Excess mortality in patients with non-functioning pituitary adenoma: a systematic review and meta-analysis.

BACKGROUND: Patients with non-functioning pituitary adenoma (NFPA) often present with a variety of clinical manifestations and comorbidities, mainly determined by the local mass effect of the tumor and by hypopituitarism. Whether this has an impact on overall mortality, however, is still unclear. METHODS: PubMed/Medline, EMBASE, and Cochrane Library databases were systematically searched until May 2023 for studies reporting data either about standardized mortality ratios (SMRs) or about predictors of mortality in patients with NFPA. Effect sizes were pooled through a random-effect model. This systematic review and meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO, #CRD42023417782). RESULTS: Eleven studies were eligible for inclusion in the systematic review; among these, five studies reported data on SMRs, with a total follow-up time of approximately 130,000 person-years. Patients with NFPA showed an increased mortality risk compared to the general population (SMR = 1.57 [95%CI: 1.20-1.99], p < 0.01). Age and sex appeared to act as effect modifiers, with a trend towards higher SMRs in females (SMR = 1.57 [95%CI: 0.91-2.41], p = 0.10) than in males (SMR = 1.00 [95%CI: 0.89-1.11], p = 0.97), and in patients diagnosed at age 40 years or younger (SMR = 3.19 [95%CI: 2.50-3.97], p < 0.01) compared to those with later onset of the disease (SMR = 1.26 [95%CI: 0.93-1.65], p = 0.13). The trend towards excess mortality was similar in patients with normal (SMR = 1.22 [95%CI: 0.94-1.53], p = 0.13) or deficient (SMR = 1.26 [95%CI: 0.82-1.79], p = 0.27) pituitary function. CONCLUSIONS: Excess mortality is observed in patients with NFPA, regardless of pituitary function, especially in women and in patients with a younger age at diagnosis.

Disease control of acromegaly does not prevent excess mortality in the long term: results of a nationwide survey in Italy.

OBJECTIVE: This study aimed to assess the long-term outcome of patients with acromegaly. DESIGN: This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up. METHODS: Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population. RESULTS: A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population. CONCLUSIONS: Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

Neuroendocrine response to diclofenac in healthy subjects: a pilot study.

PURPOSE: The precise effects of non-steroidal anti-inflammatory drugs on the neuroendocrine hydro-electrolytic regulation are not precisely understood. The aim of this pilot study was to evaluate, in healthy subjects, the neuroendocrine response of the antidiuretic system to intravenous diclofenac infusion. METHODS: For this single-blinded, cross-over study, we recruited 12 healthy subjects (50% women). Test sessions were divided into three observation times (pre-test; test; 48 h post-test), which were repeated equally on two different occasions, with the administration of diclofenac (75 mg in saline solution 0.9% 100 cc) on 1 day, or placebo (saline solution 0.9% 100 cc) on another day. The night before the test the subjects were asked to collect a salivary cortisol and cortisone sample, which was repeated on the night of the procedure session. Serial urine and blood samples were collected on the test day (for osmolality, electrolytes, ACTH, cortisol, copeptin, MR-proADM, MR-proANP; the last three represent more stable and analytically reliable molecules than their respective active peptides). Moreover, the subjects were evaluated with the bioimpedance vector analysis (BIVA) before and after the test. Forty-eight hours after the end of the procedure urine sodium, urine potassium, urine osmolality, serum sodium and copeptin were revaluated together with BIVA. RESULTS: No significant changes in circulating hormone levels were observed; anyway, 48 h after diclofenac, BIVA showed a significant water retention (p < 0.00001), especially in extracellular fluid (ECF) (16.47 ± 1.65 vs 15.67 ± 1.84, p < 0.001). Salivary cortisol and cortisone tended to increase only the night after placebo administration (p = 0.054 cortisol; p = 0.021 cortisone). CONCLUSION: Diclofenac resulted in an increased ECF at 48 h, but this phenomenon seems to be associated with a greater renal sensibility to the action of vasopressin rather than with an increase in its secretion. Moreover, a partial inhibitory effect on cortisol secretion can be hypothesized.

