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Purpose: We previously showed the clinical characteristics of acromegaly with a paradoxical growth hormone (GH) response to oral glucose or thyrotropin-releasing hormone. However, the clinical characteristics of acromegaly with an increased GH response to luteinizing hormone-releasing hormone (LHRH responders) remain unclear. The aim of the present study was to evaluate the clinical characteristics, especially gonadotroph-related characteristics of LHRH responders in acromegaly., Methods: The clinical characteristics of 33 LHRH responders and 81 LHRH nonresponders were compared., Results: No differences in age, sex or basal serum levels of GH, insulin-like growth factor-1 (IGF-1), and gonadotropin were observed between the two groups. Steroidogenic factor 1 (SF-1), gonadotropin-releasing hormone receptor (GnRHR), and LH expression was more frequently observed in LHRH responders (P < 0.05). In addition, a greater increased rate of GH after LHRH loading, and the proportion of GnRHR and gonadotropin expression was observed in pituitary tumor with SF-1 expression than that without the expression (P < 0.01). LHRH responders showed a greater GH decrease in the octreotide test and a greater IGF-1 decrease after first-generation somatostatin ligand than LHRH nonresponders (P < 0.05). Furthermore, the proportion of hypointense pituitary tumors on T2-weighted magnetic resonance imaging and tumors with densely granulated type was higher in LHRH responders than in LHRH nonresponders, respectively (P < 0.05). No difference between the two groups was observed in either somatostatin receptor 2 or 5 expression., Conclusions: The increased GH response to LHRH is associated with the gonadotroph-related characteristics. This response may reflect the biological characteristics of somatotroph tumors., (© 2024. The Author(s).)

Purpose: Copeptin efficiently predicts post-neurosurgical central diabetes insipidus (CDI) in patients with hypothalamic-pituitary lesions, but its role in characterizing changes in diuresis in individuals with acromegaly undergoing neurosurgery remains unexplored. Our study aimed to assess changes in postoperative fluid balance in acromegaly patients and correlate them with both copeptin and growth hormone (GH) levels., Methods: This was a secondary analysis of a prospective study involving 15 acromegaly patients undergoing endoscopic endonasal resection at our University Hospital. Fluid balance was assessed daily, and copeptin and GH levels were evaluated preoperatively (T0), and serially on the morning of the first (T2) and second (T3) postoperative day, with an additional measurement of copeptin one hour post-extubation (T1). Patients with pre-existing or post-neurosurgical CDI were excluded from the analysis., Results: Most patients (11/15) exhibited a negative fluid balance on the second postoperative day, with 4 developing polyuria. Postoperative GH levels did not differ significantly between polyuric and non-polyuric patients, but GH measured at T2 correlated significantly with negative total balance (r = -0.519, p = 0.048). Copeptin levels at T1 were significantly higher in those who developed polyuria (p = 0.013), and a copeptin value > 39.9 pmol/L at T1 showed excellent ability (Sensitivity 100%, Specificity 90.9%, p < 0.001) in predicting postoperative polyuria. Additionally, polyuric patients exhibited a higher T1 / T3 copeptin ratio (p = 0.013) and a negative fluid balance was associated with the remission of acromegaly at 12 months (p = 0.046)., Conclusion: The early assessment of copeptin, in addition to facilitating the rapid identification of individuals at increased risk of developing CDI, could also allow the recognition of subjects with a tendency towards non-pathological polyuria in the postoperative setting, at least in individuals affected by acromegaly., (© 2024. The Author(s).)

Context: Outcome of acromegaly surgery is assessed by IGF-1 and glucose-suppressed GH, but whether the latter provides additional clinically relevant information when IGF-1 is normal is unclear. The role of GH suppression testing after surgery requires clarification., Methods: We studied 97 acromegaly patients with normal IGF-1 after surgery by measuring GH after oral glucose longitudinally, initially at ≥ 3 months after surgery and repeated one or more times ≥ 1 year later. Nadir GH was categorized as normal or abnormal relative to the 97.5th percentile of nadir GH in 100 healthy subjects, which were ≤ 0.14 µg/L (DSL IRMA) or ≤ 0.15 µg/L(IDS iSYS). Signs and symptoms scores and insulin resistance were followed longitudinally., Results: Of 68 patients with initial normal GH suppression 63 (93%) remained in remission and of 29 with initial abnormal GH suppression, 9 (31%) recurred. Recurrence was more common in patients with abnormal suppression (P < 0.001). A total of 14 patients recurred, including 5 with normal GH suppression progressing to abnormal and then recurrence. Overall, serial signs and symptoms and insulin resistance assessments did not identify patients with abnormal suppression or recurrence., Conclusion: Risk of recurrence after surgery is increased for patients with a normal IGF-1 level, but abnormal GH suppression. We newly find, using both our and others' cut-offs, that while normal suppression predicts long-term remission in most patients, some can progress from normal to abnormal suppression and then recurrence after many years of follow up. Nadir GH levels are of prognostic value in acromegaly patients with normal IGF-1 levels after surgery.

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.

Guidelines and consensus statements ensure that physicians managing acromegaly patients have access to current information on evidence-based treatments to optimize outcomes. Given significant novel recent advances in understanding acromegaly natural history and individualized therapies, the Pituitary Society invited acromegaly experts to critically review the current literature in the context of Endocrine Society guidelines and Acromegaly Consensus Group statements. This update focuses on how recent key advances affect treatment decision-making and outcomes, and also highlights the likely role of recently FDA-approved therapies as well as novel combination therapies within the treatment armamentarium.

Purpose: Biochemical control is the main determinant of survival, clinical manifestations and comorbidities in acromegaly. Transsphenoidal selective adenomectomy (TSA) is the initial treatment of choice with reported biochemical remission rates varying between 32 and 85%. Understanding the limiting factors is essential for identification of patients who require medical treatment., Methods: We reviewed the English literature published in Medline/Pubmed until Dec 31, 2019 to identify eligible studies that described outcomes of TSA as primary therapy and performed analyses to determine the main predictors of remission., Results: Most publications reported single-institution, retrospective studies. The following preoperative parameters were consistently associated with lower remission rates: cavernous sinus invasion by imaging, larger tumor size and higher GH levels. Young age and preoperative IGF-1 levels were predictive in some studies. When controlled for covariates, the best single preoperative predictor was cavernous sinus invasion, followed by preoperative GH levels. Conversely, low GH level in the first few days postoperatively was a robust predictor of durable remission. The influence of tumor histology (sparsely granular pattern, co-expression of prolactin and proliferation markers) on surgical remission remains to be established. Few studies developed predictive models that yielded much higher predictive values than individual parameters., Conclusion: Surgical outcome prognostication systems could be further generated by machine learning algorithms in order to support development and implementation of personalized care in patients with acromegaly.

Purpose: The SAGIT® instrument, designed to assist clinicians to stage acromegaly, assess treatment response and adapt patient management, was well received by endocrinologists in a pilot study. We report an interim analysis of baseline data from the validation phase., Methods: The SAGIT® validation study (ClinicalTrials.gov NCT02539927) is an international, non-interventional study. Data collection included: demographic/disease characteristics; medical/surgical histories; concomitant acromegaly treatments; investigators' subjective evaluation of disease-control status (clinical global evaluation of disease control [CGE-DC]; controlled/not controlled/yet to be clarified) and clinical disease activity (active/not active); growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels; investigators' therapeutic decision., Results: Of 228 patients enrolled, investigators considered disease to be controlled in 110 (48.2%), not controlled in 105 (46.1%), and yet to be clarified in 13 (5.7%) according to CGE-DC. Thirty-three patients were treatment-naïve (not controlled, n = 31; yet to be clarified, n = 2). Investigators considered 48.2% patients in the controlled and 95.2% in the not-controlled groups to have clinically active disease. In the controlled group, 29.7% of patients did not exhibit hormonal control (GH ≤ 2.5 µg/L; normalized IGF-1) and 47.3% did not have rigorous hormonal control (GH < 1.0 µg/L; normalized IGF-1) by contemporary consensus. Current acromegaly treatment was continued with no change for 91.8% of patients in the controlled and 40.0% in the not-controlled groups., Conclusions: These data highlight discrepancies between investigator-evaluated disease-control status, disease activity, hormonal control, and treatment decisions in acromegaly. Once validated, the SAGIT® instrument may assist clinicians in making active management decisions for patients with acromegaly.

