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Purpose: First-line medical therapy for acromegaly management includes first-generation somatostatin receptor ligands (fgSRLs), but resistance limits their use. Despite international guidelines, the choice of second-line therapy is debated., Methods: We aim to discuss resistance to fgSRLs, identify second-line therapy determinants and assess glycemia's impact to provide valuable insights for acromegaly management in clinical practice. A group of Italian endocrinologists expert in the pituitary field participated in a two-round Delphi panel between July and September 2023. The Delphi questionnaire encompassed a total of 75 statements categorized into three sections: resistance to fgSRLs therapy and predictors of response; determinants for the selection of second-line therapy; the role of glycemia in the therapeutic management. The statements were rated on a 6-point Likert scale., Results: Fifty-nine (79%) statements reached a consensus. IGF-1 levels resulted central for evaluating resistance to fgSRLs, that should be defined considering also symptomatic clinical response, degree of tumor shrinkage and complications, using clinician- and patient-reported outcome tools available. Factors to be evaluated for the choice of second-line medical therapy are hyperglycemia-that should be managed as in non-acromegalic patients-tumor remnant, resistant headache and compliance. Costs do not represent a main determinant in the choice of second-line medical treatment., Conclusion: The experts agreed on a holistic management approach to acromegaly. It is therefore necessary to choose currently available highly effective second-line medical treatment (pegvisomant and pasireotide) based on the characteristics of the patients., (© 2024. The Author(s).)

Objective: Pasireotide LAR (PAS-LAR) was released in Italy in 2017 to treat acromegaly patients resistant to SRLs (Somatostatin Receptors Ligands). The long-term follow-up data of PAS-LAR therapy in Italy are limited. This study aimed to evaluate the efficacy and safety of PAS-LAR in acromegaly., Design: Patients with acromegaly in PAS-LAR treatment were enrolled in three tertiary Italian endocrinological centers and evaluated by a retrospective observational real-life multicentre study., Methods: Patients have been studied before (baseline) and 1, 6, 12, 24 and > 36 months after PAS-LAR start. Clinical, biochemical, and pituitary magnetic resonance data were collected, along with information on adverse events. Acromegaly disease activity was classified according to the IGF-1 index (normal value < 1.0)., Results: Fifty patients (female 23) were enrolled. PAS-LAR treatment (mean follow-up 24 ± 16 months) significantly decreased IGF-1 levels (IGF-1 index baseline vs last visit: 1.9 ± 0.6 vs 1.2 ± 0.6, p < 0.0001). At the last visit, 67% of patients had controlled disease, and 44% showed a decrease in tumor volume. Clinical and biochemical efficacy was observed as early as after 1-month of PAS-LAR treatment (IGF-1 index baseline vs 1-month: 1.9 ± 0.6 vs 1.4 ± 0.7, p < 0.0001). Also, 50% of patients referred headache improvement or disappearance. Fifteen patients discontinued PAS-LAR due to failure of treatment and poor glycaemic control. The prevalence of diabetes increased from 33% at the baseline to 54% at the last visit (p = 0.0072)., Conclusion: In real-life settings, PAS-LAR significantly decreases symptoms, IGF-1 levels, and the size of adenoma in patients with acromegaly resistant to SRLs. Beneficial effects may occur early after the first injection., (© 2024. The Author(s).)

Acromegaly is a chronic and progressive disorder caused by growth hormone (GH) and insulin-like growth factor 1 (IGF-1) excess, responsible for the onset of multiple systemic complications. Targets of acromegaly treatment are the normalization of hormonal (GH/IGF-1) parameters, the removal/reduction/stabilization of the pituitary mass, the control of existing conditions, and the prevention of new ones, so to improve quality of life and normalize life expectancy. Patients often require a multimodal therapeutic approach, including surgery, medical therapy, and radiotherapy, that allows disease cure/control in the majority of the cases. However, some pituitary tumors are resistant to treatments and/or recur. Novelties in the field of medical treatment in acromegaly can be summarized as follows: (a) new protocols applied to existing medications; (b) new devices to administer old drugs; (c) new formulations, and (d) new drugs. In this review, we aim at summarizing the current protocols and drugs to treat acromegaly (standard of care), and presenting the new pharmacological options including those drugs that are still being tested and could be released in the market in the next few years., (© 2024 S. Karger AG, Basel.)

Objective: Acromegaly is associated with somatic disfigurements which impair self-perception of well-being and quality of life. Nowadays, limited data are available on the interplay between hormonal excess and psychological discomfort. The study aimed at investigating the psychological profile, sleep quality, sexual function, cognitive functions, and quality of life in patients with acromegaly., Methods: In 223 acromegaly patients from 5 referral centres, global psychological profile, sleep quality, sexual function, cognitive function, and quality of life were investigated., Results: Depression was found in ~30% of patients, and anxiety in two-thirds, together with severe discomfort in body image mainly in women. Obstructive sleep apnoea syndrome risk and sleep disorders were found in >50% of patients and daily sleepiness in ~20%. Sexual dysfunction was reported in most of the patients, with the most severe impairment in women. Cognitive functions were compromised in ~10% of cases. Disease duration and patient's age and gender were the main determinants of these psychopathological conditions. Depression (P = 0.047), somatic-affective mood lowering (P = 0.021), state (P < 0.001) and trait (P = 0.013) anxiety, and body image distortion in body uneasiness test A (P < 0.001) and B (P = 0.006) were significantly worsened in patients <45 years and slightly worsened in those with disease duration less than 2 years. Male (P < 0.001) and female (P < 0.001) sexual function scores were significantly worsened in patients aged >64 years and slightly worsened in those with disease duration for more than 10 years, particularly in presence of cardiometabolic and respiratory complications. Cognitive symptoms were slightly worsened in older patients and in those with long disease duration., Conclusions: Acromegaly is associated with a relevant impairment of psychological profile persisting despite remission and long-term medical treatment.

Purpose: Acromegaly is a rare chronic disease characterized by systemic comorbidity and reduced quality of life. Although achieving biochemical control has always been the primary goal of acromegaly therapy, recent evidence has shown that the traditional assessment does not adequately capture the complexity of symptoms and patients' perception. These findings result in the need to improve a fast decision-making process of the clinician, who should not only take into account biochemical-instrumental criteria, but also patients' symptoms. With the aim of supporting the clinician in the diagnostic and therapeutic decision-making process several disease-specific tools have been developed. The aim of this review is to provide a description of the acromegaly-specific tools, presenting their main features, their application in daily practice, and their efficacy and utility., Methods: A systematic search of Medline/PubMed, ISI-Web of Knowledge, and Google Scholar databases was done., Results: Specific instruments and questionnaires have recently been developed to assist clinicians in the assessment of acromegaly. These are either Patient-Reported Outcome tools, such as Acromegaly Quality of Life Questionnaire (AcroQoL) and Pain Assessment Acromegaly Symptom Questionnaire (PASQ), or Clinician-Reported Outcome tools, such as ACROSCORE, SAGIT ® and Acromegaly Disease Activity Tool (ACRODAT ® ). Such tools are extremely flexible and, therefore, have been widely adopted by endocrinologists and other professionals, so much so that they have also been included as recommendations in the 2018 international guidelines., Conclusion: Questionnaires and tools are useful in the management of acromegaly patients. They help clinicians evaluate patients' symptoms and could assist in the evaluation of disease activity., (© 2022. The Author(s).)