GHRH + arginine test and body mass index: do we need to review diagnostic criteria for GH deficiency?

INTRODUCTION: The proportion of patients with low GH response to provocative tests increases with the number of other pituitary hormone deficiencies, reason why in panhypopituitary patients GH stimulation tests may be unnecessary to diagnose GH deficiency (GHD) PURPOSE: To re-evaluate the diagnostic cut-offs of GH response to GHRH + arginine (ARG) test related to BMI, considering the patients' pituitary function as the gold standard for the diagnosis of GHD. METHODS: The GH responses to GHRH + ARG were studied in 358 patients with history of hypothalamic-pituitary disease. GHD was defined by the presence of at least 3 other pituitary deficits (n = 223), while a preserved somatotropic function was defined by the lack of other pituitary deficits and an IGF-I SDS ≥ 0 (n = 135). The cut-off with the best sensitivity (SE) and specificity (SP), was identified for each BMI category using the ROC curve analysis. To avoid over-diagnosis of GHD we subsequently searched for the cut-offs with a SP ≥ 95%. RESULTS: The best GH cut-off was 8.0 µg/l (SE 95%, SP 100%) in lean, 7.0 µg/l (SE 97.3%, SP 82.8%) in overweight, and 2.8 µg/l (SE 84.3%, SP 91.7%) in obese subjects. The cut-off with a SP ≥ 95% was 2.6 µg/l (SE 68.5%, SP 96.6%) in overweight and 1.75 µg/l (SE 70.0%, SP 97.2%) in obese subjects. CONCLUSIONS: This is the first study that evaluates the diagnostic cut-offs of GH response to GHRH + ARG related to BMI using a clinical definition of GHD as gold standard. Our results suggest that with this new approach, the GHRH + ARG cut-offs should be revised to avoid GHD over-diagnosis.

Benefits of dual-release hydrocortisone treatment on central adiposity and health-related quality of life in secondary adrenal insufficiency.

PURPOSE: Patients with secondary adrenal insufficiency (SAI) have an increased morbidity and an impaired health-related quality of life (HRQoL), which seems to primarily depend on the sub-optimal replacement of hypoadrenalism with standard glucocorticoid (GC) therapy, and on the inadequate correction of other associated pituitary deficiencies. A dual-release hydrocortisone (DR-HC) formulation has shown to exert positive effects on morbidity and HRQoL, mainly in patients with primary adrenal insufficiency. We assessed the variations of anthropometric and metabolic parameters and HRQoL in patients with SAI after switching from cortisone acetate (CA) or hydrocortisone (HC) to DR-HC. METHODS: Twenty-one patients (17 M, 4 F) treated with CA (n = 16; 25 mg/day twice a day) or HC (n = 5; 20 mg/day three times a day), were evaluated for waist circumference, BMI, fasting glucose, HbA1c, insulin, HOMA-IR index, serum lipids, electrolytes, blood pressure and HRQoL at baseline, at 3, 6 and 12 months after switching from CA/HC to DR-HC. RESULTS: The study showed a significant reduction of waist circumference and BMI (p = 0.04, for both), after 3 and 6months of DR-HC treatment, respectively. No significant changes were observed for fasting glucose, insulin, HOMA-IR index, HbA1c, total cholesterol, triglycerides, LDL cholesterol, electrolytes, and blood pressure. However, HDL cholesterol significantly decreased (p = 0.003). An improvement of AddiQoL total score was observed during DR-HC treatment (p = 0.01), mainly for the category "emotions". No predictors resulted for these changes. CONCLUSION: DR-HC treatment provides some benefits in patients with SAI, reducing central adiposity and improving HRQoL; however, worsening of HDL cholesterol is observed during treatment with DR-HC.