Introduction: Cardiovascular diseases are main cause of morbidity and mortality in acromegaly. Polymorphisms of FTO gene are associated with obesity and increased risk of CVD (independently of BMI). Aim of this study was to investigate the allele frequencies of two FTO gene polymorphisms: rs9939609 and rs9930506 in patients with acromegaly and to examine the association of FTO gene polymorphisms with BMI and selected metabolic parameters., Materials and Methods: Identification of two single nucleotide polymorphisms of FTO gene was carried out in 51 patients with acromegaly using the minisequencing method., Results: The risk-allele frequencies of rs9939609 and rs9930506 polymorphisms were 0.471 and 0.529, respectively and they were higher than in general European population. There is no association of FTO gene polymorphisms with BMI, glucose, total cholesterol, LDL cholesterol and triglyceride. The risk alleles were associated with decreased HDL cholesterol concentration. Homozygotes for the rs9939609-risk allele had 1.25-fold lower HDL cholesterol concentration than carriers of the TT genotype (p = 0.0024). The estimated average decrease in HDL cholesterol concentration per risk allele for rs9930506 was 11.2%. Nevertheless, statistically significant differences were observed only between AG versus GG and AA versus GG genotypes. Homozygotes for the rs9930506-risk allele had 1.27-fold lower HDL cholesterol concentration than carriers of the AA genotype (p = 0.007)., Conclusion: The risk-allele frequencies of studied polymorphisms in acromegaly were higher than in general European population. There is an association between FTO gene polymorphisms and HDL cholesterol concentration, suggesting FTO gene polymorphisms may be associated with higher CVD risk in patients with acromegaly.

Purpose: Measuring IGF-1, a biomarker for GH activity, is critical to evaluating disordered hypothalamic-pituitary GH axis. Inconsistent IGF-1 measurements among different immunoassays are well documented. We switched from Immulite 2000 immunoassay to narrow-mass-extraction, high-resolution liquid chromatography mass-spectrometry (LC-MS) compliant with recent consensus recommendations on assay standardization. Comparability of these two assays in patients with pituitary disease in a clinical practice setting is not known. We sought to compare IGF-1 levels on Immulite 2000 and LC-MS in samples from naïve and treated patients with secretory and non-secretory pituitary masses., Methods: We prospectively collected serum samples from 101 patients treated at the Cedars-Sinai Pituitary Center between February 2012 and March 2014. We intentionally recruited more patients with acromegaly or GH deficiency to ensure a clinically representative cohort. Samples were classified as in or out of the respective reference ranges. Bland-Altman analysis was used to assess agreement between assays., Results: Twenty-four percent of samples were classified differently as below, in, or above range. Agreement between the assays was poor overall, with a significant bias for immunoassay reporting higher values than LC-MS. This pattern was also observed in patients with acromegaly and those with ≥ 2 pituitary hormone deficiencies., Conclusions: IGF-1 results may differ after switching from an older immunoassay to a consensus-compliant assay such as LC-MS. Clinicians should consider the potential impact of assay switching before altering treatment due to discrepant results, particularly in patients monitored over time, such as those with acromegaly and GH deficiency.

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.

Purpose: Approximately 25 % of cases of clinically active acromegaly cases treated in our academic center between 1996 and 2000, were diagnosed in patients who had elevated plasma IGF-1 levels, but apparently "normal" 24-h mean plasma GH levels. The current study served to update the data for patients with acromegaly referred to our facility, after increasing awareness of this "normal" GH subpopulation throughout the medical community., Methods: A retrospective chart review was conducted on 157 patients with acromegaly who underwent resection of a confirmed somatotroph pituitary adenoma at the University of Michigan Health System between the dates of 1 Jan 2001 to 23 Sept 2015., Results: Overall prevalence of acromegalic patients with "normal" GH levels, defined as GH <4.7 ng/mL, was 31 %. Over time, the percentage of patients with "normal" GH at diagnosis did not decline: 26 % from 2001 to 2005, 19 % from 2006 to 2010, and 47 % from 2011 to 2015. Mean pituitary tumor size was 1.8 ± 0.1 cm for the group with elevated GH, and 1.2 ± 0.1 cm for the group with "normal" GH (p < 0.001). Percent microadenomas was higher in a group with "normal" GH as compared to those with elevated GH (48 vs. 12 %, p < 0.001), and tumors >2 cm in the maximal diameter were encountered more frequently in the group with elevated GH (43 vs. 14 %, p < 0.001)., Conclusions: Our data show that a substantial percentage of patients with clinical acromegaly have "normal" GH, and therefore strengthens the growing body of evidence which supports the leading role of IGF-1 levels in diagnostic evaluation. At the present time, questions about the natural course of "micromegaly" and treatment benefits compared to the subpopulation with elevated GH levels remain unanswered, but research continues to build on our understanding of the heterogeneous population of individuals.

Purpose: Activity of acromegaly is gauged by levels of GH and IGF-1 and epidemiological studies demonstrate that their normalization reduces acromegaly's excess mortality rate. However, few data are available linking IGF-1 levels to features of the disease that may relate to cardiovascular (CV) risk. Therefore, we tested the hypothesis that serum IGF-1 levels relative to the upper normal limit relate to insulin sensitivity, serum CV risk markers and body composition in acromegaly., Methods: In this prospective, cross-sectional study conducted at a pituitary tumor referral center we studied 138 adult acromegaly patients, newly diagnosed and previously treated surgically, with fasting and post-oral glucose levels of endocrine and CV risk markers and body composition assessed by DXA., Results: Active acromegaly is associated with lower insulin sensitivity, body fat and CRP levels than acromegaly in remission. %ULN IGF-1 strongly predicts insulin sensitivity, better than GH and this persists after adjustment for body fat and lean tissue mass. %ULN IGF-1 also relates inversely to CRP levels and fat mass, positively to lean tissue and skeletal muscle estimated (SM(E)) by DXA, but not to blood pressure, lipids, BMI or waist circumference. Gender interacts with the IGF-1-lean tissue mass relationship., Conclusions: Active acromegaly presents a unique combination of features associated with CV risk, reduced insulin sensitivity yet lower body fat and lower levels of some serum CV risk markers, a pattern that is reversed in remission. %ULN IGF-1 levels strongly predict these features. Given the known increased CV risk of active acromegaly, these findings suggest that of these factors insulin resistance is most strongly related to disease activity and potentially to the increased CV risk of active acromegaly.

Purpose: This study aimed at investigating predicting factors for therapy response under growth hormone receptor antagonist therapy with a focus on subjective and patient-oriented measures., Methods: Observational, multicenter nested-cohort study including 271 selected patients with the diagnosis of acromegaly and a minimum of one-year follow-up period within the German ACROSTUDY cohort (total cohort: n = 514). Outcome measures were the change of the biomarker IGF-1 (IGF-1 change and IGF-1 normalisation) between baseline and after 1 year of pegvisomant therapy (12 ± 6 months). Main predictors were patient-assessed subjective measures according to the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) in conjugation with age, gender, BMI, max. dosage of pegvisomant at follow-up and IGF-1 before the start of pegvisomant therapy., Results: The mean age of the study population was 51.2 (13.9) years and the mean BMI was 29.5 (5.1) kg/m(2). In adjusted analyses, none of the individual perceived health (PASQ) scores, but age, BMI and IGF-1 at baseline were predictive for an IGF-1 decrease after 1 year of pegvisomant therapy and BMI and IGF-1, but equally none of the PASQ items, were predicting IGF-1 normalisation., Conclusions: Age, BMI and baseline IGF-1 but not subjective perceived health measures predict therapy response under second line medical therapy with pegvisomant.

Background: The association of GHR-exon 3 and -202 A/C IGFBP3 polymorphisms with clinical presentation, biochemical measurements and response to therapies in acromegaly have been suggested., Objective: To evaluate the presence of these polymorphisms in acromegaly and their influence on clinical and laboratorial characteristics of patients at diagnosis and after treatment in a large cohort of acromegalic patients., Patients and Methods: This is a cross-sectional study developed in a single tertiary reference center. Clinical data were obtained from the medical records of 186 acromegalic patients (116 women, age range 21-88 years). GH and IGF1 levels and GHR-exon 3 and -202 A/C IGFBP3 polymorphisms were evaluated in the same hospital., Results: At diagnosis, serum GH concentrations were lower in patients with GHR-d3 genotype than those with GHR-fl, whereas an association of lower IGFBP3 levels with d3 allele was observed only after neurosurgical or medical treatments. However, these associations were not confirmed in posterior statistical analysis., Conclusion: Our results suggest that GHR-exon 3 and -202 A/C IGFBP3 polymorphisms did not show any consistent association on clinical and laboratorial features of acromegalic patients even after treatment.