Purpose: Current treatment of acromegaly restores a normal life expectancy in most cases. So, the study of persistent complications affecting patients' quality of life (QoL) is of paramount importance, especially motor disability and depression. In a large cohort of acromegalic patients we aimed at establishing the prevalence of depression, to look for clinical and sociodemographic factors associated with it, and to investigate the respective roles (and interactions) of depression and arthropathy in influencing QoL., Methods: One hundred and seventy-one acromegalic patients (95 women and 76 men, aged 20-85 years) among those recruited in a cross-sectional Italian multicentric study were investigated. Each patient filled in three validated questionnaires: AcroQoL, WOMAC (measuring articular pain, stiffness and functionality), and AIMS (evaluating articular symptoms and depression)., Results: A very high (up to 28%) depression rate was detected in acromegalic subjects. Two patients showing pathological AIMS depression scores, committed suicide during the three years observational period. In our population poor psychological status was significantly associated with female sex. Furthermore, a significant strong correlation was found between AIMS depression score and WOMAC score. Both depression and arthropathy-related motor disability turned out to independently contribute with similar strength to the impairment of QoL., Conclusions: We report a high prevalence of depression in acromegaly, which is associated with female sex and arthropathy. Both depression and arthropathy strongly and independently contribute to the impaired QoL of patients. Our study shows that assessment and monitoring of psychological status is mandatory in acromegaly, also suggesting an inexpensive tool for this assessment., (© 2022. The Author(s).)

Objective: A comprehensive picture of pegvisomant use for treating acromegaly in routine clinical practice in different countries is lacking. We aimed, therefore, to document country-specific behaviors in real-life pegvisomant use, and the main safety and effectiveness outcomes in the ACROSTUDY., Design: ACROSTUDY is an open-label, non-interventional, post-marketing safety surveillance study., Methods: A descriptive analysis was performed using data from the six top-recruiter ACROSTUDY countries, i.e., Germany (n = 548 patients), Italy (n = 466), France (n = 312), USA (n = 207), Spain (n = 200) and the Netherlands (n = 175). These nations accounted for > 85% of the ACROSTUDY cases., Results: The mean pegvisomant dose at treatment start was lowest in the Netherlands (9.4 mg/day), whereas it ranged between 10.9 and 12.6 mg/day in the other countries. At year 5, the mean pegvisomant dose was around 15 mg/day in all countries, except France (18.1 mg/day). At starting pegvisomant, patients treated with monotherapy ranged between 15% in the Netherlands and 72% in Spain. Monotherapy remained lowest over time in the Netherlands. In all countries, the percentage of patients with normal IGF-1 increased steeply from < 20% at baseline to 43-58% at month 6 and 51-67% at year 1. After that, we observed minor changes in the rate of acromegaly control in all countries. The Netherlands peaked in disease control at year 2 (72%). The proportion of patients reporting changes in pituitary tumor size was generally low. Serious treatment-related adverse events were < 5% in all countries., Conclusions: Our study provided a detailed summary of real-life use of pegvisomant in the six top-recruiter ACROSTUDY nations., (© 2022. The Author(s).)

Purpose: To report the effects of pegvisomant (PEGV) treatment on patient-reported outcomes in acromegaly patients., Methods: We conducted an extension study of an open-label, multinational, non-interventional study (ACROSTUDY) evaluating the long-term safety and efficacy of PEGV for acromegaly in routine clinical practice. Enrolled patients were rollover patients from ACROSTUDY, or treatment naïve/semi-naïve (NSN; no PEGV within 6 months of enrollment). Exploratory efficacy endpoints were changes in symptoms with the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) and quality of life with the Acromegaly Quality of Life questionnaire (AcroQoL) analyzed by controlled or uncontrolled IGF-I levels. Results were analyzed in all patients, in NSN patient subgroup, and by diabetes status., Results: A total of 544 patients with acromegaly were enrolled, including 434 rollover subjects from ACROSTUDY and 110 NSN patients. Mean PEGV treatment duration was 7.8 years (range, 0-19.6 years). Overall, the majority of PASQ scores improved over time, but there was no significant difference between IGF-I controlled or uncontrolled groups. In the NSN subgroup, most PASQ and AcroQoL scores remained similar to baseline up to 1 year, regardless of IGF-I control. Patients with diabetes reported better PASQ scores over time with PEGV treatment, regardless of IGF-I control. IGF-I normalization increased from 10% of patients at baseline to more than 78% at year 10, with a mean daily PEGV dose of 18.7 mg., Conclusions: Overall, patients treated with PEGV had small improvements in PASQ. While IGF-I normalization increased with PEGV treatment, IGF-I control had no effects on PASQ and AcroQoL scores., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Oro-facial manifestations of acromegaly are among the earliest signs of the disease and are reported by a significant number of patients at diagnosis. Despite this high prevalence of acromegaly oral manifestation, dentists do not play a pivotal role in acromegaly identification and diagnosis. The aim of our study was to evaluate the ability of dentists and orthodontists in the early recognition of the oro-facial manifestations of acromegaly., Methods: A telematic questionnaire was administered to dentists and orthodontists. The questionnaire included photos with facial and oral-dental details and lateral teleradiography of acromegaly patients (ACRO)., Results: The study included 426 participants: 220 dentists and 206 orthodontists. Upon reviewing the photos, dentists most often observed mandibular prognathism and lips projection, while orthodontists also reported the impairment of relative soft tissue. Orthodontists, who usually use photos to document patients' oral-facial characteristics, paid more attention to oral-facial impairment than dentists. During dental assessment, 90% of the participants usually evaluated tongue size and appearance, diastemas presence, and signs of sleep impairment (mainly orthodontists). Orthodontists were also more able to identify sella turcica enlargement at teleradiography. A total of 10.8% of the participants had ACRO as patients and 11.3% referred at least one patient for acromegaly suspicion., Conclusion: The study highlighted dentists' strategic role in identifying ACRO. Increasing dentists' awareness about acromegaly clinical issues may improve early diagnosis, potentially resulting in an increased quality of life and decreased mortality among ACRO., (© 2021. The Author(s).)

Background: Acromegaly is disease associated with a specific cardiomyopathy. Hitherto, it has been widely understood that acromegaly carries an increased risk of arrhythmia., Purpose: In this review we show that evidences are limited to a small number of case-control studies that reported increased rates of premature ventricular beats (PVB) but no more significant arrhythmia. In contrast, there are several studies that have reported impaired preclinical markers of arrhythmia, including reduced heart rate variability, increased late potentials, QT interval dispersion, impaired heart rate recovery after physical exercise and left ventricular dysynchrony. Whilst these markers are associated with an adverse cardiovascular prognosis in the general population, they do not have a high independent positive predictive accuracy for arrhythmia. In acromegaly, case reports have described sudden cardiac death, ventricular tachyarrhythmia and advanced atrio-ventricular block that required implantation of a cardio-defibrillator or permanent pacemaker. Treatment with somatostatin analogues can reduce cardiac dysrhythmia in some cases by reducing heart rate, PVBs and QT interval. Pegvisomant reduces mean heart rate. Pasireotide is associated with QT prolongation. In the absence of good quality data on risk of arrhythmia in acromegaly, the majority of position statements and guidelines suggest routine 12-lead electrocardiography (ECG) and transthoracic echocardiography (TTE) in every patient at diagnosis and then follow up dependent on initial findings.

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.

