Active Acromegaly Research Articles

Short-term and long-term remission after endoscopic transnasal adenomectomy in patients with acromegaly

Neurosurgery is the most effective treatment for acromegaly. As most of the patients present with macroadenomas, surgical treatment is not always successful, even with the expert level of a neurosurgeon. Assessment of the postoperative remission rates in acromegaly preoperative predictors of treatment efficacy is an urgent task of modern research. To assess the short-term and long-term remission of acromegaly after endoscopic transnasal adenomectomy in a tertiary medical center and assess preoperative predictors of the treatment effectiveness. A single-center, prospective, uncontrolled study was conducted. We included patients with active acromegaly who did not receive medical therapy with somatostatin analogues and were referred for endoscopic transsphenoidal adenomectomy. Plasma miRNA expression was assessed by quantitative reverse transcription PCR. Postoperative samples of adenomas were sent for study, with the determination of the immunohistochemical staining for somatostatin receptors 2 and 5 subtypes and morphology was performed on postoperative adenoma samples. The study included 44 patients: 32.8% men, median age 47.0 [34.0; 55.0], IGF-1 744.75 ng/ml [548.83;889.85], growth hormone 9.5 ng/ml [4.94; 17.07]. Tumor volume 832 mm3 [419.25; 2532.38]. Early postoperative remission was achieved in 35 patients (79.5%). Patients who achieved short-term remission had higher IGF-1 and basal growth hormone levels. Median follow-up was 19.0 months [12.5;29.0]. Long-term remission was achieved in 61.4% (27 patients), no remission in 9 (20.5%), recurrency in 2 patients (4.5%), 6 patients were to follow-up (13.6%). In patients with long-term remission, we observed lower growth hormone and IGF-1 levels. No differences in miRNA expression was observesd. The predictive value of basal GH before surgery for long-term remission was assessed: area under the curve 0.811 (95% CI: 0.649; 0.973). A cut-off value of 15.55 ng/mL corresponded to a sensitivity of 70.0% (34.8%; 93.3%), a specificity of 85.7% (67.3%; 96.0%), an accuracy of 81.6% (65 .7%; 92.3%), PPV 63.6% (39.3%; 82.5%), NPV 88.9% (75.4%; 95.4%). Rates of short-term and long-term remission after endoscopic transsphenoidal adenomectomy in our cohort is 79,5% и 61,4%, respectively, and is comparable with literature data for expert pituitary centers. Preoperative GH shows potential value in predicting the long-term remission of acromegaly, but further studies in a larger sample are needed to obtain more accurate cut-off values.

Delayed postoperative hyponatremia in patients with acromegaly: incidence and predictive factors.

Delayed postoperative hyponatremia (DPH) is a unique complication of transsphenoidal surgery (TSS) in pituitary tumors. Growth hormone (GH) enhances renal sodium reabsorption; however, the association between postoperative GH reduction and DPH in acromegaly is unclear. This study was performed to clarify the incidence of and the predictive factors for DPH in patients with acromegaly who underwent TSS. Ninety-four patients with active acromegaly were examined retrospectively. During the postoperative course, patients with serum sodium levels ≤ 134mEq/L were classified into the DPH group. We compared basic clinical characteristics, tumor characteristics, and preoperative and postoperative examination findings between the DPH and non-DPH groups. DPH occurred in 39 patients (41.5%), and the lowest serum sodium levels were generally observed during postoperative days (PODs) 7-9. They needed a 3-day longer hospital stay than those without DPH. The DPH group had lower preoperative body weight and body mass index. In addition, a transient increase in body weight during PODs 5-7 occurred with a transient decrease in urinary volume in the DPH group. Preoperative and postoperative GH and insulin-like growth factor-1 levels did not differ between the twogroups. The findings suggested that lower preoperative weight and a postoperative transient gain in body weight are associated with an increased risk of DPH in acromegaly patients undergoing transsphenoidal surgery.