Purpose: Data regarding atherosclerosis in acromegaly is controversial in literature. We aimed to investigate the markers of early atherosclerosis, oxidative stress, inflammation and their relationships with each other in acromegaly., Methods: Thirty-nine patients with acromegaly and 40 control subjects were enrolled. Patients were classified into two groups; active acromegaly (AA) and controlled acromegaly (CA). Controls were matched by age, gender, body mass index and presence of cardiovascular risk factors. Flow mediated dilatation (FMD), carotid intima media thickness (CIMT), epicardial adipose tissue thickness (EAT) were measured and serum levels of oxidative stress parameters, high mobility group box 1 protein (HMGB1) and high sensitive CRP (hs CRP) were evaluated., Results: Significantly decreased FMD, increased CIMT and EAT were found in patients with acromegaly compared to controls (p < 0.01, p < 0.05, p < 0.001, respectively). EAT correlated negatively with FMD (r = -0.24, p = 0.038) and positively with CIMT (r = 0.37, p < 0.01). Presence of acromegaly, hypertension and age were found to be the predictors of early atherosclerosis (p < 0.05). Hs CRP was decreased in AA compared to controls (p = 0.01). There were no significant differences for HMGB1 and oxidized LDL (ox-LDL) cholesterol levels and total antioxidant capacity (TAC) between AA, CA and controls (p > 0.05)., Conclusion: Early atherosclerosis measured with FMD, CIMT and EAT may exist in acromegaly. However, decreased hs CRP and unchanged HMGB1, ox-LDL and TAC levels suggest that inflammation and oxidative stress do not seem to contribute to the development of atherosclerosis in these patients.

Purpose: Colorectal neoplasms are well known to be a complication in cases of acromegaly; however, data on the prevalence of colorectal neoplasms in Asian patients with acromegaly are limited. Further, the factors associated with colorectal neoplasms in cases of acromegaly are controversial. Therefore, we aimed to clarify the prevalence of and factors associated with colorectal neoplasms in Japanese patients with acromegaly in a single center., Methods: We analyzed consecutive 57 patients who had undergone full-length colonoscopy at the time of diagnosis at Kobe University Hospital between 1986 and 2012., Results: Of the 57 patients, 22 (38.6%), 18 (31.6%) and 3 (5.3%) patients were diagnosed with hyperplastic polyps, adenomas, and adenocarcinomas, respectively and the prevalence was significantly higher than in a historical control group, Chinese patients with irritable bowel syndrome (The odds ratio was 4.0, 8.7, and 17.5, respectively). The prevalence of adenocarcinomas was also significantly higher in these patients than in the general Japanese population (odds ratio 14.5). Patients with acromegaly who had colorectal neoplasms had longer disease duration than those without colorectal neoplasms. Of note, the area under the growth hormone (GH) concentration-time curve (GH AUC) during the oral glucose tolerance test was significantly higher in patients with adenocarcinomas than in those with no colonic lesion or those with hyperplastic polyps., Conclusion: Japanese patients with acromegaly exhibited an increased risk of colorectal neoplasms, especially colorectal adenocarcinomas. An increased GH AUC was associated with an increased risk for colon adenocarcinomas in patients with acromegaly.

Context: Acromegaly is associated with impaired quality of life (QoL) and causes anatomical disproportions, which may contribute to the decreased QoL after successful treatment. The Derriford appearance scale 59 (DAS59) is a questionnaire measuring psychological distress and disruptions to everyday life associated with self-consciousness of appearance., Objective: Investigate the psychological distress and dysfunction related to self-consciousness about appearance and its effect on QoL in patients in long-term remission of acromegaly., Patients, Design and Methods: Patients (>18 years old) treated for acromegaly at the Department of Endocrinology of the Radboud University Medical Center Nijmegen were invited to participate. A gender-, age- and body mass index matched control group was provided by the patients themselves. Participants were asked to complete the modified DAS59-, research and development 36- (RAND-36), acromegaly quality of life questionnaire (AcroQoL) and a sociodemographic questionnaire. Differences between patient- and control groups and correlations between questionnaire scores and clinical characteristics collected from medical records were analyzed., Main Outcome Measures: Questionnaire scores., Results: Of the 120 respondents, 73 agreed to participate [all cured or under biochemical control, median remission time 10.5 years (range 2.3-43.6 years)]. Of these, 34 (46.6%) reported self-consciousness about their appearance. Twenty-nine of these patients (85.3%) pointed out their face to be a prominent source of self-consciousness. Fifty-seven matched control subjects were included as well. Significant correlations were found between the scores of the DAS59 and the AcroQoL, RAND-36 and VAS in patients., Conclusions: Even after long-term remission of acromegaly, a large number of patients are self-conscious about their appearance, leading to psychological distress and disruptions to everyday life and decreased QoL. Facial features were the most important source of self-consciousness. This stresses the importance of addressing self-consciousness of appearance and the need for additional support in this regard during follow-up in these patients.

Purpose: A large, randomized, double-blind, Phase III core study demonstrated that pasireotide LAR was significantly superior to octreotide LAR at providing GH <2.5 μg/L and normalized IGF-1 after 12 months' treatment in patients with acromegaly. We report the efficacy and safety of pasireotide LAR and octreotide LAR after up to 26 months' treatment., Methods: Patients with GH <2.5 μg/L and IGF-1 ≤1× ULN at month 12, or patients considered to be experiencing clinical benefit, were eligible to continue receiving their randomized therapy in the extension. Efficacy and safety in the pasireotide LAR and octreotide LAR groups were evaluated for up to 26 months., Results: Overall, 120 patients who completed the core study continued receiving pasireotide LAR (n = 74) or octreotide LAR (n = 46) in the extension. At month 25, biochemical control (GH <2.5 μg/L and normal IGF-1) was achieved by 48.6% (36/74) and 45.7% (21/46) of patients in the pasireotide LAR and octreotide LAR arms [60.8% (45/74) and 52.2% (24/46) when including patients with IGF-1 < LLN], respectively. In total, 74.7% of pasireotide LAR and 71.6% of octreotide LAR patients had tumor volume decrease ≥20% from baseline to month 26. Most AEs were mild or moderate. Hyperglycemia-related AEs were seen in 62.9 and 25.0% of pasireotide LAR and octreotide LAR patients, respectively. No new safety signals were observed in the extension compared with the core study., Conclusions: GH and IGF-1 suppression is maintained for up to 25 months during pasireotide LAR treatment. The safety profile of pasireotide LAR is typical of a somatostatin analogue, except for the frequency and degree of hyperglycemia.

Purpose: The subtypes of somatotroph-cell pituitary adenomas have been correlated with clinical and histopathological variables. Densely granulated somatotroph-cell (DG) adenomas are typically highly responsive to somatostatin analog drugs, whereas sparsely granulated somatotroph-cell (SG) are less responsive. The aim of the study is to determine the effect of stereotactic radiosurgery (SRS) on remission and development of new pituitary deficiency according to the different subtypes of growth hormone (GH) secreting adenomas., Methods: A total of 176 patients underwent SRS for acromegaly at the University of Virginia. Diagnosis of acromegaly was based on the combination of clinical features and biochemical assessment including the serum GH level, and age- and gender-matched serum insulin-like growth factor-1 level. All patients underwent endocrine and neuro-imaging evaluations before and after SRS. Histological specimens were available in 73 patients., Results: The histopathological examination showed 34 patients had a DG adenoma, 19 had a SG adenoma, eight had a mixed DG/SG pattern, while other rare mixed subtypes were present in 12 patients. Patients who had a SG adenoma were more likely to be younger and female, and the SG adenomas appeared to be more invasive into the cavernous sinus. With a median follow-up of 67 months (range 6-188 months), 55/73 patients (75.3%) achieved remission. The median time to remission was 26 months (range 6-102 months). The actuarial remission rates in the DG adenoma group at 2, 4, and 6 years post-radiosurgery were 35.1, 71.4, and 79.3%, respectively, while those in SG adenoma group were 35.4, 73.1, and 82.1%, respectively., Conclusion: While patients who had a SG adenoma may be less responsive to medical therapy, they exhibited similar responses to SRS as patients with a DG adenoma. For SG adenomas, which respond less well to medical therapy, earlier SRS may be reasonable for consideration.