Objective: The aim of the Acromegaly Consensus Group was to revise and update the consensus on diagnosis and treatment of acromegaly comorbidities last published in 2013., Participants: The Consensus Group, convened by 11 Steering Committee members, consisted of 45 experts in the medical and surgical management of acromegaly. The authors received no corporate funding or remuneration., Evidence: This evidence-based consensus was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence following critical discussion of the current literature on the diagnosis and treatment of acromegaly comorbidities., Consensus Process: Acromegaly Consensus Group participants conducted comprehensive literature searches for English-language papers on selected topics, reviewed brief presentations on each topic, and discussed current practice and recommendations in breakout groups. Consensus recommendations were developed based on all presentations and discussions. Members of the Scientific Committee graded the quality of the supporting evidence and the consensus recommendations using the GRADE system., Conclusions: Evidence-based approach consensus recommendations address important clinical issues regarding multidisciplinary management of acromegaly-related cardiovascular, endocrine, metabolic, and oncologic comorbidities, sleep apnea, and bone and joint disorders and their sequelae, as well as their effects on quality of life and mortality., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Obstructive sleep apnea (OSA) is a common disorder characterized by upper airway collapse requiring nocturnal ventilatory assistance. Multiple studies have investigated the relationship between acromegaly and OSA, reporting discordant results., Aim: To conduct a meta-analysis on the risk for OSA in acromegaly, and in particular to assess the role of disease activity and the effect of treatments., Methods and Study Selection: A search through literature databases retrieved 21 articles for a total of 24 studies (n = 734). Selected outcomes were OSA prevalence and apnea-hypopnea index (AHI) in studies comparing acromegalic patients with active (ACT) vs inactive (INACT) disease and pretreatment and posttreatment measures. Factors used for moderator and meta-regression analysis included the percentage of patients with severe OSA, patient sex, age, body mass index, levels of insulin-like growth factor 1, disease duration and follow-up, and therapy., Results: OSA prevalence was similar in patients with acromegaly who had ACT and INACT disease (ES = -0.16; 95% CI, -0.47 to 0.15; number of studies [k] = 10; P = 0.32). In addition, AHI was similar in ACT and INACT acromegaly patients (ES = -0.03; 95% CI, -0.49 to 0.43; k = 6; P = 0.89). When AHI was compared before and after treatment in patients with acromegaly (median follow-up of 6 months), a significant improvement was observed after treatment (ES = -0.36; 95% CI, -0.49 to -0.23; k = 10; P < 0.0001). In moderator analysis, the percentage of patients with severe OSA in the populations significantly influenced the difference in OSA prevalence (P = 0.038) and AHI (P = 0.04) in ACT vs INACT patients., Conclusion: Prevalence of OSA and AHI is similar in ACT and INACT patients in cross-sectional studies. However, when AHI was measured longitudinally before and after treatment, a significant improvement was observed after treatment., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Acromegaly is a rare disease caused by an excess of growth hormone and insulin-like growth factor 1. It is usually diagnosed because of typical signs such as macroglossia, acral enlargement, jaw prognathism and malocclusion. Systemic complications are a major cause of morbidity and mortality in acromegaly, and many patients remain undiagnosed for several years. Increased ultrasound (US) application in the general population, and including among acromegaly patients, has revealed many suggestive features which, taken together with clinical suspicion, could induce suspicion of this disease., Purpose: This review describes main US features in acromegaly. Echocardiography shows a typical cardiomyopathy, characterized by left ventricular hypertrophy, diastolic and systolic dysfunction, aortic and mitral regurgitation, and increased aortic root diameters. US preclinical markers of atherosclerosis, such as intima media thickness (IMT), seem also to be impaired. Visceromegaly and increased organ stiffness are other features of acromegaly, including enlarged prostate, kidneys, liver, and thyroid. In addition, other US findings are: renal cysts, micronephrolithiasis, impairment of renal haemodynamic parameters, gallstones and gallbladder polyps, hepatic steatosis, thyroid nodules, multinodular goiter, and polycystic ovaries. Musculoskeletal US findings are increased cartilage thickness, impaired density and elasticity of bones, nerve enlargement, carpal and cubital tunnel syndrome, and trigger finger., Conclusions: Acromegaly patients frequently present systemic complications and a diagnostic delay. US features of acromegaly are not specific, but could potentially have a key role in early detection of the disease in the presence of typical clinical features.

Acromegaly is a rare disease. Improvements in lifespan in these patients have recently been reported due to transsphenoidal surgery (TSS), advances in medical therapy, and strict criteria for defining disease remission. This document reports the opinions of a group of Italian experts who have gathered together their prolonged clinical experience in the diagnostic and therapeutic challenges of acromegaly patients. Both GH and IGF-I (only IGF-I in those treated with Pegvisomant) are needed in the diagnosis and follow-up. Comorbidities (cardio-cerebrovascular disease, sleep apnea, metabolic derangement, neoplasms, and bone/joint disease) should be specifically addressed. Any newly diagnosed patient should be referred to a multidisciplinary team experienced in the treatment of pituitary adenomas., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Any newly diagnosed patient should be referred to a multidisciplinary team experienced in the treatment of pituitary adenomas. The therapeutic management of acromegaly always requires a personalized strategy. Normal age-matched IGF-I values are the treatment goal. Transsphenoidal surgery by an expert neurosurgeon is the primary treatment modality for most patients, especially if there are neurological complications. In patients with poor clinical conditions or who refuse surgery, primary medical treatment should be offered, firstly with somatostatin analogs (SSAs). In patients who do not reach hormonal targets with first-generation depot SSAs, a second pharmacological option with pasireotide LAR or pegvisomant (alone or combined with SSA) should be offered. Irradiation could be proposed to patients with surgical remnants who would like to be free from long-term medical therapies or those with persistent disease activity or tumor growth despite surgery or medical therapy. Since the therapeutic tools available enable therapeutic targets to be achieved in most cases, the challenge is to focus more on the quality of life., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: In the general population, sleep disorders are associated with an increased risk of cognitive impairment. The prevalence of sleep disorders, such as sleep apnea, in acromegalic patients is higher than in the general population, and they may have additional risk of cognitive impairment due to acromegaly treatment and comorbidities. We aim to study the relationship between sleep disturbances and cognitive dysfunction in a group of acromegalic patients., Methods: We studied 67 consecutive acromegalic patients. We performed a neurocognitive assessment and patients completed the Acromegaly Quality of Life Questionnaire (AcroQoL), Epworth Sleepiness Scale, and Pittsburgh Sleep Quality Index., Results: Of the 67 acromegaly patients in the study, 38.8% were male and median age at the neurological examination was 56 (IQR 48, 65). Approximately 6-10% of patients had impaired cognitive assessment, depending on the test. In linear regression models adjusted for age, sex, BMI, disease duration, and disease activity, poorer sleep quality was associated with lower global cognitive z-score (B = -0.03, 95% CI -0.06, -0.002). Daytime somnolence was associated with poorer physical AcroQoL sub-score (B = -0.04, 95% CI -0.08, -0.002). Sleep quality was associated with poorer overall AcroQoL (B = -0.03, 95% CI -0.05, -0.006), physical AcroQoL (B = -0.04, 95% CI -0.07, -0.005), psychological AcroQoL (B = -0.02, 95% CI -0.04, -0.001), and social AcroQoL (B = -0.02, 95% CI -0.04, -0.0009)., Conclusions: In acromegaly patients, we found robust evidence that poor sleep quality is associated with poorer quality of life, and some evidence that it is associated with poorer cognitive function.

Purpose: Arthropathy is a common and disabling complication of acromegaly. Since in this condition radiological findings rarely correspond to functional impairment, we elected to quantify in a large cohort of acromegalic patients: the degree of motor disability compared with data from general population, the impact of joint involvement on quality of life and work productivity, and to look for associated factors., Methods: In 211 acromegalic patients, 131 with controlled disease and 80 with active disease, eight validated scales were used to evaluate the (i) prevalence and distribution of arthropathy, (ii) degree of motor disability and joint symptoms (VAS, AIMS symptoms and WOMAC), (iii) quality of life (AcroQoL and PASQ) and work capability (WPAI:GH) as consequences of joint complications., Results: Using the WOMAC questionnaire, for which population based normative values are available, a significantly higher prevalence and severity of motor disability was detected in acromegalics compared to the general population from literature. The results provided by the different questionnaires turned out to be highly concordant. All measures of motor disability correlated both with impaired quality of life and motor disability and were worse in females and in patients with higher BMI., Conclusions: The questionnaires VAS, AIMS symptoms, and WOMAC (this latter both as a whole and with its functionality subscale), with their scores, proved to be the most adequate tools to evaluate motor disability and its consequences on both quality of life and work productivity in acromegaly. Female gender and higher BMI are associated with worse articular symptoms.