PMON161 Decreased serum Wnt antagonist levels in patients with active acromegaly

Abstract Objectives The Wnt signalling pathway is an important modulator of bone metabolism. This study aims to clarify the changes in Wnt antagonists in active and biochemically controlled acromegalic patients. Methods We recruited 77 patients newly diagnosed with acromegaly. Of those, 41 patients with complete follow-up data were included. Thirty healthy patients matched for age, sex, and body mass index served as controls. Wnt antagonists [sclerostin (SOST), dickkopf-related protein 1 (DKK-1), and Wnt inhibitory factor 1 (WIF-1)], bone turnover markers [osteocalcin, procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX)] and the bone remodelling index were investigated at baseline and posttreatment. Results Acromegalic patients had higher serum osteocalcin, P1NP, and CTX and a higher bone remodelling index than controls (all P < 0.01). Serum SOST, DKK-1 and WIF-1 levels were significantly decreased in acromegalic patients compared to controls (all P < 0.01). Serum SOST and WIF-1 levels correlated negatively with growth hormone levels; SOST levels were positively correlated with WIF-1. Posttreatment, serum bone turnover markers and the bone remodelling index decreased, while SOST and WIF-1 significantly increased (P < 0.05). DKK-1 levels did not change compared to baseline (P > 0.05). In biochemically controlled patients, SOST, WIF-1 and bone turnover markers almost reached normal levels (all P > 0.05). Conclusion Patients with active acromegaly exhibited significantly decreased Wnt antagonist levels. The reduction in Wnt antagonists might be involved in the compensatory mechanism of increased bone fragility in active acromegaly. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

LBMON175 Nadir Growth Hormone Concentrations In Patients With Acromegaly Relate To Disease Activity, Glucose Metabolism, BMI And Sex

Abstract Background In healthy subjects, nadir growth hormone (GH) concentrations following an oral glucose load are related to BMI, gender and estrogen use. To date, very few data exist on factors influencing nadir GH in patients with acromegaly. Methods Glucose suppression tests (2h-75g) were performed in 166 patients with acromegaly not receiving any acromegaly-specific medical therapy: 132 OGTTs were performed at the initial disease diagnosis and 126 after at least one pituitary surgery. Glucose, insulin and C-peptide were measured every 30 minutes and the metabolic response was evaluated by minimal model analysis. Uni- and multivariate regression analysis was performed to test the relationship between nadir GH concentrations, patient characteristics and parameters of disease activity, lipid and glucose metabolism. Results In patients with active acromegaly (46% males), nadir glucose concentrations positively correlated to fasting IGF-1 (expressed as fold-ULN; p<0. 001), fasting insulin and C-peptide (both p=0. 004), HOMA-insulin resistance index (p=0. 016), and prehepatic beta-cell function (p=0. 002), but not to BMI and gender. In multivariate analysis, fasting C-peptide and IGF-1 were both independent predictors of nadir GH levels in patients with newly diagnosed acromegaly (p<0. 001). When testing for sex-specific predictors of nadir GH, we found a negative relationship between nadir GH and age in male patients, but not in females. After surgery, IGF-1 decreased from 805.5 (3.2 xULN, IQR 437.8) to 277.5 ng/ml (1.1 xULN, IQR 234. 0) and nadir GH after glucose suppression decreased from 8.8 (IQR 16.2) to 0.5 ng/ml (IQR 1.9). The decrease in biomarkers of disease activity following surgery leads to changes in predictors of nadir GH: postoperatively nadir GH relates to IGF-1 (p<0. 001), prehepatic beta-cell function (p=0. 02), weight (p=0. 031) and BMI (p=0. 044), with beta-cell-function being the only independent predictor in multivariate analysis (p=0. 003). When postoperative OGTTs performed in men and women were separately analyzed, nadir GH remained in a positive relationship to GH and IGF-1 in both sexes, but the relationship with beta-cell-function and other parameters of glucose metabolism remained significant only in male patients. In addition, postoperative nadir GH in male patients positively relates to LDL-cholesterol and triglycerides, and negatively to gonadal axis activity. Conclusion Here we describe that nadir GH concentrations in patients with acromegaly are mainly determined by parameters of disease activity and beta-cell function, but not by BMI and sex. A positive relationship between nadir GH and weight/BMI is only observed following improvement of disease activity after surgery, but appears mainly influenced by morphologic gender differences, as it disappears when male and female cohorts are analyzed separately. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Frequency of hyperostosis frontalis interna in patients with active acromegaly: is there a possible role of GH excess or hyperprolactinemia in its etiopathogenesis?