Development and internal validation of a predictive score for the diagnosis of central adrenal insufficiency when morning cortisol is in the grey zone.

BACKGROUND: When evaluating a patient for central adrenal insufficiency (CAI), there is a wide range of morning cortisol values for which no definite conclusion on hypothalamus-pituitary-adrenal (HPA) axis function can be drawn; in these cases, a stimulation test is required. Aim of this study was to develop an integrated model for CAI prediction when morning cortisol is in the grey zone, here defined as 40.0-160.0 µg/L. METHODS: Overall, 119 patients with history of sellar tumour which underwent insulin tolerance test (ITT) for the evaluation of HPA axis were enrolled. Supervised regression techniques were used for model development. RESULTS: An integrated predictive model was developed and internally validated, and showed a significantly better diagnostic performance than morning cortisol alone (AUC 0.811 vs 0.699, p = 0.003). A novel predictive score (CAI-score) was retrieved, on a 5.5-point scale, by considering morning cortisol (0 points if 130.1-160.0 µg/L, 1 point if 100.1-130.0 µg/L, 1.5 points if 70.1-100.0 µg/L, 2.5 points if 40.0-70.0 µg/L), other pituitary deficits (2 points if ≥ 3 deficits), and sex (1 point if male). A diagnostic algorithm integrating CAI-score and ITT was finally proposed, with an overall accuracy of 99%, and the possibility to avoid the execution of stimulation tests in 25% of patients. CONCLUSIONS: This was the first study that proposed an integrated score for the prediction of CAI when morning cortisol is in the grey zone. This score might be helpful to reduce the number of patients who need a stimulation test for the assessment of HPA axis function.

Mean GH profile is more accurate than single fasting GH in the evaluation of acromegaly disease control during somatostatin receptor ligands therapy.

PURPOSE: This study aims to compare the accuracy of mean GH profile (GHP) < 2.5 ng/ml and single fasting GH (SGH) < 1 ng/ml in the evaluation of disease control in acromegaly patients during somatostatin receptor ligands (SRLs) therapy. METHODS: We retrospectively enrolled 100 acromegaly patients, 68 responder, and 32 partial responder to SRLs. Controlled disease has been defined as IGF-I levels within age-related normal limits, while partial response as pathological IGF-I values despite a reduction ≥ 50%. In all patients, GHP, SGH, IGF-I, and IGFBP-3 were evaluated. RESULTS: Median GHP levels (1.2 ng/ml, IQR 0.5-2.3 ng/ml) were lower (p = 0.001) than SGH (1.9 ng/ml, IQR 1.0-3.6 ng/ml). Accuracy of GHP was 81%, whereas that of SGH was 55%, with a Kappa index of 0.520 and 0.237, respectively. In multivariable analysis GHP (p = 0.002) and IGFBP-3 (p = 0.004), but not SGH, were independently associated with normal IGF-I levels. At receiver-operator characteristic curve (ROC) analysis GHP cut-off sensitivity and specificity were 94.1% and 50.0%, respectively, while SGH sensitivity and specificity were 35.3% and 93.7%, respectively. Finally, in obese patients the GH cut-off level (both as SGH and GHP) associated to good disease control was significantly different with respect to not obese ones. CONCLUSIONS: GHP associates with IGF-I (and therefore with appropriate control of disease) with higher accuracy than SGH. When GH evaluation is needed, the measurement of mean GHP should be preferred and use of BMI-related cut-offs is suggested.

Are there country-specific differences in the use of pegvisomant for acromegaly in clinical practice? An analysis from ACROSTUDY.

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.

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

BACKGROUND: 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 30 min (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. METHODS: 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. RESULTS: The sampling at 90' was the one in which a GH level < 1 µg/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'. CONCLUSION: 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.

First but not second postoperative day growth hormone assessments as early predictive tests for long-term acromegaly persistence.