Context: The oral glucose tolerance test (OGTT) is considered the most useful method for diagnosing active acromegaly and for patient follow-up after neurosurgery. Despite its widespread use, only a few small studies have so far focused on patients' clinical features associated with different GH responsiveness to OGTT., Objective: We aimed to investigate the association between glucose-induced GH response and endocrine profiles, clinical manifestations, and response to therapy in a large cohort of patients with acromegaly., Patients: According to GH response to OGTT, patients were grouped as paradoxical (GH-Par) or nonparadoxical (GH-NPar), and their clinical and pathological features were compared in terms of pituitary tumor size, invasiveness, biochemical profiles, and response to therapy., Results: The study concerned 496 patients with acromegaly. At diagnosis, those with GH-Par (n = 184) were older than those with GH-NPar (n = 312) (mean ± SD, 44.1 ± 13.7 years vs 40.5 ± 12.7 years; P < 0.01) and had smaller tumors (0.82 vs 1.57 cm3; P < 0.01) that less frequently invaded the cavernous sinus (15% vs 27%; P < 0.01). The GH-Par group also had a higher basal GH per volume ratio (14.3 vs 10.5 μg/L ⋅ cm3; P < 0.05) and a lower incidence of hyperprolactinemia (17% vs 30%; P < 0.01) than the GH-NPar group. Importantly, the GH-Par group had a higher rate of remission in response to somatostatin analogues (52% vs 26%; P < 0.01) and a more marked drop in IGF-1 and GH after 6 months of therapy., Conclusions: Our data strongly suggest that serum GH responsiveness to oral glucose challenge reflects some important biological features of pituitary tumors and that the OGTT may have some prognostic value.

Objective: Multiple studies investigated preclinical markers of peripheral vascular damage in acromegaly (ACRO) reporting discordant results. The aim of this study was to run a meta-analysis to examine whether intima media thickness (IMT), flow mediated dilation (FMD) and arterial pulse wave velocity (PWV) are affected in acromegalic patients and to assess the impact of effective treatment of growth hormone excess on these outcomes., Study Selection: Twenty-seven studies comparing ACRO vs control (CON) populations and active (ACT) vs inactive (INACT) ACRO were included in the meta-analysis., Data Synthesis: ACRO compared to CON have higher IMT (ES = 0.83, 95% C.I. 0.35-1.30), p = 0.001, impaired FMD (ES = - 1.59, 95% C.I. - 2.33 to - 0.85, p < 0.0001) and higher PWV (ES = 0.76 95% C.I. 0.37-1.16, p = 0.0001). When patients with ACT vs INACT disease were considered IMT was higher (ES = 0.43, 95% C.I. 0.02-0.84, p = 0.041) and FMD was impaired (ES = - 0.66, 95% C.I. - 1.28 to 0.04, p = 0.038) in ACT patients. Meta-regression analysis of studies comparing IMT in ACT vs INACT acromegalic patients showed a significant and inverse association between the effect size and the percent of hypertensive (p = 0.025) and diabetic (p = 0.041) patients., Conclusions: IMT, FMD and arterial stiffness are impaired in acromegaly showing that these patients may be at increased risk of atherosclerosis. In patients with active disease these preclinical markers of atherosclerosis are worse compared to patients with inactive disease but the role of diabetes and hypertension is prevailing on growth hormone excess.

Background: Radiation therapy (RT) effectiveness on hormonal reduction is proven in acromegaly; however, collateral long-term effects are still undetermined. This transversal neuroimaging study on a large cohort of acromegalic patients aimed to investigate the rate of parenchymal and vascular changes after RT., Materials and Methods: Thirty-six acromegalic patients underwent RT (RT+) after unsuccessful surgery and were compared to RT- acromegalic patients matched for age, gender, adenoma features, clinical and surgical history. All patients underwent magnetic resonance angiography (MRA) to investigate intracranial artery abnormalities and FLAIR sequence to assess white matter changes according to the Wahlund scale., Results: RT+ acromegalic patients had a higher rate of controlled disease (29/36 vs. 12/36, P<0.001). RT+ acromegalic patients had MRI/MRA evaluation 15.3±9.6 years after RT. RT+ acromegalic patients had a significantly higher Wahlund score than RT- acromegalic patients (6.03±6.41 vs. 2.53±3.66, P=0.006) due to increased white matter signal abnormalities at the level of the temporal lobes, the basal ganglia (insula) and the infratentorial regions, bilaterally. Among RT+ patients one died because of temporo-polar anaplastic astrocytoma, one suffered from a stroke due to right internal carotid artery occlusion, one presented with cystic degeneration of the temporal poles. Long-dated RT (>10 years before MR evaluation) was associated with a higher rate of RT-related white matter changes (P=0.0004)., Conclusions: RT seems to have created a cohort of patients with brain parenchymal changes whose clinical and cognitive impact is still unknown. These patients might require a prolonged MRI and MRA follow-up to promptly detect delayed RT-related complications and minimize their clinical consequences., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Purpose: Pegvisomant (PEGV) treatment in acromegaly patients resistant to somatostatin analogues is less effective in the real life than in clinical trials. This is a multicenter, observational, retrospective, longitudinal study. The aim was to detect characteristics which improve long-term PEGV effectiveness., Methods: 87 acromegalic patients treated with PEGV have been enrolled in seven referral Italian centres. PEGV was administered for up to 4 years, at doses up titrated until IGF-1 normalization or to ≥ 30 mg/day. The rate of patients who reached IGF-1 normalization at last visit has been calculated., Results: IGF-1 was normalized in 75.9% of patients after 1 year and in 89.6% at last visit. Disease control was associated with lower baseline GH, IGF-1 and IGF-1 xULN and was more frequent when baseline IGF-1 was < 2.7 × ULN (p < 0.02). PEGV dose was dependent on baseline IGF-1 > 2.7 × ULN (p < 0.05) and doses > 1.0 mg/BMI/day were administered more frequently when baseline IGF-1 was > 2.0 × ULN (p = 0.03). PEGV resistance was associated with higher BMI (p = 0.006) and was more frequent when BMI was > 30 kg/m 2 (p = 0.07). There were no significant differences between patients treated with monotherapy or combined treatment. IGF-1 normalization, PEGV dose and rate of associated treatment were similar between males and females. PEGV effectiveness was independent from previous management. Diabetic patients needed higher doses of PEGV than non-diabetic ones., Conclusions: PEGV effectiveness improves when up titration is appropriate. Higher PEGV doses at start and a more rapid up-titration are necessary in patients with obesity and/or IGF-1 > 2.7 × ULN.

Purpose: The aim of this study is to investigate guideline application and colonoscopy findings in real-life practice in acromegaly., Methods: We conducted a retrospective observational non-interventional and cross-sectional analysis on 146 patients with acromegaly (ACRO) referred to our clinic. We evaluated colonoscopy data, focusing on the correlation between colonoscopy findings and hormonal/metabolic values., Results: The total number of colonoscopies performed in ACRO patients increased from 6 in the period 1990-1994 to 57 in the period 2010-2014. Colonoscopy procedures were performed according to guidelines in 25% of ACRO patients at diagnosis, 51% at follow-up and 11% globally (both at diagnosis and follow-up). Among the 146 ACRO patients, 68% were subjected to at least one colonoscopy and in 32% of the cases a polyp was detected during the procedure. The presence of polyps was significantly associated with mean levels of growth hormone (GH), insulin-like growth factor 1 (IGF-1), fasting glucose and insulin levels (p < 0.05). Polyps were detected in 48% of untreated patients and in 26% of patients under treatment for acromegaly (p = 0.04). The general risk of polyps and adenomatous polyps in ACRO patients was higher compared to the control population of Veneto Region, Italy (odds ratio 1.33 and 1.16, respectively). No cancerous polyps were detected in our analysis., Conclusion: In real-life practice, adherence to ACRO colonoscopy clinical guidelines was lower than expected. Among patients who underwent colonoscopy, the prevalence of colon polyps was higher for ACRO patients, suggesting the need for new strategies to ensure adherence to colonoscopy guidelines.