Objective: To report our day-to day experience with the long-term use of octreotide LAR in the treatment of acromegaly., Patients and Methods: Patients with acromegaly managed between 2003 and 2012 with octreotide LAR for a median of 27 months (interquartile ranges 12-60) and who had not received radiation therapy or concomitant treatment with cabergoline were retrospectively evaluated. Both primarily treated patients (n = 33) and patients who received octreotide after failed pituitary surgery (adjunctive treatment, n = 124) were included. Full biochemical response was defined as the achievement of a GH <2.5 ng/mL and an IGF-1 <1.2 times the upper limit of normal (× ULN); we also evaluated efficacy using a GH cut off of <1 ng/mL., Results: Over 60% of the patients achieved a GH of <2.5 ng/mL. The combined GH (<2.5 ng/mL) and IGF-1 (<1.2 × ULN) target was achieved by 35.5 and 33.6% of the patients treated primarily and adjunctively, respectively; these figures dropped to 22.6 and 23% when using a GH target of <1 ng/mL. All patients reported a significant improvement in acromegalic symptoms. Lower pretreatment GH and IGF-1 levels were both associated with a higher probability of achieving the composite biochemical target., Conclusion: Currently recommended GH and IGF-1 targets are reached by <36% of patients treated with octreotide LAR in a day-to day practice context. Nevertheless, in most instances a clinical benefit and an improvement in biochemical markers can be clearly documented.

Purpose: The exact quantification of craniofacial characteristics in patients with acromegaly is important because it provides insight in the pathophysiology of the disease and offers a tool to evaluate the effects of treatment on tissue specific endpoints. However, until recently this was not feasible due to limitations of available cephalometric methods. The new technique of three-dimensional (3D) cephalometry enables the accurate quantification of facial anatomical characteristics of both soft tissue and bone. This is the first study that uses 3D cephalometry to analyze craniofacial disproportions in patients in long-term remission of acromegaly., Methods: Sixteen patients in remission of acromegaly for over 24 months (50% male, mean age 56.0 ± 10.7 years, mean body mass index 29.3 ± 5.5 kg/m(2)) were compared to 16 matched control subjects. A 3D cone beam computed tomography scan and 3D stereophotograph of each individual were acquired and analyzed using 3D cephalometry., Results: In addition to an accurate quantification of the classical craniofacial characteristics, 3D cephalometry, shows that many typical soft tissue deformities persist, even after long-term remission. Furthermore, we found that, compared to controls, the patients in remission of acromegaly have a wider face at the level of the zygoma and longer maxilla (p < 0.05)., Conclusions: 3D cephalometry is an attractive novel imaging modality to accurately investigate craniofacial disproportions of both soft tissue and bony parts of the face in patients with acromegaly, which makes it a promising technique for future research purposes and clinical practice.

Purpose: The goals of this study were to determine: (1) 25OH vitamin D (25OHD) and calcium levels in patients with acromegaly and their association with insulin-like growth factor (IGF-1) and (2) whether somatostatin analog (SSA) therapy effects calcium and 25OHD levels., Methods: 125 patients with acromegaly were studied. Serum calcium and 25OHD levels were compared prior to and after vitamin D supplementation between patients receiving versus not receiving SSA in whom medical therapy included pegvisomant and/or dopamine agonists. Calcium and 25OHD levels were also evaluated longitudinally prior to and during short-term (mean 3 months, range 1-5) and long-term (mean 49 months, range 7-180) SSA administration. Vitamin D2 50,000 units weekly were given to 3 patients in the cross sectional and 1 in the longitudinal group; 400-4,000 units/day of D3 were given to 11 and 5 in respective groups., Results: In patients with a comparable mean IGF-1 index and season of testing, mean serum levels of 25OHD prior to vitamin D supplementation did not differ in patients receiving versus not receiving SSA (30 ± 3 vs. 30 ± 1 ng/ml, p = 0.99) and the prevalence of vitamin D sufficiency was similar between SSA and non SSA groups (42 vs. 57%, p = 0.20), prior to vitamin D supplementation. In patients with a comparable mean IGF-1 index and season of testing, mean serum 25OHD levels in patients increased after vitamin D supplementation in both those who were (37 ± 2 ng/ml, N = 23, p = 0.007) and were not receiving SSA (35 ± 1 ng/ml, N = 69, p = 0.005) compared to pre-D supplementation levels but were not different between these groups, p = 0.95) after D supplementation. Calcium and albumin were normal throughout longitudinal follow up. Calcium correlated with IGF-1 index (ρ = 0.29, p = 0.001, N = 125). In the longitudinal subset, serum calcium decreased transiently, in patients receiving short-term SSA (pretreatment 9.9 ± 0.1 mg/dl vs. short-term SSA 9.5 ± 0.1, p = 0.004). After long-term SSA therapy, calcium increased compared to levels on short-term therapy (9.8 ± 0.1 mg/dl vs. 9.5 ± 0.1, p = 0.017) and were unchanged compared to baseline. Mean vitamin D levels were sufficient at baseline prior to SSA therapy (33 ± 5.0 ng/ml), and did not change during short term (29 ± 6 ng/ml, p = 0.85) and long term SSA therapy (35 ± 5 ng/ml, p = 0.43)., Conclusions: Prior to and after vitamin D supplementation, patients with acromegaly receiving long-term SSA had vitamin D levels similar to those receiving other therapies, suggesting that long-term SSA therapy does not affect serum vitamin D. However, given the limitations of this retrospective study, further prospective studies evaluating the impact of SSA on vitamin D levels are necessary to confirm these findings definitively. Calcium levels are positively associated with IGF-1 index in patients with acromegaly. There is a transient decrease in calcium levels with short-term SSA use. The acute effect of SSA on calcium does not appear to be mediated by albumin, 25OHD or PTH and resolves with long-term SSA treatment. The transient decrease in calcium with short-term SSA use resolved with long-term SSA therapy.

Reported biochemical remission rates following surgical intervention for acromegaly range from 38 to 83%. In patients not achieving surgical remission, few options remain, mostly limited to medical management and radiation therapy. There is debate over whether or not to offer reoperation to patients in whom surgical remission is not achieved with initial resection. Retrospective chart review was undertaken to determine all patients having acromegaly with persistently elevated GH and/or IGF-1 levels after initial pituitary adenoma resection, and who underwent reoperation using endoscopic endonasal approach at a single institution. Biochemical remission was defined as a postoperative GH level <1 ng/mL and a normal postoperative IGF-1 level in the absence of any medical therapy. In total, 14 patients underwent repeat surgical intervention for acromegaly via endoscopic transsphenoidal approach. Of the 14 patients, 8 (57%) achieved biochemical remission following repeat surgical intervention. Lower preoperative GH levels were associated with greater chance of biochemical remission (P = 0.048). New endocrinopathies were seen in 2 patients (14%), and both were transient diabetes insipidus. Meningitis occurred in 2 patients (14%); both were aseptic meningitis with no sequelae. No mortality was encountered. Repeat surgical intervention for acromegaly via endoscopic transsphenoidal approach appears safe and effective. With no mortality and minimal morbidity, repeat surgical intervention via endoscopic transsphenoidal approach appears a reasonable option for these hard-to-treat patients and should be considered for patients in whom surgical remission is not achieved with initial surgery.

Growth hormone deficiency (GHD) in surgically-cured acromegalics has been reported to negatively affect their metabolic condition and quality of life (QOL). The incidence of GHD, its causes, and its effects on their physio-psychological condition remain to be examined in detail. We performed a retrospective study to investigate GH secretory function in surgically-cured acromegalics, prognostic factors of GHD, and its impact on QOL. The study population consisted of 72 acromegalics who were determined to be surgically cured according to the Cortina consensus criteria. We recorded the incidence of impaired GH secretory function based on the peak GH level during postoperative insulin tolerance test (ITT) which lowered their nadir blood sugar to under 50 mg/dL. Their QOL was evaluated by SF-36. In surgically-cured acromegalics, the incidence of severe GHD (peak GH during ITT ≦ 3.0 μg/L) was 12.5 % (9/72). The preoperative tumor size was significantly larger in patients with severe GHD than without severe GHD (21.9 ± 9.0 vs. 15.5 ± 7.1 mm, p = 0.017). The peak GH levels during postoperative ITT were statistically correlated with the physical but not the mental component summary of the SF-36 score. The incidence of GHD was 12.5 % in our surgically-cured acromegalics. As some QOL aspects are positively related with peak GH levels during postoperative ITT, efforts should be made to preserve pituitary function in acromegalic patients undergoing adenomectomy.