PURPOSE: Postoperative assessment of acromegaly activity is typically performed at least 3 months after neurosurgery (NS). Few studies have evaluated the use of early postoperative growth hormone (GH) levels as a test to predict short- and long-term remission of acromegaly. Our objective was to evaluate the diagnostic performance of serum random GH on a postoperative day one (D1-rGH) and two (D2-rGH), particularly in predicting long-term disease persistence. MATERIALS AND METHODS: Forty-one subjects with acromegaly who were undergoing NS were enrolled (mean age ± SD 47.4 ± 13.1 years at diagnosis; women 54%; macroadenomas 71%). The final assessment of disease activity was performed one year after NS. ROC curves were used to evaluate the diagnostic performance of D1-rGH and D2-rGH. RESULTS: After a 1-year follow-up, the overall remission rate was 55%. ROC analysis identified an optimal D1-rGH cut-off value of 2.1 ng/mL for diagnosing long-term disease persistence (55.6% SE; 90.9% SP). The cut-off point became 2.5 ng/mL after maximizing specificity for disease persistence (yielding a 100% positive predictive value) and 0.3 ng/mL after maximizing sensitivity for disease remission. The optimal D2-rGH cut-off value was 0.6 ng/mL (81.8% SE; 50% SP); the cut-off point became 2.9 ng/mL after maximizing specificity and 0.1 ng/mL after maximizing sensitivity, with no clinical utility. CONCLUSIONS: D1-rGH could be a highly specific test for the early diagnosis of long-term acromegaly persistence, which is predicted by a value > 2.5 ng/mL with a great degree of certainty. The diagnostic performance of D2-rGH was insufficient. Further research is required to validate these preliminary results prior to modifying the postoperative management of acromegaly.

Pituitary surgery during Covid-19: a first hand experience and evaluation.

PURPOSE: During the Covid-19 pandemic every hospital has had to change its internal organization. Different institutions have highlighted the risks connected with endoscopic endonasal surgery. The goal of this paper is to illustrate the feasibility of pituitary region surgery during the SARS-CoV-2 pandemic. METHODS: After two negative Covid tests were obtained, three patients with macro GH-secreting tumors, and two patients with micro ACTH-secreting tumors resistant to medical treatment underwent surgery during the pandemic. During the surgery, every patient was treated as if they were positive. RESULTS: Neither operator, nor patient have developed Covid symptoms. The two neurosurgeons performing the operations underwent two Covid swab, which resulted negative. CONCLUSIONS: Pituitary surgery is a high risk non-urgent surgery. However, the method described has so far been effective and is safe for both patients and healthcare providers.

The prevalence of silent acromegaly in prolactinomas is very low.

PURPOSE: The aim of this study was to evaluate the somatotroph axis in a large series of patients with prolactinoma to verify the prevalence of silent acromegaly in this population. METHODS: A hundred and forty-four patients were enrolled in a multicenter study: 90 were already on cabergoline (CAB) and enrolled in a cross-sectional arm (group A) with random PRL, GH and IGF-I determination on treatment (≥ 3 months), whereas 54 untreated patients were enrolled at diagnosis in a prospective arm (group B) with PRL, GH and IGF-I measurement before and after 6 and 12 months of treatment. In the presence of high IGF-I, CAB was withdrawn for 3 months and GH, IGF-I, PRL and GH during an oral Glucose Tolerance Test (OGTT) were obtained. RESULTS: High IGF-I levels (ULN 1.01-1.56) were observed in 9 patients (6.25%, 5F). After CAB withdrawal, IGF-I levels normalized in 5/9 patients, GH was < 0.4 ng/ml after OGTT in 7/9 cases or at random GH determination in one case. After CAB re-introduction, IGF-I levels re-increased in a single case. Overall, a single young female patient harboring a macroadenoma in group A was diagnosed with silent acromegaly and underwent successful transsphenoidal removal of a GH/PRL-secreting adenoma. CONCLUSION: The prevalence of silent acromegaly in prolactinomas (0.7%) is lower than previously reported and OGTT is helpful to recognize silent acromegaly. We suggest that the somatotroph axis should be evaluated at diagnosis in all cases and not systematically during follow-up.