Background and Aims: Acromegaly increases the risk of cardiovascular mortality. Data on the cardiovascular risk in asymptomatic acromegaly are limited. In particular, data on coronary microvascular abnormalities are lacking. We assessed coronary flow reserve (CFR) as a marker of coronary microvascular function in asymptomatic acromegaly., Methods: We studied 40 acromegalic patients (23 male, age 52 ± 11 years) without clinical evidence of cardiovascular disease, and 40 control subjects matched for age and sex. Coronary flow velocity in the left anterior descending coronary artery was detected by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. CFR was the ratio of hyperaemic to resting diastolic flow velocity., Results: CFR was lower in patients than in controls (2.9 ± 0.8 vs. 3.7 ± 0.6, p < 0.0001) and was abnormal (≤2.5) in 13 patients (32.5%) compared with any control subjects (0%) (p < 0.0001). CFR was inversely related to insulin-like growth factor 1 (IGF-1) levels (r = -0.5, p < 0.004). In patients with CFR≤2.5, IGF-1 was higher (756 [381-898] μg/l versus 246 [186-484] μg/l, p < 0.007) whereas growth hormone (GH) levels were similar (6.3 [2.8-13.7] μg/l versus 5 [2.8-8.9] μg/l, p = 0.8). In multivariable linear regression analysis, IGF-1 was independently associated with CFR (p < 0.0001). In multiple logistic regression analysis, IGF-1 independently increased the probability of CFR≤2.5 (p = 0.009). In four patients with active disease (all with CFR<2.5), treatment with somatostatin analogues normalized CFR. However the other four patients with active disease were not responder., Conclusions: Acromegalic patients have coronary microvascular dysfunction that may be restored by therapy with somatostatin analogues. IGF-1 independently correlates with the coronary microvascular impairment, suggesting the pivotal role of this hormone in explaining the increased cardiovascular risk in acromegaly., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Context: Increase in drug frequency or dose is recommended for acromegaly patients with partial response to long-acting somatostatin receptor ligands (SRLs). However, the efficacy and safety data with lanreotide (LAN) Autogel (LAN-ATG) at high dose (HD) or high frequency (HF) are still scanty., Objective: To evaluate the biochemical efficacy and safety of HF and HD LAN-ATG in patients with active acromegaly., Design: Twenty-four-week prospective, multicenter, randomized, open-label trial., Patients and Interventions: Thirty patients with active acromegaly, partial responders to SRLs, were randomized to HF (120 mg/21 days; 15 patients) or HD (180 mg/28 days; 15 patients) LAN-ATG., Outcomes: Normalization of serum insulin-like growth factor-I (IGF-I) and reduction in random growth hormone (GH) values < 1.0 µg/L, reduction in serum IGF-I and GH from baseline, differences in biochemical response between HF and HD LAN-ATG, adverse events., Results: IGF-I decreased significantly (P = 0.007) during the 24-week treatment, with greater decrease in HD (P = 0.03) vs HF group (P = 0.08). Normalization in IGF-I values occurred in 27.6% of patients (P = 0.016 vs baseline), without a significant difference between HF and HD groups (P = 0.59). The decrease in serum IGF-I significantly correlated with serum LAN values (P = 0.04), and normalization of IGF-I was predicted by baseline IGF-I values (P = 0.02). Serum GH values did not change significantly (P = 0.22). Overall, 19 patients (63.3%) experienced adverse events, all being mild to moderate and transient, without differences between the two therapeutic arms., Conclusion: HF and HD LAN-ATG regimens are effective in normalizing IGF-I values in about one-third of patients with active acromegaly inadequately controlled by long-term conventional SRLs therapy., (Copyright © 2017 Endocrine Society)

Background: In 2007, we published an opinion document to review the role of pegvisomant (PEG) in the treatment of acromegaly. Since then, new evidence emerged on the biochemical and clinical effects of PEG and on its long-term efficacy and safety., Aim: We here reviewed the emerging aspects of the use of PEG in clinical practice in the light of the most recent literature., Results: The clinical use of PEG is still suboptimal, considering that it remains the most powerful tool to control IGF-I in acromegaly allowing to obtain, with a pharmacological treatment, the most important clinical effects in terms of signs and symptoms, quality of life and comorbidities. The number of patients with acromegaly exposed to PEG worldwide has become quite elevated and the prolonged follow-up allows now to deal quite satisfactorily with many clinical issues including major safety issues, such as the concerns about possible tumour (re)growth under PEG. The positive or neutral impact of PEG on glucose metabolism has been highlighted, and the clinical experience, although limited, with sleep apnoea and pregnancy has been reviewed. Finally, the current concept of somatostatin receptor ligands (SRL) resistance has been addressed, in order to better define the acromegaly patients to whom the PEG option may be offered., Conclusions: PEG increasingly appears to be an effective and safe medical option for many patients not controlled by SRL but its use still needs to be optimized.

Objective: GH receptor antagonist pegvisomant is indicated for treatment of patients with resistant acromegaly. We compared safety and treatment outcomes of pegvisomant therapy in patients managed by Italian centers enrolling less or more than 15 cases in ACROSTUDY, a safety surveillance study of long-term pegvisomant treatment of patients with acromegaly. A noninterventional safety surveillance study in which safety and treatment outcomes of pegvisomant were evaluated on the basis of data collected during a 7-year period., Methods: A total of 204 acromegaly patients treated by seven centers enrolling 16-49 patients each (group A) and 137 subjects by 18 centers following 3-14 cases ( group B)., Results: Patients of group A and B were treated for 4.4 ± 2.7 and 4.2 ± 2.2 years, respectively. IGF-1 ULN normalized in 64.4 % (n = 56) and 54.4 % (n = 31) in group A and B, respectively, after 1-year treatment, and in 57.3 % (n = 106) and 72.5 % (n = 87) at last visit. Starting doses were significantly higher in group A. They were progressively increased during treatment in both groups, but were higher in uncontrolled patients than in controlled ones only in group A. Reported adverse events were more frequent, and the prevalence of patients with adverse events was higher in group B., Conclusions: On the basis of this original study approach, we could speculate that in the centers in which more patients are treated with pegvisomant, less adverse events are reported, but the long-term effectiveness is lower than in centers with less cases, perhaps because of an inadequate patient's selection.

Background: Cardiovascular complications, including arrhythmias and cardiac sudden death, are the most common causes of enhanced mortality in acromegaly. However, few data are available on cardiac autonomic functions and sympathovagal balance in acromegalic patients., Objective: The aim of this study was to investigate both the time and frequency domain parameters of Heart Rate Variability (HRV), in order to characterize the cardiac autonomic functions in patients affected by acromegaly. This study correlated anthropometric, metabolic, echocardiographic parameters and blood pressure with those relating to HRV, to identify the main factors responsible for the HRV related alterations possibly present. We also aimed to analyze the effects of the treatment with somatostatin analogues (SSAs) on HRV., Materials and Methods: This study enrolled 47 acromegalic patients (23 males, age 49.1 ± 13.5 years) and 37 (13 males) age matched (52.3 ± 13.3 years) healthy subjects. All participants underwent 12-lead 24 h ECG Holter recordings and a HRV analysis of the ECG tracings was performed. The parameters obtained from the time domain analysis of HRV included pNN50, SDNN, SDNN index, SDANN and RMSSD. The power spectral analysis of HRV was obtained by summing powers of the LF (low frequency) and the HF (high frequency) band. Sympathovagal balance was estimated by calculating the LF/HF ratio during 24 h and 15 min of clinostatism. The HRV of 28 acromegalic patients was studied before and after SSAs treatment., Results: Acromegalic patients showed significantly lower SDNN and SDANN compared to controls. Diabetic and non-diabetic acromegalic patients showed decreased SDNN and SDANN, when compared to healthy subjects. Diabetic acromegalic patients had a lower LF/HF ratio during 24 h when compared to non-diabetic acromegalic patients. Similar results were obtained analyzing patients affected by acromegaly and impaired glucose tolerance. SDNN and SDANN were lowered by hypertension in the acromegalic population, when compared to controls, and hypertensive acromegalic patients also displayed a decreased LF/HF ratio during 24 h when compared to normotensive acromegalic subjects. Patients with ventricular arrhythmias in Lown classes 3-5 showed a decreased SDANN compared to patients in Lown class 0-2. The treatment with SSAs was able to ameliorate all the time domain parameters of HRV, without altering the 24 h LF/HF ratio., Conclusion: Cardiac autonomic functions and sympathovagal balance are altered in patients affected by acromegaly and could be ameliorated by SSAs therapy. HRV analysis allows an estimation of the autonomic sympathovagal balance and may be a useful clinical tool for the cardiac risk stratification in acromegalic patients.