In normal subjects growth hormone (GH) and insulin-like growth factor-I (IGF-I) have opposing effects on glucose metabolism. Active acromegaly is associated with insulin resistance (IR) and glucose intolerance although both GH and IGF-I are elevated. Our objective was to compare whether GH or IGF-I correlates more closely with IR and glucose intolerance in acromegaly. Basal serum IGF-I and GH, glucose and insulin during an oral glucose tolerance test were measured in 70 normoglycemic and 44 hyperglycemic acromegalic patients (21 impaired fasting glucose, 11 impaired glucose tolerance and 12 diabetes mellitus) according to American Diabetes Association criteria. 55 patients were assessed before any treatment for acromegaly and 59 after surgery and/or radiotherapy (15 patients had normal IGF-I after treatment). Patients treated with somatostatin analogs, GH-receptor antagonists or antidiabetic drugs were excluded. IR was assessed by various basal and stimulated indices. Homeostatic Model Assessment 2-Insulin Resistance (HOMA2-IR) index correlated more closely with IGF-I (r = 0.65, p < 0.0001) than nadir (r = 0.23, p = 0.008) or random GH (r = 0.26, p = 0.002). HOMA2-IR correlated better with IGF-I than nadir or random GH also in normoglycemic (n = 70; r = 0.74, p < 0.0001 vs. r = 0.36, p = 0.001 vs. r = 0.39, p < 0.001) and hyperglycemic patients (n = 44; r = 0.54, p = 0.0002 vs. r = 0.09, p = 0.4 vs. r = 0.14, p = 0.26). In multivariate logistic regression analysis IGF-I but not GH was a significant risk factor for glucose intolerance after adjusting for age, sex, weight and acromegaly duration (OR = 1.56, p = 0.01). In acromegaly IGF-I correlates more closely than GH with IR. IGF-I levels but not GH are associated with glucose intolerance.

Acromegaly is a rare disorder due to an excessive production of growth hormone (GH), typically caused by a GH-secreting pituitary adenoma. Anti-pituitary antibodies (APAs) are often seen in patients with different kinds of pituitary pathologies. Because GH has been proposed as a possible antigen recognized by such antibodies, the prevalence of APAs may be higher in conditions characterized by excessive GH secretion. The primary aim of this study was to compare the prevalence of APAs in patients with acromegaly and in controls with other types of pituitary tumors and healthy subjects. Secondary aim was to characterize the pituitary cells targeted by the APAs. Thirty eight acromegaly patients and 215 controls, including 38 patients with prolactinomas, 64 with non-functioning pituitary adenomas (NFPA), and 113 healthy subjects were enrolled in the study. All subjects were tested for APAs using indirect immunofluorescence. Target cells recognized by APAs were identified by double staining immunofluorescence. APAs were significantly more prevalent in acromegaly cases than in healthy controls (10.5% vs. 1.8%, P < 0.05). This prevalence was similar to that found in patients with prolactinomas (7.9%) and NFPA (12.5%). Among APAs-positive subjects, antibodies recognizing somatotrope cells were more common in acromegaly cases than in healthy controls (3/4 vs. 0/113, P < 0.0001), but had similar frequencies in NFPA (2/8) and prolactinomas (1/3). APAs are more frequently found in patients with pituitary adenomas than healthy subjects, with no significant difference among the tumor types studied. GH-secreting cells could represent a target of the autoimmune response.

New criteria that define acromegaly remission are more stringent: normal (age/sex-adjusted) insulin-like growth factor type 1 (IGF-1), growth hormone (GH) random (GHr) <1 μg/L, and a GH nadir (GHn) during oral glucose tolerance test (OGTT) of <0.4 μg/L. Discordance between GH and IGF-1 values is often attributed to somatostatin receptor ligands (SRLs) or radiation. The purpose of this study was to evaluate rates of discordant IGF-1 and GH levels in patients with GH secreting adenomas (after pituitary surgery), who were naïve to any other treatment. We retrospectively analyzed data over a 5 year time period (2006-2010), in post-surgery acromegaly patients who had elevated IGF-1 but normal GH levels (per the new cure criteria). Symptoms of acromegaly were scored according to a 4-point scale. Fifty-four patients had post-operative GHr and IGF-1 measurements, 28 patients had GHn during OGTT, and 16 patients had 5-point 2-h GH day curve tests. Thirteen of 54 (24%) patients were found to have intermittent persistent discordant values; high IGF-1 and normal GH at final evaluation (77% of these patients were women). Patients had a median number of IGF-1 evaluations of 7.5 (range: 2-15) over a median of 22 months (range: 3-47 months). Mean elevated IGF-1 in the discordant population was 1.25 × upper limit of normal (ULN) ± 0.17 (range: 1.01-1.6 × ULN). Twelve of the 13 (92%) patients had macroadenomas; 10 of the 13 (69%) patients had mammosomatotroph, mixed lacto/somatotroph tumors or prolactin staining. No patient in the discordant population was on estrogen replacement therapy or had overt cardiac disease. When the relatively asymptomatic discordant population was compared with 35 patients from the concordant population (six were excluded because of preoperative medical treatment for acromegaly), no significant difference between age, gender distribution, body mass index (BMI), presence of diabetes mellitus (DM) or glucose intolerance and adrenal insufficiency between groups was noted. In our study of postoperative patients with acromegaly naïve to both SRLs and radiation, using new GH cut-off levels, 24% had intermittent or persistent discordant values. Our results highlight that relying on IGF-1 or GH measurements alone is not adequate for assessing disease control in surgically treated acromegaly patients. Management of such patients needs to be individualized and long-term studies evaluating morbidity and mortality incorporated into treatment decisions. Further studies with larger patient populations and longer follow-up are required to determine the long-term implications of discordant GH and IGF-1 value patterns.

To describe glucose status changes in patients with acromegaly receiving somatostatin analog lanreotide as primary treatment. This retrospective, single-center study conducted during 1996-2008, included acromegalic patients receiving primary lanreotide treatment. Baseline and last follow-up visit assessments included glucose status (according to American Diabetes Association criteria), growth hormone (GH), and insulin-like growth factor-1 (IGF-1) levels. Glucose control was considered improved when fasting plasma glucose or antidiabetic treatments were reduced, and deteriorated if fasting glucose was the same/higher but with increased antidiabetic treatments. 42 patients (median age 50 years; range 29-75 years) were included. At baseline, 26 (62%) were normoglycemic, eight (19%) had impaired glucose tolerance/fasting glycemia, and eight (19%) had diabetes mellitus; family history of diabetes mellitus was significantly associated with abnormal glucose status. At final visit, the mean (SE) lanreotide dose was 108 (21) mg/month. Median treatment duration was 23 months, range 3-138 months, and 74% of patients received the 120-mg dose. Median GH levels decreased significantly (baseline, 12 [5-20] μg/l; final visit, 2.1 [1.0-4.7] μg/l; P < 0.0001); IGF-1 levels were age- and sex-normalized in 33% of patients. Glucose control deteriorated in seven patients (17%) and improved from abnormal levels in 10 (24%). Deterioration was associated with smaller GH decreases (median change, -3.4 μg/l vs. -10.7 μg/l, P = 0.014) and improvement with trend to lower BMI and younger age. During primary lanreotide treated acromegalic patients 60% had no change, 24% had an improvement and 17% had a worsening of glucose status. Deterioration was significantly associated with smaller GH decreases during primary lanreotide treatment.