Increased prevalence of impulse control disorder symptoms in endocrine diseases treated with dopamine agonists: a cross-sectional study.

INTRODUCTION: Impulse control disorders (ICDs) have been described as a side effect of dopamine agonists (DAs) in neurological as well as endocrine conditions. Few studies have evaluated the neuropsychological effect of DAs in hyperprolactinemic patients, and these have reported a relationship between DAs and ICDs. Our objective was to screen for ICD symptoms in individuals with DA-treated endocrine conditions. MATERIALS AND METHODS: A cross-sectional analysis was conducted on 132 patients with pituitary disorders treated with DAs (DA exposed), as well as 58 patients with pituitary disorders and no history of DA exposure (non-DA exposed). Participants responded to the full version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP). RESULTS: Compared with the non-DA-exposed group, a higher prevalence of DA-exposed patients tested positive for symptoms of any ICD or related behavior (52% vs. 31%, p < 0.01), any ICD (46% vs. 24%, p < 0.01), any related behavior (31% vs. 17%, p < 0.05), compulsive sexual behavior (27% vs. 14%, p < 0.04), and punding (20% vs. 7%, p < 0.02) by QUIP. On univariate analysis, DA treatment was associated with a two- to threefold increased risk of any ICD or related behavior [odds ratio (OR) 2.43] and any ICD (OR 2.70). In a multivariate analysis, independent risk factors for any ICD or related behavior were DA use (adjusted OR 2.22) and age (adjusted OR 6.76). Male gender was predictive of the risk of hypersexuality (adjusted OR 3.82). DISCUSSION: Despite the QUIP limitations, a clear sign of increased risk of ICDs emerges in individuals with DA-treated pituitary disorders. Our data contribute to the growing evidence of DA-induced ICDs in endocrine conditions.

Biliary adverse events in acromegaly during somatostatin receptor ligands: predictors of onset and response to ursodeoxycholic acid treatment.

PURPOSE: Somatostatin receptor ligands (SRL) are the first-line medical treatment for acromegaly. Gallbladder alterations are one of most important SRL side effect, but according to some authors growth hormone hypersecretion itself is a risk factor for gallstones. This single center, longitudinal retrospective study evaluated the incidence and the predictors of biliary adverse events (BAE) in acromegaly during SRL therapy and their response to ursodeoxycholic acid (UDCA). METHODS: 91 acromegaly patients with indication to SRL were enrolled. Evaluations of acromegaly activity (GH, IGF-I, IGF-I/ULN) and metabolic profile were collected before starting treatment, yearly during follow-up and at BAE onset. In patients developing BAE we searched for predictors of UDCA effectiveness. RESULTS: 61.5% of patients developed BAE (58.9% cholelithiasis; 41.1% only sludge). IGF-I and IGF-I/ULN proved to be positive predictor of BAE, which occur about 5 years after SRL starting. None of metabolic markers proved to be associated with BAE. Only five patients (5.5%) underwent cholecystectomy for symptomatic cholelithiasis. 71% of patients started UDCA treatment, achieving regression of BAE in 60% of cases (88% in patients developing only sludge and 30% in patients affected by cholelithiasis, p < 0.001). BMI and obesity were negative predictors of UDCA efficacy. In 50% of the subjects BAE resolved after 36 months of therapy with a lower rate if cholelithiasis was present. CONCLUSION: Biliary stone disease is a frequent SRL adverse event, although it is often symptomless. Ultrasound follow-up mainly in the first 5 years of therapy, early UDCA starting and proper lifestyle represent a valid strategy in their detection and management.