ACROSTUDY is a world-wide non-interventional, post marketing surveillance study performed to monitor the safety and outcomes of pegvisomant (PEG) in clinical practice. We report data from acromegaly patients who have been included in the Italian ACROSTUDY registry. The data of 341 acromegaly patients (171 males) were available for analysis using data freeze (12/9/2012). Patients were enrolled in 25 Italian endocrine centres. Before and during PEG treatment IGF-I, liver enzymes, metabolic parameters, and pituitary MRI were assessed. Before PEG, 54.3% patients had been treated with medical therapy and surgery, 22.9% medical therapy only, and 15.8% medical plus radiation and surgical therapy. 199 adverse events were reported in 98 patients (28.7%). Serious adverse events were documented in 29 patients (8.5%). 71.1% of patients had no significant change in tumor volume. Central MRI reading was performed in 34 patients; in 7 patients, an increase in tumor volume was found. Hormonal efficacy progressively increased since the start of PEG. After 6 years, normal IGF-I levels were found in 70.9% of patients (mean daily dose 18.1 mg). 87.1% of patients were treated with daily PEG although in 8.8% of patients, it was administered 2-6 times per week and in 3.8% with weekly injections. 74.8% received a PEG dose 10-15 mg/daily. PEG is a drug with a favorable safety profile which is efficacious also considering that in Italy it is currently available as third-line therapy.

Context: Acromegaly increases cardiovascular risk, possibly due to the high prevalence of classical risk factors. However, in vitro studies show a protective role of GH/IGF-1 on the endothelium., Objective: The objective of the study was to investigate circulating endothelial progenitor cells (EPCs), a marker of vascular regeneration, in acromegalic patients and how they are affected by acromegaly treatment., Design: This was a cross-sectional case-control and observational study., Setting: The study was conducted at a tertiary ambulatory referral endocrinology center., Patients: Forty-three acromegalic patients (26 active; 17 inactive) and 43 control subjects matched by age, gender, and degree of glucose tolerance participated in the study., Intervention: Circulating EPCs were quantified by flow cytometry based on the expression of CD34, CD133, and kinase insert domain-containing receptor (KDR). Nine patients with active acromegaly were reevaluated after 24 weeks of treatment with somatostatin analogs (SSAs)., Main Outcome Measure: Differences in EPC levels between patients and controls were measured., Results: Acromegalic patients showed a significant reduction of the total CD34(+)KDR(+) EPC population compared with controls, which was more evident in patients without diabetes or hypertension. More definite CD34(+)CD133(+)KDR(+) EPCs were reduced in patients with active compared with those with inactive acromegaly and compared with controls. The number of CD34(+)CD133(+)KDR(+) EPCs correlated with IGF-1 levels (r = -0.45; P < .001), fasting plasma glucose (r = -0.40; P = .004), and the homeostasis model assessment index of insulin resistance (r = -0.32; P = .026). CD34(+)CD133(+)KDR(+) EPCs increased 2-fold after SSA treatment., Conclusions: Acromegalic patients have a reduced endothelial regenerative capacity, possibly due to activation of the GH/IGF-1, rather than concomitant risk factors. Treatment with SSAs can restore immature EPCs to normal levels.

Purpose: Although cerebrovascular mortality is increased up to eightfold in acromegaly, intracranial internal carotid artery (ICA) changes have not been well investigated. This is a magnetic resonance angiography (MRA) quantitative cross-sectional study of ICA tortuosity, ectasia and intercarotid distance in acromegalic patients with subsequent analysis of concomitant clinical, laboratory and neuroimaging findings., Methods: One hundred seventy six acromegalic patients (mean-age 55 ± 14 years, age range 21-88, 92 females) and 104 subjects with headache or transient neurological deficits underwent MRA with the same 1.5 T scanner. Clinical data, laboratory and pituitary adenoma imaging findings were recorded. Using a commercially available software, we measured the tortuosity index [(curved/linear ICA length from C3-midpoint to intracranial bifurcation) - 1], ICA ectasia index (intracavernous/petrous ICA diameter) and intercarotid distance at C3 and C4 levels., Results: Mean ICA tortuosity and ectasia indices were increased in acromegalic patients compared with controls (1.06 ± 0.29 vs 0.93 ± 0.26, p < 0.001; 1.02 ± 0.10 vs 0.92 ± 0.09, p < 0.001). Mean intercarotid distance was reduced at C3 and increased at C4 in acromegalic patients (16.7 ± 3.4 vs 17.9 ± 2.5 mm, p < 0.001; 16.7 ± 4.6 vs 15.4 ± 4.1 mm, p < 0.05; t test). ICA tortuosity and ectasia correlated neither with laboratory findings nor with previous or current treatment. On multivariate analysis, C3 intercarotid distance was reduced in patients on dopamine agonist treatment (p < 0.01) and increased in patients with GH-deficit (p = 0.01), while C4 intercarotid distance was increased with macroadenoma (p = 0.01) and reduced in patients under dopamine agonist (p < 0.01) or somatostatin analogue (p < 0.05) treatment., Conclusions: Intracranial ICA changes are common findings in acromegaly, and further studies focused on their possible clinical impact are needed.

Herniation of cerebellar tonsils (CTH) might occur in acromegaly patients and improve after acromegaly treatment. Our study investigated CTH prevalence in acromegaly, its relationship with clinical, laboratory and neuroimaging findings and its possible pathogenesis and clinical impact. 150 acromegaly patients (median-age 56 years, age-range 21-88, 83 females) underwent brain magnetic resonance imaging (MRI). Clinical data, laboratory and pituitary adenoma imaging findings were recorded. CTH, posterior cranial fossa area, tentorial angle, clivus, supraocciput and Twining's line length were measured in acromegaly patients and controls, who included MRI of 115 consecutive subjects with headache or transient neurological deficits (control group-1) and 24 symptomatic classic Chiari 1 malformation patients (control group-2). Acromegaly patients were interviewed for symptoms known to be related with CTH. 22/150 acromegaly patients (15 %) and 8/115 control group-1 subjects presented with CTH (p = 0.04). In acromegaly patients, CTH correlated positively with younger age and inversely with GH-receptor antagonist treatment. Control group-2 had a shorter clivus than CTH acromegaly patients (40.4 ± 3.2 mm vs 42.5 ± 3.3 mm, p < 0.05), while posterior fossa measures did not differ among acromegaly subgroups (with and without CTH) and control group-1. Headache and vision problems were more frequent in CTH acromegaly patients (p < 0.05); two acromegaly patients presented with imaging and neurological signs of syringomyelia. Despite no signs of posterior fossa underdevelopment or cranial constriction, CTH is more frequent in acromegaly patients and seems to contribute to some disabling neurological symptoms.