The objective of the study was to evaluate arterial morphologic changes of early atherosclerosis and changes in procalcitonin (PCT) levels in patients with acromegaly according to disease activity. Thirty-three active and 20 inactive acromegaly patients followed at Endocrinology-Metabolism out-patient clinic of Cerrahpasa Medical Faculty between 2004 and 2008 were included in the study. Twenty gender and age matched healthy subjects were included as the control group. Intima-media thickness (IMT) of the carotid arteries was measured by ultrasonography. Blood was drawn for biochemical tests and the serum concentrations of C-reactive protein (CRP) and PCT. Intergroup analysis revealed no significant differences between Growth hormone (GH), insulin like growth factor-1 (IGF-1), and IMT (P = 0.42, P = 0.47 respectively). No significant differences were found in the fibrinogen, CRP and PCT levels of the acromegaly patients and the subjects in the control group (P = 0.57, P = 0.84, P = 0.68 respectively). In the patients with IMT ≥ 1 mm, PCT (0.4 [IQR: 0.4-0.55]) levels were significantly different from the patients without atherosclerosis (0.06 [IQR: 0.05-0.12], P < 0.001). The correlation between IMT and PCT (P = 0.001, r = 0.47) was more significant than the correlation between IMT and CRP (P = 0.01, r = 0.28). There was a positive correlation between IMT and atherosclerotic risk factors such as age (P = 0.01, r = 0.27) and body mass index (BMI; P = 0.005, r = 0.32). Our results showed that PCT increases before CRP and it can be useful for the assessment of premature atherosclerosis in acromegaly as well.

Polycythemia associated with acromegaly is usually caused by the systemic manifestations of the disease, such as sleep-apnea or concomitant erythropoietin-secreting kidney tumors. The recognition of underlying pathologies requires a thorough diagnostic process. We report a unique case of acromegaly with polycythemia, not caused by commonly described manifestations of the disease, and receding with octreotide therapy. The medical history of 141 acromegalic patients followed by the Endocrinology Unit of the San Martino University Hospital in Genoa has been also reviewed, together with the literature evidence for similar cases. The diagnostic workflow and 2-years follow-up of a 43-years old acromegalic, polycythemic man with a history of past smoking, moderate hypertension, and mental retardation are described. The hematological parameters of our cohort was retrospectively compared with those of a healthy, age/gender-related control group as well. Therapy with octreotide LAR, 20 mg i.m. q28d was begun soon after diagnosis of acromegaly in the polycythemic patient. Haematocrit level, hormonal setting, as well as pituitary tumor size and visual perimetry during treatment were recorded. Octreotide LAR treatment normalized hormonal alterations, as well as hematological parameters. Polycythemia has not recurred after 2 years of therapy. The median hemoglobin and hematocrit levels of the retrospectively analyzed cohort of acromegalic were significantly lower than normal ranges of a healthy, age/sex- related control population. In conclusions, polycythemia can be a direct, albeit rare, secondary manifestation of acromegaly, that must be considered during the diagnostic work-up of acromegalic patients presenting with such disorder.

The objective of this study is to assess the secretory pattern of GH after Oral Glucose Tolerance Test (OGTT) or day-curve (DC), in relation with IGF-I and to evaluate the influence of therapy on OGTT. A retrospective analysis in 279 OGTTs performed in 93 acromegalic patients in our unit from January 1988 to December 2005, in 77 patients also DC data were retrived. GH concentration was evaluated by 3 different systems (RIA, IRMA and chemiluminescence assays), and IGF-I by two RIAs. About 12% of OGTT samples were discordant with the baseline, while discordance between nadir and 120th minute was much lower (5%), with all discordant values, except one, near the cut-off lines. Correlation between DC and OGTT data was around 0.99 among all values, discordance rate between nadir and minimum DC was much lower than that with mean DC. In almost 80% of cases there was a complete concordance between OGTT and DC results, and in about 30% IGF-I was discordant with GH. Correlation analysis between IGF-I and GH was highest with DC data and lowest with OGTT baseline (T0). Considering different treatments discrepancy rates between GH and IGF-I were comparable. The best GH parameter is the minimum GH DC, although in the clinical practice the evaluation of OGTT GH in association with IGF-I is the most practical approach. In this case, the basal and T120 GH values can replace multiple sampling. Different treatment modalities do not influence the discordance rate between GH and IGF-I.

To determine the prevalence of diabetes, glucose intolerance and impaired fasting glucose in Mexican patients with acromegaly and establish associations with clinical, anthropometric and biochemical variables. 257 patients with acromegaly were evaluated by a 75 g-oral glucose tolerance test with measurements of both GH and glucose (0, 30, 60, 90 120 min) as well as baseline IGF-1. Normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and diabetes (DM) were defined based on the 2003 ADA criteria. NGT, IFG, IGT and DM were found in 27.6, 8.9, 31.6 and 31.9% of the subjects, respectively; 42 of the DM patients were unaware of the diagnosis. Patients with diabetes were older than subjects in the other 3 categories (P = 0.001), and the proportion of women was significantly higher in the DM (74%) and IGT (68%) groups than in the NGT group (52%) (P = 0.004). Odds ratio for the development of DM was 3.29 (95% CI 3.28-3.3). GH and IGF-1 levels were comparable among the different groups. In a multivariable analysis DM was significantly associated with age, presence of a macroadenoma, disease duration and a basal GH > 30 μg/dl. DM and probably IGT are more prevalent in acromegaly than in the general Mexican population. DM was more frequent in females of all ages, in subjects with severely elevated GH concentrations, in patients with macroadenomas, and long-standing disease duration. The odds ratio for DM in our subjects with acromegaly is more than 3 times higher than in the general population.

The aim of the study was to evaluate the frequency of occurrence of pituitary failure following neurosurgery and the efficacy of transsphenoidal tumour resection in acromegalic patients. We retrospectively evaluated 85 patients (60 female and 25 male), of mean age 43.9 ± 13.2 years, treated by transsphenoidal neurosurgery. Macroadenoma and microadenoma of pituitary were found in 66 (77.6%) and 19 (22.4%) of these patients, respectively. Criteria of cure following neurosurgery were: basal GH<2.5 μg/l, GH at 120 min in OGTT<1.0 μg/l and serum concentration of IGF-1 within normal ranges for age and sex. After surgery 32 patients (37.6%) were cured and 53 patients (62.4%) required somatostatin analogue treatment. In patients cured by surgery, lower levels of basal GH (P<0.05), IGF-1 (P<0.001), GH at 120 min in OGTT and smaller size of pituitary tumour (P<0.05) were found at diagnosis, as compared to patients in whom surgery was unsuccessful. Significant correlation between basal serum level of GH at diagnosis and size of pituitary tumour was found (P<0.001). Invasive tumours were found in 45 of 53 (84.9%) patients not cured and in only 8 of 32 (25.0%) patients cured (P<0.001). Impaired function of pituitary anterior lobe after surgery was observed in 30% and 4% of patients with macro- and microadenoma, respectively (P<0.05). The efficacy of neurosurgery is affected by concentration of basal serum GH and IGF-1, GH at 120 min in OGTT, tumour size and invasiveness. Hypopituitarism after surgery is more frequent in patients with macroadenoma. Pituitary insufficiency, as a consequence of surgery, was found in 21% of patients with normal pituitary function prior to operation., (© The Author(s) 2010. This article is published with open access at Springerlink.com)

Long-term treatment of acromegaly prevents aggravation and reverses associated heart disease. A previous study has shown a temporary increase in serum levels of the N-terminal fraction of pro B-type natriuretic peptide (NT-proBNP) suggesting an initial decline in cardiac function when treatment of acromegaly is initiated. This was a three months prospective study investigating short-term cardiac effects of treatment in acromegalic patients. Cardiac function was evaluated by the gold standard method cardiac magnetic resonance imaging (CMRI) and circulating levels of B-type natriuretic peptides (BNP and NT-proBNP). CMRI was performed at baseline and after 3 months of treatment. Levels of IGF-I, BNP and NT-proBNP were measured after 0, 1, 2 and 3 months. Eight patients (5 males and 3 females, mean age 53 ± 12 years (range 30-70)) and 8 matched healthy control subjects were included. Median IGF-I Z-score decreased from 4.5 (range 2.5-6.4) to 2.3 (-0.1 to 3.3). At baseline the patients had increased left ventricle mass index (LVMI) compared to control subjects (ΔLVMI 35 g/m(2) (95% CI 8-63 g/m(2), P = 0.016). After 3 months of treatment there was an increase in end-diastolic volume index EDVI (ΔEDVI 9 mL/m(2) (95% CI 3-14), P = 0.007) and an increase in levels of BNP (median (ranges) 7 (0.58-286) vs. 20 (1-489) pg/mL, P = 0.033) and of NT-proBNP (63 (20-1004) vs. 80 (20-3391) pg/mL, P = 0.027). Assessed by the highly sensitive and precise CMRI method, 3 months treatment of acromegaly resulted in an increase in EDVI, and increased levels of BNP and NT-proBNP suggesting an initial decrease in cardiac function.