Acromegaly is characterized by bone changes due to excessive growth hormone (GH) secretion. Hyperostosis frontalis interna (HFI) is described as an overgrowth in the inner plate of the frontal bone. An increased incidence of HFI has been reported in patients with acromegaly. Since the etiology of HFI is poorly understood, we have analyzed whether there is a relationship between the hormonal and metabolic status of patients with acromegaly (with or without hyperprolactinemia) and the pathogenesis of HFI. Forty-five patients with acromegaly and two control groups consisting of 25 patients with prolactinoma (group 1) and 47 healthy subjects (group 2) were included in this retrospective study. Baseline hormonal data and cranial imaging were obtained from medical records and analyzed. Mean frontal bone thickness was 6.75mm in acromegaly, 4.85mm in group 1, and 5.1mm in group 2 of controls (p < 0.001). The frequency of HFI was higher in acromegalic patients than in the controls (22%, 0%, and 2.2%, respectively). There was no difference between the HFI positive and negative acromegalic patients in basal GH, IGF-1, and PRL levels, IGF-1 index, diagnosis lag time, and insulin resistance. There was no difference between groups regarding parietal and occipital bone thickness. Although the frequency of HFI is 22% in patients with acromegaly, neither excess GH nor hyperprolactinemia plays a role in its etiopathogenesis. Various genetic or epigenetic factors may contribute to its etiology.

Assessment of right ventricular functions in acromegaly: comparison of active disease with remission.

Aim Cardiac involvement in acromegaly is defined as acromegalic cardiomyopathy, an insidious and chronic disease. Previous research on acromegalic cardiomyopathy was largely focused on morphological and functional assessment of the left heart. Since the literature data regarding right heart function in acromegalic patients are limited, we aimed to evaluate the structure and function of the right heart in such patients.Material and Methods We included 43 adult participants as the acromegaly group and 42 individuals as the control group. All patients underwent echocardiographic evaluation. The results were compared between acromegaly and control groups and between active and controlled acromegaly groups.Results The acromegaly group had increased interventricular septum thickness, right ventricular (RV) free wall thickness, right atrium (RA) minor diameter, RV basal and longitudinal diameters, RV end-diastolic and end-systolic areas, E / E' ratio, isovolumetric relaxation time, and RV ejection time. The E / A ratio and E' velocity were reduced. GH and IGF-1 were positively correlated with RV longitudinal diameter, indexed RA minor-axis dimension, and indexed RV end-diastolic area. Patients with active acromegaly had increased RV index of myocardial performance (RVIMP) and isovolumetric contraction time and shortened RV ejection time compared to patients in remission. A RVIMP value of 0.435 predicted active acromegaly with a sensitivity and specificity of 0.83 and 0.64, respectively (p=0.002).Conclusions Increases in the size and diameters of the right heart chambers along with RV free wall thickness may be attributed to acromegalic cardiomyopathy. RVIMP, isovolumetric contraction time, and ejection time are parameters that can be used in the evaluation of active acromegaly disease.

Impact of the diagnostic delay of acromegaly on bone health: data from a real life and long term follow-up experience

IntroductionAcromegaly is a chronic disease with systemic complications. Disease onset is insidious and consequently typically burdened by diagnostic delay. A longer diagnostic delay induces more frequently cardiovascular, respiratory, metabolic, neuropsychiatric and musculoskeletal comorbidities. No data are available on the effect of diagnostic delay on skeletal fragility. We aimed to evaluate the effect of diagnostic delay on the frequency of incident and prevalent of vertebral fractures (i-VFs and p-VFs) in a large cohort of acromegaly patients.Patients and methodsA longitudinal, retrospective and multicenter study was conducted on 172 acromegaly patients.ResultsMedian diagnostic delay and duration of follow-up were respectively 10 years (IQR: 6) and 10 years (IQR: 8). P-VFs were observed in 18.6% and i-VFs occurred in 34.3% of patients. The median estimated diagnostic delay was longer in patients with i-VFs (median: 11 years, IQR: 3), in comparison to those without i-VFs (median: 8 years, IQR: 7; p = 0.02). Age at acromegaly diagnosis and at last follow-up were higher in patients with i-VFs, with respect to those without i-VFs. The age at acromegaly diagnosis was positively associated with the diagnostic delay (p < 0.001, r = 0.216). A longer history of active acromegaly was associated with a high frequency of i-VFs (p = 0.03). The logistic regression confirmed that patients with a diagnostic delay > 10 years had 1.5-folds increased risk of developing i-VFs (OR: 1.5; 95%CI: 1.1–2; p = 0.017).ConclusionOur data showed that the diagnostic delay in acromegaly has a significant impact on VF risk, further supporting the clinical relevance of an early acromegaly diagnosis.

