical complications evaluated were intraoperative and postoperative cerebrospinal fluid (CSF) leaks; meningitis; permanent diabetes insipidus (DI) and hypopituitarism; worsening visual acuity; ophthalmoplegias; visual field defects; otorhinolaryngological, systemic and vascular complications; and death. The variables that were potentially associated with surgical complications were gender, age, comorbidities, lumbar drain use, duration of lumbar drain use, invasion of the sphenoid and cavernous sinuses, presence and degree of suprasellar expansion, preoperative identification of the pituitary, CSF leaks and intraoperative pituitary identification. Intraoperative CSF leaks, visual field losses and worsening visual acuity were more common for revision surgeries. There were no between-group differences in the occurrence of postoperative CSF leaks; systemic, vascular and otorhinolaryngological complications; meningitis; DI and hypopituitarism; ophthalmoplegias; or death. Intraoperative identification of the pituitary was associated with lower rates of permanent DI and hypopituitarism, systemic complications, intraoperative CSF leaks and worsening visual acuity. Suprasellar expansion increased the risk of intraoperative CSF leaks but not endocrinological deficits or visual impairment. Intraoperative CSF leaks were associated with postoperative CSF leaks, meningitis, anterior hypopituitarism, DI and worsening visual acuity. Intraoperative CSF leaks, worsening visual acuity and visual field losses were more common in reoperated patients.

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.

Adaptation and validation of the quality of life assessment of the Cambridge pulmonary hypertension outcome review (CAMPHOR) for Brazil.

BACKGROUND: Pulmonary Hypertension (PH) impacts negatively on patients' health-related quality of life (HRQoL). The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) was the first PH-specific and validated instrument for use in different languages worldwide. This report describes the adaptation and psychometric validation of the CAMPHOR into Brazilian Portuguese language. METHODS: The translation and validation process included a bilingual and lay panel translation; cognitive debriefing interviews; psychometric testing in two repeated times assessing internal consistency, reproducibility and validity of the questionnaire. The Nottingham Health Profile (NHP) questionnaire was used as a comparator to test for convergent validity. RESULTS: The translation captured the same concepts as the English questionnaire and produced a comprehensive instrument in a Brazilian-Portuguese version expressing common, natural language. The psychometric evaluation involved 102 patients (48.8 ± 14.5 years, 80,4% female]. Cronbach's alpha coefficients were above 0.9 on all three CAMPHOR scales. There was excellent test-retest reliability (coefficients above 0.85 on all scales). CAMPHOR Symptoms scale and Activities scale correlated highly with Physical Mobility section and CAMPHOR QoL scale was strongly associated with the Emotional Reactions and Social Isolation sections of NHP. There was a significant association between gender and perceived general health (p < 0.05). There were significant differences in CAMPHOR scale scores between patients who differed according to their perceived disease severity and general health. CONCLUSIONS: The present CAMPHOR version demonstrated good psychometric properties and provides a reliable instrument for assessing HRQL and QoL in Brazilian PH patients, addressing patients' perspective of their illness in a comprehensive way.

Assessment of the performance of the Brazilian Portuguese Nottingham Health Profile in adult growth hormone deficiency and pulmonary hypertension.

Background: The Nottingham Health Profile (NHP) is a generic measure of perceived distress that has been used widely as an outcome measure in clinical practice and trials. The availability of two Brazilian datasets provided the opportunity to assess the psychometric performance of the NHP in different populations - adult growth hormone deficiency (GHD) and pulmonary hypertension (PH). The purpose of the study was to see how valuable the NHP could be in assessing outcomes in diseases where no disease-specific measures are available. Methods: Secondary analyses were performed with NHP data. Patients diagnosed with adult GHD or PH were administered the NHP during clinic visits on two occasions, two weeks apart. A disease-specific measure of quality of life (QoL) was also administered to the relevant sample of patients on each occasion. Results: The psychometric properties of the NHP were good for both disease groups. As expected, both samples reported high scores on energy level, the PH sample scored high on physical functioning and the GHD sample on emotional reactions. For both samples, most of the NHP sections were able to distinguish between groups of respondents with different ratings of perceived general health. While most sections of the NHP were relatively highly correlated with the QoL measures, pain and sleep did not seem to be important predictors of QoL in either of the samples. Conclusions: The use of the NHP in adult GHD and PH populations in Brazil is not recommended as there are high-quality disease-specific measures available for each disease. However, where no disease-specific measures are available, the NHP can provide good descriptive information of the impact of disease on different patient populations.