Growth hormone (GH) measurements are routinely used for important treatment decisions in patients with acromegaly, yet their reliability is affected by numerous factors including assay precision and variability, sampling intensity, and hormone pulsatility. The day-to-day variation in GH in acromegaly has not been studied. This study quantified the magnitude of day-to-day GH variability in patients with acromegaly by performing an analysis of previously obtained plasma GH profiles. The analysis was performed at the Michigan Clinical Research Unit at the University of Michigan. A total of nine 48 h Q10 min GH profiles obtained in nine patients with active acromegaly were examined. The study was planned after data collection and analysis was conducted using Altman-Bland methods. Day 1 vs. Day 2 values were examined. 95% confidence intervals of the D2 vs. D1 ratios were calculated on all individual subject data as well as on a single 0800 h GH sample and composite mean data for 2-, 5-, 9-, and 24-h sampling protocols. Confidence interval range was 0.66-1.50 for the 0800 h sample and was similar for all sampling protocols except somewhat more narrow for the 24-h sampling (0.75-1.32). Daily variations in GH levels introduce an additional confounding element when using a single GH level or even daily GH curves to assess a patient's GH milieu. It may have an impact on result interpretation and subsequent treatment decisions especially when GH results are considered borderline.

Oral estrogens reduce GH-induced IGF-1 production and preliminary studies have shown that adjuvant estroprogestin (EP) therapy with octreotide LAR may control disease activity in some female patients who are partially responsive to octreotide LAR. Our aim was to verify if EP alone or in combination with octreotide LAR can achieve remission of acromegaly in selected cases of patients uncontrolled by surgery. Eleven women with persistent active acromegaly following surgery participated in this unblinded open label pilot study. Their mean age was 49.8 ± 4.3 years. Two patients were drug naïve, two patients had stopped octreotide LAR because of intolerance and seven were treated with octreotide LAR. The patients received either EP (EP pill, 20 μg ethinylestradiol, 100 μg levonorgestrel) alone (4 patients) or added to octreotide LAR (7 patients). Fasting GH, IGF-1, glucose, HDL- and LDL-cholesterol, and triglycerides were measured at baseline and at last visit. MRI was controlled at baseline and at last visit. Duration of estrogen treatment was 3.1 ± 0.5 years. Serum IGF-1 levels were normalized in 8/11 patients (73%). Serum GH concentrations did not change significantly during treatment (11.6 ± 5.6 μg/L prior to EP vs 5.5 ± 1.2 μg/L following EP). In patients treated with EP alone, remission was achieved in 2/4 patients (IGF-1 percentages of the upper limit of normal age-matched range (%ULN): 211 ± 40% before EP compared to 95 ± 15% after EP, P = 0.028). In the seven patients treated by EP added to octreotide LAR, remission was achieved in 6 patients (IGF-1%ULN: 158 ± 9% before EP compared to 86 ± 4% after EP, P = 0.0003). Glucose and cholesterol levels were unchanged by EP treatment (data not shown). MRI did not show any evidence of tumour progression with EP in patients who had a tumour remnant. In conclusion, oral estrogen treatment appears to normalize serum IGF-1 concentrations in over 70% of women with acromegaly uncured by surgery irrespective of their sensitivity to octreotide LAR. We suggest that estrogens may be a temporary cost-effective and safe treatment for women with postoperative persistent acromegaly.

GH and IGF-1 play an important role in the regulation of metabolism and body composition. In patients with uncontrolled acromegaly, cardiovascular morbidity and mortality are increased but are supposed to be normalised after biochemical control is achieved. We aimed at comparing body composition and the cardiovascular risk profile in patients with controlled acromegaly and controls. A cross-sectional study. We evaluated anthropometric parameters (height, weight, body mass index (BMI), waist and hip circumference, waist to height ratio) and, additionally, cardiovascular risk biomarkers (fasting plasma glucose, HbA1c, triglycerides, total cholesterol, HDL, LDL, and lipoprotein (a), in 81 acromegalic patients (58% cured) compared to 320 age- and gender-matched controls (ratio 1:4), sampled from the primary care patient cohort DETECT. The whole group of 81 acromegalic patients presented with significantly higher anthropometric parameters, such as weight, BMI, waist and hip circumference, but with more favourable cardiovascular risk biomarkers, such as fasting plasma glucose, total cholesterol, triglycerides and HDL levels, in comparison to their respective controls. Biochemically controlled acromegalic patients again showed significantly higher measurements of obesity, mainly visceral adiposity, than age- and gender-matched control patients (BMI 29.5 +/- 5.9 vs. 27.3 +/- 5.8 kg/m(2); P = 0.020; waist circumference 100.9 +/- 16.8 vs. 94.8 +/- 15.5 cm; P = 0.031; hip circumference 110.7 +/- 9.9 vs. 105.0 +/- 11.7 cm; P = 0.001). No differences in the classical cardiovascular biomarkers were detected except for fasting plasma glucose and triglycerides. This effect could not be attributed to a higher prevalence of type 2 diabetes mellitus in the acromegalic patient group, since stratified analyses between the subgroup of patients with acromegaly and controls, both with type 2 diabetes mellitus, revealed that there were no significant differences in the anthropometric measurements. Biochemically cured acromegalic patients pertain an adverse anthropometric risk profile, mainly because of elevated adiposity measurements, such as BMI, waist and hip circumference, compared to an age- and gender-matched primary care population.

We present the case of a 46-year-old woman with acromegaly currently being treated with the growth hormone (GH) receptor antagonist pegvisomant showing strongly fluctuating IGF-I levels. We prospectively measured estradiol, IGF-I, IGF-I binding protein, acid labile subunit, basal endogenous GH, binding protein and pegvisomant levels for 6 months every week. Estradiol levels showed a strongly negative correlation with IGF-I (r = -0.733, P < 0.001), and less so with ALS (r = -0.433, P < 0.05) and IGFBP3 (r = -0.590, P < 0.01). Estradiol was not significantly correlated with endogenous GH or pegvisomant levels. Likewise, IGF-I did not correlate with endogenous GH or pegvisomant levels. In our patient, endogenous estradiol levels have a significant influence on IGF-I levels. When female acromegalic patients on permanent pegvisomant treatment show fluctuating IGF-I levels, estradiol levels should be taken into consideration.

The study was designed to evaluate the long-term efficacy and safety of the 28-day prolonged-release Autogel formulation of the somatostatin analogue lanreotide (Lan-Autogel) in unselected patients with acromegaly. The study comprised four phases: washout; a double-blind comparison with placebo, at a single randomized dose (60, 90 or 120 mg) of Lan-Autogel; a single-blind, fixed-dose phase for four injections (placebo group was re-allocated to active treatment); and eight injections with doses tailored according to biochemical response. Serum samples were assessed for growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels, at weeks 4, 13, 14, 15, 16, 32 and 52. 108 patients were enrolled and 99 completed 52 weeks' treatment. Four weeks after the first injection, serum GH levels decreased by >50% from baseline in 63% of patients receiving Lan-Autogel compared with 0% receiving placebo (P < 0.001). After four injections, 72% of patients had a >50% reduction in GH levels; 49% patients achieved GH levels < or = 2.5 ng/ml; 54% had normalized IGF-1; and 38% achieved the combined criterion of GH level < or = 2.5 ng/ml and normalized IGF-1. The corresponding proportions by week 52 were 82, 54, 59 and 43%, respectively. In patients not requiring dose escalation to 120 mg, 85% achieved biochemical control (combined criterion). Treatment was well tolerated by all patients. In conclusion, Lan-Autogel was effective in controlling GH and IGF-1 hypersecretion in patients with acromegaly and showed a rapid onset of action.