Objective: Acromegaly is associated with increased cardiovascular morbidity and mortality and with specific heart and vascular abnormalities. The aim of our study was to investigate arterial stiffness using the ambulatory arterial stiffness index (AASI) and symmetric AASI (Sym-AASI), two indexes derived from 24-h ambulatory blood pressure monitoring (ABPM), in a group of normotensive and hypertensive patients with active acromegaly, compared with normotensive controls (NOR-CTR) or hypertensive controls (HYP-CTR)., Subjects and Methods: Ninety-six consecutive patients with active acromegaly (46 males, mean age 49±14 years) underwent 24-h ABPM and evaluation of cardiovascular risk factors. Based on ABPM measurement, acromegalic patients were divided into 64 normotensive (normotensive acromegalic patients (NOR-ACRO)) and 32 hypertensive (hypertensive acromegalic patients (HYP-ACRO)) patients, and were compared with 35 normotensive (NOR-CTR) and 34 hypertensive (HYP-CTR) age-, sex,- and ABPM-matched control subjects., Results: The AASI and Sym-AASI indexes were significantly higher in acromegalic patients than in controls, either in the normotensive (NOR-ACRO vs NOR-CTR, P<0.0001 for AASI and P=0.005 for Sym-AASI) or in the hypertensive (HYP-ACRO vs HYP-CTR, P=0.01 for AASI and P=0.01 for Sym-AASI) group. Multiple logistic regression analysis showed a significant association of the highest AASI tertile with serum IGF1 (P=0.034) in the whole acromegalic group., Conclusion: AASIs are increased in acromegaly, independent of blood pressure (BP) elevation, and may have an important role in predicting cardiovascular risk in this disease.

Background: The concurrence of intracranial aneurysms and acromegaly has been reported and debated previously. Our study in a large number of patients aimed to verify whether acromegaly patients carry a higher risk of harboring intracranial saccular aneurysms and to evaluate the possible relationship using clinical, laboratory, and imaging techniques., Materials and Methods: A total of 152 of 161 consecutive acromegaly patients (median age, 55.7 yr; 82 females) underwent neuroimaging evaluation of the circle of Willis. Clinical data (disease duration and disease control, hypertension, smoking history, diabetes and dyslipidemia, previous surgery or radiotherapy, previous or current pharmacological therapy), laboratory findings (GH and IGF-I at onset and shortly before examination), and pituitary adenoma imaging features (size and invasiveness of the cavernous sinus) were recorded., Results: Twenty-six patients (17.3%) harbored 40 newly diagnosed intracranial aneurysms; two other patients had previously undergone aneurysm clipping due to subarachnoid hemorrhage. Ten patients had multiple aneurysms; most of the aneurysms were located in the intracranial tract of the internal carotid artery (67.5%); no aneurysms belonged to the vertebrobasilar circulation. The presence of intracranial aneurysms correlated with GH serum values at disease onset (P < 0.05) and showed a trend to a positive correlation with poor disease control (P = 0.06); no other laboratory, clinical, and radiological findings correlated with the presence of intracranial aneurysms., Conclusions: GH serum excess seems to carry an increased risk of developing intracranial aneurysms. A neuroradiological evaluation of the intracranial circulation might therefore be considered in the diagnostic work-up of patients affected with acromegaly.

Background: Only six women who were treated with somatostatin analogues (SSAs) throughout their pregnancies have been described so far. The influence of SSAs on the course of pregnancy and newborn outcomes remains largely unknown. Many aspects of SSAs pharmacokinetics in mother and foetus have not yet been defined., Methods and Findings: We report a case study on the effects of octreotide on uterine artery blood flow, octreotide concentrations in biological fluids of mother and newborn, and somatostatin (SST) receptor expression and binding at the level of the maternal-foetal barrier tissues in an acromegalic woman treated with short-acting octreotide throughout her pregnancy. An acute decrease in uterine artery blood flow was observed after octreotide injections, without affecting the pregnancy course, delivery, or foetal development. Octreotide concentrations were high in maternal serum and colostrum and lower in umbilical cord serum, amniotic fluid, and newborn serum. All SST receptor subtypes can be expressed in placental tissue but their binding profile was weak both in the placenta and umbilical cord. The child was healthy and developed normally up to age 6 from an anthropometric, metabolic, and endocrine point of view. We reviewed all published reports on pregnancy SSA exposure and outcomes were compared to a time-matched group of acromegalic women not exposed to SSA. No significant effect on the mother or foetus was observed., Conclusions: Short-acting octreotide appears not to affect the function of the maternal-foetal barrier or foetal development, except for the occurrence of acute, reversible, and clinically irrelevant haemodynamic changes. These data support the feasibility and safety of treatment with short-acting octreotide in acromegalic women during pregnancy and excludes major matters of concern about the effects of this medication on pregnancy itself and its outcome.

We report a case of ischemic stroke in a 43 year-old woman with no traditional cardiovascular risk factors and a history of cranial surgery and cranial radiation therapy (CRT) for a GH-secreting pituitary macroadenoma. The neurological work-up on this patient disclosed several cerebral ischemic lesions and demonstrated the occlusion of the right middle cerebral artery together with the narrowing of the right carotid artery; post-radiation brain damage was also visible by nuclear magnetic resonance. We postulate the existence in this patient of a radiation-induced vascular damage, which is a well recognized process thoroughly described in in vitro studies. We remark that life-long follow-up of acromegalic patients receiving CRT is essential so that early diagnosis of radiation-induced vascular injury can be made.

Acromegaly, when left untreated, is associated with premature mortality which is chiefly related to cardiovascular complications. We report on a 50-year-old acromegalic woman, resistant to therapy, who died suddenly because of thoracic aortic rupture and massive bleeding into the left pleural space. The postmortem examination disclosed, nearby the point of rupture, a pulmonary abscess as well as extensive intrinsic alteration of arteries originating from the aortic arch and aorta itself, which featured microscopic cystic medial necrosis. We discussed how these aspects could be related to long-term exposition to growth hormone excess. In particular, this case gives further evidence of vascular system frailty in acromegaly.

Context: The pathogenesis of increased blood pressure (BP) in acromegaly is unclear, and the role of IGF-I levels and the renin-angiotensin-aldosterone system (RAAS) in this disease remains controversial., Objective and Design: The aim of this study was to investigate the role of gene polymorphisms of the RAAS and involved in sodium handling on BP in acromegaly., Setting and Patients: We conducted a multicentric retrospective study that included 100 consecutive patients with acromegaly referred during the period 2000-2003., Intervention: All patients were genotyped for ACE I/D, AGT M235T, CYP11B2 -344T/C, B2R -58T/C, and alpha-adducin G460W polymorphisms., Main Outcome Measure: We assessed the prevalence of hypertension and BP according to the genotype., Results: Patients with the CYP11B2 -344CC genotype displayed a significant increase in the risk of hypertension compared with patients with CT/TT genotypes (odds ratio = 4.0; 95% confidence interval = 1.4-11.6; P = 0.01). Consistently, a significant proportion of patients with the CYP11B2 -344CC genotypes were under antihypertensive treatment (73.1%) compared with patients with the TT/TC genotypes (38.2%; P = 0.003). Patients with the -344CC genotype displayed a significant increase in systolic BP (10.2 +/- 4.3 mm Hg; P = 0.02) but not a significant increase in diastolic BP (2.6 +/- 2.6 mm Hg; P = 0.32) compared with patients with the CT/TT genotype., Conclusions: We have shown an association of the -344T/C CYP11B2 gene polymorphism with BP in patients affected by acromegaly. These findings suggest that the RAAS is implicated in the pathogenesis of hypertension in acromegaly.

Background: Sudden death and increased prevalence of ventricular arrhythmias have already been described in acromegaly. Although late potentials (LPs) have been proved to be a new technique in detecting patients at risk for ventricular tachyarrhythmias its use in acromegaly is still unknown., Methods: We studied 70 acromegalic patients [32 males, 38 females; age 49+/-12 years (mean+/-S.D.)] and 70 control subjects age- and sex-matched [(35 males and 35 females; 46+/-12 years (mean+/-S.D.)]. Besides hormonal tests, we performed the following cardiovascular investigations: ECG, 24-h ECG Holter monitoring, echocardiography, and signal-averaged ECG (SAECG) time-domain analysis., Results: LPs occurrence was significantly higher in acromegalic patients as compared to the control group (22.9% vs. 2.9%; p=0.001). A greater duration of disease in patients with positive LPs compared to negative ones was pointed out (18 vs. 12 years; p=0.024). In the group of acromegalic patients with positive LPs we observed a significant association with premature ventricular complexes (PVCs) detected by means of 24-h Holter ECG recording (13 out of 15 patients: 86.7%; p=0.024). The positivity or negativity of LPs proved to be significantly associated with Lown scale PVC trends recorded by 24-h Holter ECG (p=0.014). In the group of patients with left ventricular hypertrophy a significant and pathological worsening of SAECG signals (QRS, LAS, RMS) was documented., Conclusions: We observed a higher prevalence of LPs in acromegaly which significantly correlated with Lown scale of PVCs.