Low-rank fusion convolutional neural network for prediction of remission after stereotactic radiosurgery in patients with acromegaly: a proof-of-concept study.

Artificial intelligence approaches to analyze pathological images (pathomic) for outcome prediction have not been sufficiently considered in the field of pituitary research. A total of 5,504 hematoxylin & eosin-stained pathology image tiles from 58 acromegalic patients with a good or poor outcome were integrated with other clinical and genetic information to train a low-rank fusion convolutional neural network (LFCNN). The model was externally validated in 1,536 patches from an external cohort. The primary outcome was the time to the first endocrine remission after stereotactic radiosurgery (SRS). The median time of initial endocrine remission was 43 months (interquartile range [IQR]: 13-60 months) after SRS, and the 24-month initial cumulative remission rate was 57.9% (IQR: 46.4-72.3%). The patient-wise accuracy of the LFCNN model in predicting the primary outcome was 92.9% in the internal test dataset, and the sensitivity and specificity were 87.5 and 100.0%, respectively. The LFCNN model was a strong predictor of initial cumulative remission in the training cohort (hazard ratio [HR] 9.58, 95% confidence interval [CI] 3.89-23.59; p < 0.001) and was higher than that of established prognostic markers. The predictive value of the LFCNN model was further validated in an external cohort (HR 9.06, 95% CI 1.14-72.25; p = 0.012). In this proof-of-concept study, clinically and genetically useful prognostic markers were integrated with digital images to predict endocrine outcomes after SRS in patients with active acromegaly. The model considerably outperformed established prognostic markers and can potentially be used by clinicians to improve decision-making regarding adjuvant treatment choices. © 2022 The Pathological Society of Great Britain and Ireland.

Disabling peripheral neuropathy and radiculomyelopathy at the time of presentation in a patient with active acromegaly; A case report

Official Journal of the Endocrine Society of Sri Lanka. The Sri Lanka Journal of Diabetes Endocrinology and Metabolism (SJDEM) publishes original research articles, reviews, and other special features related to diabetes, endocrinology and metabolism in humans and human tissue.

Clinical and functional outcome of total hip arthroplasty in patients with acromegaly: mean twelveyear follow-up.

Acromegaly is a rare and chronic hormonal disorder. Persons with acromegaly frequently live well into adulthood. Patients with active acromegaly have multiple joint-related issues; however, acromegalic arthropathy (AA), which is secondary osteoarthritis (OA), is considered one of the most common musculoskeletal complications of acromegaly. This study aims to analyze a cohort of patients who underwent total hip arthroplasty (THA) for AA at our institution and present the long-term clinical outcomes and causes of revision in these patients. All patients, who underwent total hip arthroplasty due to secondary osteoarthritis related to acromegaly between January 2001 and December 2019 at our institution, were included in this retrospective study. There were 15 patients (22 hips) with a mean follow-up of 12years (range 4-20). Survivorship free of component revision was determined using Kaplan-Meier analysis. Patient-reported clinical outcomes were assessed using Harris Hip Scores. At the final follow-up, the status of the implant was known in all 15 hips. No patients were lost to follow-up. Five patients (9 hips) were deceased. Three hips (14%) underwent a revision surgery at a mean of six years (range 3-10). Survivorship free of component revision was 81% at 15years. Mean Harris Hip Scores at final follow-up were fair (mean 64.3, range 32-91), but significantly improved compared to preoperative scores (p < 0.05). Acromegaly is a rare disorder that has direct effects on bone and joints. Our results suggest that THA can result in successful clinical and functional outcomes in patients with AA of the hip however the risk of aseptic loosening should also be considered in this patient population.