Acromegaly and joint pain: is there something more? A cross-sectional study to evaluate rheumatic disorders in growth hormone secreting tumor patients.

PURPOSE: The aim of the present study was to evaluate the rheumatic profile in acromegalic patients to better characterize joint pain. METHODS: The immunological pattern (rheumatoid factor; antinuclear antibodies-ANA, extractable nuclear antigens-ENA-Ab; anti-citrullinated protein antibodies; erythrocyte sedimentation rate) was evaluated in 20 acromegaly subjects (AS) and 20 control subjects (CS). Bilateral joint ultrasound of hands/wrists and nail capillaroscopy were also performed. RESULTS: Articular pain was more frequent in AS than in CS (p = 0.027). No difference was detected in immunological parameters. ANA and ENA-Ab were positive in only 10% of AS and in 5% of CS, while no difference was found in anti-citrullinated protein antibodies. No difference was detected between rheumatoid factor positivity, but threefold higher IgG were detected in AS compared to CS. The erythrocyte sedimentation rate was significantly higher in AS than CS (p = 0.040), while in AS, there was a trend in increased Power Doppler (PWD) articular uptake. The capillaroscopic evaluation showed a significant difference in almost each parameter (presence and number of tortuous capillaries, capillary enlargements, and hemorrhages), showing a moderate-to-severe microangiopathy in AS. CONCLUSION: The results of our study suggest that joint damage in acromegaly has not an autoimmune etiology. Increased erythrocyte sedimentation rate levels and PWD alteration in acromegalic population reflect a possible inflammatory nature, while the capillaroscopic findings suggest a moderate-to-severe microangiopathy that could help to identify patients with a greater macroangiopathic risk.

Untreated adult GH deficiency is not associated with the development of metabolic risk factors: a long-term observational study.

PURPOSE: Uncertainties exist about the predictors of the severity of the clinical picture of GH deficiency (GHD) syndrome. Aim of the study was to evaluate, in adult patients with GHD, the predictors of the development of hypercholesterolemia, hypertension, diabetes mellitus, and osteoporosis. METHODS: We retrospectively studied 327 adult patients (age 47.1 ± 17.1 years) with untreated severe GHD (mean follow-up 110.9 ± 56.8 months). GHD was defined by GHRH + arginine test using BMI cut-offs. The possible development of hypercholesterolemia, hypertension, diabetes mellitus, and osteoporosis was investigated by Kaplan-Meier survival analysis. For each clinical outcome, either a univariate or multivariate analysis according to the Cox proportional-hazards model was performed to identify those factors that were associated with the development of the event. RESULTS: GH secretion parameters were not associated with the outcomes. Hypercholesterolemia was positively and negatively predicted by a BMI ≥ 30 kg/m2 (HR 2.50, p 0.00) and the dose of l-thyroxine possibly in place (HR 0.98, p 0.02), respectively. Hypertension was positively predicted by a BMI ≥ 30 kg/m2 (HR 2.64, p 0.00) and IGF-I SDS values (HR 2.26, p 0.00). Diabetes mellitus was positively predicted by hypertension (HR 11.76, p 0.01). Osteoporosis was positively and negatively predicted by hypercholesterolemia (HR 3.25, p 0.01) and hypertension (HR 0.21, p 0.00), respectively. CONCLUSIONS: The severity of the impairment of GH secretion does not predict the development of the clinical picture of GHD syndrome: untreated adult GHD does not increase the development of metabolic risk factors in hypopituitaric patients.

Arthropathy in acromegaly: a questionnaire-based estimation of motor disability and its relation with quality of life and work productivity.

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.

How to improve effectiveness of pegvisomant treatment in acromegalic patients.

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/m2 (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.

Correction to: Pegvisomant in acromegaly: an update.

Unfortunately, in page 584, second column, the first sentence under the heading "Type of switch" has been published incorrectly. The complete correct sentence is given below.