Recently, a new slow-release (SR) formulation of lanreotide (LAN) comprising 60 mg of the drug incorporated in microspheres of biodegradable polymers (SR-LAN 60) has become available. The aim of our study was to assess the effectiveness of SR-LAN 60, administered every 21 to 28 days, as well as its tolerability in the long-term treatment of acromegalic patients treated with SR-LAN 30. Twenty patients with acromegaly (10 males and 10 females) were enrolled in this open study. Thirteen patients had undergone surgery, but with incomplete resection of the pituitary tumor. All patients, treated with intramuscular (IM) SR-LAN 30 injections every 10 days for 12 to 24 months, started SR-LAN 60 (Ipsen-Beaufour, Milan, Italy) administration 10 days after the last injection of SR-LAN 30. Growth hormone (GH) levels were determined on the day of the first injection of SR-LAN 60, and 10, 20, and 30 days after. According to the GH levels reached on day 30, patients received SR-LAN 60 every 28 days if GH levels were below 2.5 microg/L (group A) and every 21 days if GH levels were above 2.5 microg/L (group B). In group A, after the 8th month, SR-LAN 60 treatment resulted in well-controlled GH levels in 9 of 10 patients in comparison to SR-LAN 30 treatment every 10 days (6 of 10 patients). Normal age-adjusted insulin-like growth factor-I (IGF-I) levels were achieved in 4 of 10 patients, as in treatment with SR-LAN 30. In group B, SR-LAN 60 treatment resulted in well-controlled GH levels in 4 of 10 patients, as in treatment with SR-LAN 30 every 10 days. Normal age-adjusted IGF-I levels were achieved in 3 of 10 patients after SR-LAN 60 in comparison to SR-LAN 30 treatment every 10 days (1 of 10 patients). During SR-LAN 60 therapy, an improvement was also observed in signs and symptoms of active acromegaly and no relevant side effects were detected. In conclusion, this study shows that SR-LAN 60 treatment is able to induce a good control of circulating GH and IGF-I levels in most acromegalic patients. The first injections of SR-LAN 60 are very helpful in predicting the optimal long-term injection frequency. Patients on SR-LAN 30 can be safely and effectively shifted to SR-LAN 60., (Copyright 2002 by W.B. Saunders Company)

Background: Hypertension represents a well-known risk factor for cardiovascular diseases. The pathogenesis of hypertension in acromegaly is commonly viewed as multifactorial, but the possible influence of metabolic disorders on blood pressure (BP) in affected patients is largely unknown., Objective: The aim of the present study was to evaluate the impact of glucose metabolism abnormalities on BP values in a series of patients with active acromegaly., Design: An open multicentre prospective study., Patients: Sixty-eight patients with active disease, aged 47.5 +/- 11.7 years, have been studied. Thirty-nine had normal glucose tolerance (NGT), 16 impaired glucose tolerance (IGT) and 13 suffered from diabetes mellitus (DM)., Measurements: Mean clinical BP values were calculated as the mean of BP values obtained by sphygmomanometric measurement in three separate occasions and mean 24-h, diurnal and nocturnal systolic (SBP) and diastolic (DBP) values were obtained by 24-h ambulatory blood pressure monitoring (ABPM)., Results: Patient's age and the degree of glucose tolerance abnormalities were found to significantly and independently influence BP values. All clinical and ABPM SBP and DBP values significantly increased with age by linear regression (P < 0.02 for all BP values, 0.30 < or = R < or = 0.43), and the independent influence of this parameter on BP values was confirmed by mutivariate analysis. Similarly, the independent influence of glucose tolerance abnormalities on BP values was confirmed when introducing age as a covariable in a multivariate analysis, and patients with DM presented significantly higher clinical SBP and 24-h, diurnal and nocturnal SBP and DBP than patients with NGT (P < 0.02 for clinical SBP, P < 0.015 for all ABPM values, respectively). In addition, patients with DM showed significantly higher 24-h, diurnal and nocturnal DBP than those with IGT (P < 0.05 in all cases). In contrast, no significant difference was found between NGT and IGT patients. No significant influence of disease duration, BMI, GH, IGF-I, or fasting and 2-h post glucose load insulinaemia on BP values was observed., Conclusions: Abnormalities of glucose metabolism significantly contribute to increase systolic blood pressure and especially diastolic blood pressure in acromegalic patients. Careful control of blood pressure and of risk factors for developing systemic hypertension, with special reference to glucose tolerance, is mandatory to decrease cardiovascular morbidity and mortality in such patients.

Although wide range investigations on the heart and great vessels have been reported in acromegaly, the field of microcirculation is still largely vacant. The nailfold is a window through which we can observe in vivo the vascular bed. This study investigates through nailfold capillaroscopy the morphology of cutaneous microcirculation in acromegaly in relationship with the usual hormonal parameters of disease activity. Twenty-five acromegalic patients and 26 normal subjects, age and sex matched, were studied. A subgroup of acromegalics (8 patients) was considered in stable remission, and the remaining 17 had active disease. Capillaroscopy was performed in each subject by in vivo computer aided stereomicroscopy (magnification, x400). The following morphological parameters were calculated: the number of tortuous loops, meandering capillaries, and capillaries per millimeter; avascular areas; visibility of subpapillary plexus; the capillary length; and intercapillary distance. We were unable to perform the exam in 4 of 25 patients because visibility was poor. The capillary number and length were significantly reduced in acromegalics compared to controls [8.9 +/- 1.5 vs. 10.3 +/- 1.2 no./mm (P = 0.0010) and 174 +/- 49 vs. 255 +/- 24 microm (P < 0.0001)]. Moreover, in acromegalics, the numbers of tortuous loops and meandering capillaries were significantly increased [19 +/- 8 vs. 13 +/- 5 (P = 0.0027) and 10 +/- 12 vs. 0.7 +/- 1.1 (P < 0.0001)]. The capillaroscopic alterations were still observed in a smaller group of 8 nondiabetic and nonhypertensive acromegalics. We found branch-like capillaries in 4 acromegalic patients, but not in the control group. Finally, we observed a meaningful different and ameliorated capillaroscopic morphology in acromegalic patients in stable remission compared to active disease patients as far as the total number (density) and meandering capillaries were concerned. In conclusion, our study shows that in acromegaly, morphological alterations also affect the peripheral microcirculation, which seems to be influenced by the activity of the disease. We believe that nailfold capillaroscopy may represent an additional useful tool in the follow-up of acromegalic patients.

Ventricular late potentials are obtained by signal-averaged surface electrocardiography. Late potentials in normal subjects may be influenced by physiological elements such as gender, height and body mass index. Considering that growth hormone (GH) hypersecretion is able to markedly alter different anthropometric variables, we studied the relation between these elements and the late potentials of 22 acromegalic patients. Males registered higher absolute QRS duration and LAS40 (low-amplitude signal) and, on the opposite, lower RMS40 (root mean square) in comparison to females; QRS duration and LAS40 seem to depend, however, on the different anthropometric variables, since their normalization with height and lean body mass (LBM) abolishes gender-dependent differences. On the contrary, the persistence, among males, of lower RMS40 in respect to females even after normalization for height, LBM and insulin-like growth factor 1 values makes it likely that the latter ECG variable is independent of the anthropometric ones and from the disease's activity. Moreover, males appear to be more vulnerable to GH heart-harming activity.