Gene expression profiling of subcutaneous adipose tissue reveals new biomarkers in active acromegaly

Gene expression profiling of subcutaneous adipose tissue reveals new biomarkers in active acromegaly

Medical treatment of active acromegaly - the results from the Croatian Acromegaly Registry

Medical treatment of active acromegaly - the results from the Croatian Acromegaly Registry

Abstract 108: A case of familial acromegaly

We present a 22-year-old female who complained of headache and coarsening of facial appearance over 3 years without any visual disturbance/galactorrhoea/menstrual disturbance. There was a similar history in her mother at 44 years of age who underwent surgery and radiotherapy. On examination she had clinical features suggestive of active acromegaly with unremarkable systemic examination. Biochemistry revealed high IGF-1 (891 ng/ml), non suppressed post glucose load GH (19.3 ng/ml) without other pituitary hormone deficits. MRI Sella showed sellar suprasellar lesion suggestive of pituitary macroadenoma with chiasmal compression. In view of strong family history, a clinical exome sequencing was done which showed a heterozygous nonsense variation in exon 6 of the AIP gene (chr11:g.67490910C>T).

Characterization of vitamin D metabolism in active acromegaly in the setting of bolus (150,000 IU) cholecalciferol treatment.

To reveal distinctive features of vitamin D metabolism in patients with active acromegaly compared to healthy individuals, particularly in the setting of cholecalciferol treatment. The study group included 34 adults with active acromegaly, and the control group included 30 apparently healthy adults with similar age, sex, and BMI. All participants received a single dose (150,000 IU) of cholecalciferol aqueous solution orally. Laboratory assessments including serum vitamin D metabolites (25(OH)D3, 25(OH)D2, 1,25(OH)2D3, 3-epi-25(OH)D3 and 24,25(OH)2D3), free 25(OH)D, vitamin D-binding protein (DBP) and parathyroid hormone (PTH) as well as serum and urine biochemical parameters were performed before the intake and on Days 1, 3, and 7 after the administration. All data were analyzed with nonparametric statistics. Patients with acromegaly had tendency to lower baseline 25(OH)D3 levels (p = 0.05) and lower 25(OH)D3 levels (p < 0.05) during the follow-up. They were also characterized by PTH suppression (lower baseline PTH levels and lower prevalence of secondary hyperparathyroidism), altered production of main vitamin D metabolites (higher 1,25(OH)2D3 and lower 24,25(OH)2D3 levels with corresponding lower 25(ОН)D3/1,25(ОН)2D3 and higher 25(ОН)D3/24,25(ОН)2D3 ratios) as well as concordant biochemical features (higher levels of serum phosphorus and albumin-adjusted calcium levels) throughout the study (p < 0.05). The acromegaly group showed an increase in DBP levels after cholecalciferol intake as opposed to the control group (p < 0.05) and had lower increase in free 25(OH)D levels (p < 0.05). Δ25(OH)D3 was similar between the groups (p > 0.05), showed a negative correlation with the disease activity markers-both IGF-1 levels (r = -0.44, p < 0.05) and fasting GH levels (r = -0.56, p < 0.05)-and lacked correlation with BMI in the acromegaly group (p > 0.05). Patients with active acromegaly have dysregulated vitamin D metabolism characterized by higher 1,25(ОН)2D3, lower 24,25(ОН)2D3 and altered DBP production. The response to vitamin D supplementation in acromegaly patients might be influenced by hormonal excess. Obtained results require reproducibility check and further study to develop specific clinical recommendations. NCT04844164 (release date: April 9, 2021; retrospectively registered).

Subclinical Ventricular Dysfunction in Long-Term Acromegaly Assessed by Speckle-Tracking Echocardiography.

IntroductionSymptomatic heart disease may be present in patients with advanced-stage acromegaly. However, earlier assessment of subclinical ventricular systolic dysfunction can be accomplished through speckle-tracking echocardiography (STE) for the study of myocardial strain. The few such studies in this population to date have produced conflicting results. This study was performed to evaluate the parameters of ventricular strain in patients with acromegaly with no cardiac symptoms.MethodsIn this prospective observational study, STE was performed in patients with active acromegaly with no detectable heart disease and in a control group to assess ventricular dysfunction through global longitudinal strain (GLS), radial strain, circumferential strain, and twist. The left ventricular (LV) ejection fraction, LV mass index, and relative wall thickness were also compared between the groups.ResultsTwenty-five patients with active acromegaly (median age, 49 years; median disease duration, 11 years) and 44 controls were included. LV hypertrophy was more prevalent in the acromegaly group (40% vs. 19%, p < 0.01). The LV ejection fraction was similar between the groups (65.2% ± 5.99% vs. 62.9% ± 7.41%). The mean GLS (−18.8 ± 2.49 vs. −19.7 ± 3.29, p = 0.24), circumferential strain (−16.7 ± 3.18 vs. −16.6 ± 3.42, p = 0.90), and twist (14.6 ± 5.02 vs. 15.1 ± 3.94, p = 0.60) were not significantly different between the groups.ConclusionDespite showing higher rates of LV hypertrophy, patients with long-term acromegaly had no impairment of ventricular contractility as assessed by strain echocardiography when compared with a control group.

Decreased Serum Wnt Antagonist Levels in Patients With Active Acromegaly

ObjectiveThe Wnt signaling pathway is an important modulator of bone metabolism. This study aims to clarify the changes in Wnt antagonists in active and biochemically controlled acromegalic patients. MethodsWe recruited 77 patients recently diagnosed with acromegaly. Of those, 41 patients with complete follow-up data were included. Thirty healthy patients matched for age, sex, and body mass index served as controls. At baseline and posttreatment, Wnt antagonists (sclerostin [SOST], dickkopf-related protein 1 [DKK-1], and Wnt inhibitory factor 1 [WIF-1]), bone turnover markers (osteocalcin, procollagen type 1 N-terminal propeptide [P1NP], and C-terminal telopeptide of type 1 collagen [CTX]) and the bone remodeling index were investigated. ResultsAcromegalic patients had higher serum osteocalcin, P1NP, and CTX and a higher bone remodeling index than controls (P < .01). Serum SOST, DKK-1, and WIF-1 levels were significantly decreased in patients compared to controls (all P < .01). Serum SOST and WIF-1 levels were negatively correlated with growth hormone levels; SOST levels were positively correlated with WIF-1. After treatment, serum bone turnover markers and the bone remodeling index decreased, while SOST and WIF-1 significantly increased (P < .05). DKK-1 levels did not change compared to baseline (P > .05). In biochemically controlled patients, SOST and WIF-1 levels and bone turnover markers were restored and did not differ from those of the control participants (all P > .05). ConclusionPatients with active acromegaly exhibited significantly decreased Wnt antagonist levels. The reduction in Wnt antagonists is a compensatory mechanism to counteract increased bone fragility in active acromegaly.

Optimal timing of blood samplings to detect GH inhibition during oral glucose tolerance test.

In patients with suspected acromegaly, evaluation of IGF-I is recommended as first-line test, while the assessment of GH-nadir during oral glucose tolerance test (OGTT) is advised as confirmatory test. The procedure of this test generally involves GH measurement every 30min (30') from baseline to +120' or +180'. However, the optimal timing of samplings for the distinction between patients with or without active acromegaly is still a matter of debate. Sixty-seven healthy subjects and 46 acromegalic patients who achieved documented and persistent long-term cure were enrolled. A greedy algorithm was used to identify the minimal subset of time-points that sufficed to correctly detect GH suppression. The sampling at 90' was the one in which a GH level < 1μg/L was most frequently achieved (i.e., in 91.3% of cured acromegalic patients and in 91.0% of healthy subjects). Considering the whole cohort, the best combination of 2 time-points was +90' and +150' and achieved 95.6% accuracy; the best combination of 3 time-points was +60', +90' and +150' and achieved 99.1% accuracy. The minimal subset of GH determinations that demonstrated perfect accuracy (100%) needed the inclusion of 4 time-points, namely +60', +90', +120' and +150'. A subset of 4 time-points (60' - 90' - 120' - 150') was identified as the most relevant to detect GH suppression at OGTT, with a perfect classification of 100% of subjects. This supports the possibility to restrict the blood samplings to these time-points when assessing disease cure, with possible advantages in terms of saving time and lowering costs.

Prevalence of sleep apnea and lung function abnormalities in patients with acromegaly.

Background:Sleep apnea (SA) is highly prevalent in acromegaly. Ethnicity influences the prevalence of SA in the general population. We studied the prevalence of SA and other respiratory comorbidities in North Indian patients with active acromegaly.Design:Prospective, observational.Materials and Methods:Consecutive adult patients with active acromegaly (n = 35, age 39.7 ± 13.2 years) and hypersomatotropism (nonsuppression of serum growth hormone after oral glucose and elevated serum insulin-like growth factor-1 [IGF-1]) were evaluated for respiratory symptoms, scoring for SA (Epworth Sleepiness Score [ESS] and STOP-BANG), pulmonary function tests (PFT), high-resolution computerized tomography (HRCT) of the thorax, polysomnography (PSG), and transthoracic echocardiography. Age- and sex-matched healthy individuals (n = 34) served as controls.Results:Acromegaly subjects had dyspnea (34%), cough (37%), excessive daytime somnolence (43%), and fatigue (49%). Clinically significant ESS (>10) and STOP-BANG score (≥3) were present in 41% and 68.6% of subjects, respectively. PFT showed restrictive and obstructive patterns in 45.7% and 11.4% of acromegalics respectively; with higher total lung capacity (TLC), thoracic gas volume (TGV), and residual volume (RV). PSG revealed significantly higher SA events in acromegalics (central [acromegaly 24.63 ± 37.82 vs. control 3.21 ± 5.5], mixed [11 ± 19.46 vs. 3.50 ± 5.96], obstructive [34.86 ± 44.37 vs. 9.71 ± 10.48], and mean apnea-hypopnea index [AHI] [16.91 ± 18.0 vs. 7.86 ± 7.84]). Acromegalics had significantly higher prevalence of obstructive SA (71.4% [mild 31.4%, moderate 20%, severe 20%]) as compared to controls (38.2%). There was no correlation of AHI with serum IGF-1 and disease duration.Conclusion:Acromegaly subjects have a significantly higher prevalence of respiratory symptoms, SA, and abnormalities in PFT. Screening for respiratory comorbidities should be routinely recommended in all patients with acromegaly.

Reversible insulin resistance in muscle and fat unrelated to the metabolic syndrome in patients with acromegaly.

SummaryBackgroundPatients with active acromegaly exhibit insulin resistance despite a lean phenotype whereas controlled disease improves insulin sensitivity and increases fat mass. The mechanisms underlying this paradox remain elusive, but growth hormone (GH)-induced lipolysis plays a central role. The aim of the study was to investigative the molecular mechanisms of insulin resistance dissociated from obesity in patients with acromegaly.MethodsIn a prospective study, twenty-one patients with newly diagnosed acromegaly were studied at diagnosis and after disease control obtained by either surgery alone (n=10) or somatostatin analogue (SA) treatment (n=11) with assessment of body composition (DXA scan), whole body and tissue-specific insulin sensitivity and GH and insulin signalling in adipose tissue and skeletal muscle.FindingsDisease control of acromegaly significantly reduced lean body mass (p<0.001) and increased fat mass (p<0.001). At diagnosis, GH signalling (pSTAT5) was constitutively activated in fat and enhanced expression of GH-regulated genes (CISH and IGF-I) were detected in muscle and fat. Insulin sensitivity in skeletal muscle, liver and adipose tissue increased after disease control regardless of treatment modality. This was associated with enhanced insulin signalling in both muscle and fat including downregulation of phosphatase and tensin homolog (PTEN) together with reduced signalling of GH and lipolytic activators in fat.InterpretationIn conclusion, the study support that uncontrolled lipolysis is a major feature of insulin resistance in active acromegaly, and is characterized by upregulation of PTEN and suppression of insulin signalling in both muscle and fat.FundingThis work was supported by a grant from the Independent Research Fund, Denmark (7016-00303A) and from the Alfred Benzon Foundation, Denmark.

“Subclinical atherosclerosis in acromegaly: Possible association with cardiovascular risk factors rather than disease activity”

ObjectiveCardiovascular (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. DesignWe 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. Resultsmean ± 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). ConclusionsOur 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.