Acromegaly is associated with increased morbidity and mortality from cardiovascular disease. Inflammatory markers, such as C-reactive protein and leucocyte count, haemostatic markers, such as fibrinogen and factor VIII and cardiac hypertrophy marker, B-type natriuretic peptide, have emerged as important cardiovascular risk markers in the general population. The objective of this study was to assess the serum levels of conventional, inflammatory, haemostatic markers and NT-pro BNP in mostly non-diabetic normotensive patients with acromegaly, as well as the effect of 6 months of octreotide LAR therapy on these markers. We studied 12 patients with active acromegaly, 12 patients in whom remission of acromegaly had been achieved by surgery and 12 healthy control subjects matched for age, gender and body mass index. At baseline fasting blood was obtained for measurements of GH, IGF-1, glucose, insulin, lipids, lipoprotein (a), C-reactive protein, leucocyte count, fibrinogen, factor VIII and NT-pro BNP. After baseline evaluation, patients with active acromegaly were treated with octreotide LAR for 24 weeks. At 24 weeks, measurements were repeated as on baseline. Insulin resistance index and fibrinogen levels were higher in patients with active acromegaly than patients and subjects in control groups. CRP, leucocyte count, factor VIII and NT-pro BNP were similar in the three groups. Octreotide LAR reduced GH, IGF-1 and insulin resistance index but did not alter levels of CRP and NT-pro BNP.

The aim of this longitudinal study was to evaluate the echocardiographic outcome of acromegalic heart disease in patients undergoing different therapeutic approaches, in order to investigate whether SSA could provide therapeutic advantages as compared with neurosurgery. In total of 36, consecutive patients undergoing SSA treatment after neurosurgery were enrolled in this study (Gr.Surg.-SSA). After 12 months of treatment, 21 patients had a controlled disease, while the remaining 15 patients displayed uncontrolled disease. Twelve acromegalic patients who did not undergo SSA treatment due to controlled disease after neurosurgery were enrolled as control group (Gr.Surg). The echocardiographic-Doppler study was performed before neurosurgery and after 12-months of follow-up. After follow-up, a significant reduction in serum GH and IGF-I values, Left Ventricular Mass index (LVMi) and LVH rate with an improvement in diastolic function was observed in both groups of patients. We found a significant reduction of LVMi either in patients with controlled disease or in those with poorly controlled disease undergoing SSA treatment. Diastolic function and of LVH percentage improved in all groups, but significantly so only in controlled patients, no significant difference in any echocardiographic parameters and in the prevalence of the LVH rate were observed between the three groups of patients at the end of follow-up. Therefore, our data appear to show that for echographic parameters medical treatment additive beneficial effects is compared to neurosurgery alone. SSA also appears to contribute to the improvement of acromegalic cardiomyopathy also in patients who did not achieve biochemical control of the disease.

Dopamine agonists are effective in some patients with acromegaly and in this condition treatment is considered to be chronic. We describe two acromegalic patients who responded adequately to the long-acting dopamine agonist cabergoline, but surprisingly maintained normal GH and IGF-I levels once therapy was discontinued after 42 and 76 months because of possibly related side effects. A 32-year-old woman with mild acromegaly (IGF-I: 423 microg/l, GH after OGTT: 2.5 microg/l, adenoma 4 mm) was treated with cabergoline as primary therapy and reached safe GH levels (2 microg/l or less) and normal IGF-I levels with 3.5 mg cabergoline weekly. After 42 months of therapy the patient experienced a progressive decrease of libido, which she attributed to the intake of cabergoline. After stopping medication, serum levels of GH and IGF-I remained normal during the following 2.5 years. A 53-year-old man with moderate acromegaly (serum IGF-I: 547 microg/l, GH after OGTT: 5.9 microg/l, adenoma 7 mm) preferred cabergoline as primary therapy. Serum GH levels below 2 microg/l and normal levels of IGF-I were obtained with 3.5 mg cabergoline weekly. When the patient experienced severe stomach pains after 76 months of treatment, cabergoline was held responsible and discontinued. Serum GH and IGF-I did not increase again and stayed at the same level during a follow-up of 5.5 years. These two cases demonstrate that acromegalic patients with a good response to cabergoline may occasionally remain in remission after stopping therapy. This phenomenon has previously only been described in patients with a prolactinoma.

Acromegaly is a slowly progressive disease characterized by 30% increase of mortality rate for cardiovascular disease, respiratory complications and malignancies. The estimated prevalence of the disease is 40 cases/1000000 population with 3-4 new cases/1000000 population per year. The biochemical diagnosis is based upon the demonstration of high circulating levels of GH and IGF-I. A random GH level lower than 0.4 microg/l and an IGF-I value in the age- and sex-matched normal range makes the diagnosis of acromegaly unlikely. In doubtful cases, the lack of GH suppressibility below 1 microg/l (0.3 microg/l according to recent reports) after an oral glucose load will confirm the diagnosis. A pituitary adenoma is demonstrated in most cases by CT scan or MRI. A negative X-ray finding or the presence of empty sella do not exclude the diagnosis. Cardiovascular complications (acromegalic cardiomyopathy and arterial hypertension) should be looked for and, if present, followed-up by echocardiography and 24h-electrocardiogram. Sleep apnoea, when clinically suspicious, should be confirmed by polisomnography. At the moment of diagnosis all patients should undergo colonscopy. Lipid profile should be obtained and glucose tolerance evaluated. Surgery, radiotherapy and medical treatment represent the therapeutic options for acromegaly. The outcome of transsphenoidal surgery is far better for microadenomas (80-90%) than for macroadenomas (less than 50%), which unluckily represent more than 70% of all GH-secreting pituitary tumours. Therefore, pituitary surgery is the first line treatment for microadenomas. Medical therapy is based on GH-lowering drugs (somatostatin receptor agonists and, in some cases, dopaminergic agents) and GH receptor antagonists (pegvisomant). The former are traditionally indicated after unsuccessful surgery and while awaiting the effectiveness of radiation therapy. However, GH-lowering drugs are also used as primary therapy when surgery is contraindicated or in the case of large GH-secreting macroadenomas which are not likely to be completely removed by surgery. These compounds may also be indicated in the preoperative management of some acromegalic patients in order to lower the risk of surgical and anaesthetic complications. For the moment pegvisomant is indicated for patients resistant to the GH-lowering drugs and there is no evidence for drug-induced enlargement of the pituitary tumour. In order to avoid this possibility, however, a combination of pegvisomant and GH-lowering compound can also be conceived. With pegvisomant, IGF-I plasma levels are the marker of therapeutic efficacy and normalize in 97% of patients. Radiotherapy is employed sparingly due to the number of side effects (80% of hypopituitarism). It is indicated after unsuccessful surgical and/or medical treatment and allows the control of hormonal secretion and tumour growth in approx. 40% and 100% of cases, respectively. Acromegaly is defined as controlled when, in the absence of clinical activity, IGF-I levels are in the age- and sex-matched normal range and GH is normally suppressible by the oral glucose load.

Hypothalamic GHRH is secreted into the portal system, binds to specific surface receptors of the somatotroph cell and elicits intracellular signals that modulate pituitary GH synthesis and/or secretion. Moreover, GHRH is synthesized and expressed in multiple extrapituitary tissues. Excessive peripheral production of GHRH by a tumor source would therefore be expected to cause somatotroph cell hyperstimulation, increased GH secretion and eventually pituitary acromegaly. Immunoreactive GHRH is present in several tumors, including carcinoid tumors, pancreatic cell tumors, small cell lung cancers, endometrial tumors, adrenal adenomas, and pheochromocytomas which have been reported to secrete GHRH. Acromegaly in these patients, however, is uncommon. The distinction of pituitary vs. extrapituitary acromegaly is extremely important in planning effective management. Regardless of the cause, GH and IGF-1 are invariably elevated and GH levels fail to suppress (<1 microg/l) after an oral glucose load in all forms of acromegaly. Dynamic pituitary tests are not helpful in distinguishing acromegalic patients with pituitary tumors from those harbouring extrapituitary tumors. Plasma GHRH levels are usually elevated in patients with peripheral GHRH-secreting tumors, and are normal or low in patients with pituitary acromegaly. Unique and unexpected clinical features in an acromegalic patient, including respiratory wheezing or dyspnea, facial flushing, peptic ulcers, or renal stones sometimes are helpful in alerting the physician to diagnosing non pituitary endocrine tumors. If no facility to measure plasma GHRH is available, and in the absence of MRI evidence of pituitary adenoma, a CT scan of the thorax and abdominal ultrasound could be performed to exclude with good approximation the possibility of an ectopic GHRH syndrome. Surgical resection of the tumor secreting ectopic GHRH should be the logical approach to a patient with ectopic GHRH syndrome. Standard chemotherapy directed at GHRH-producing carcinoid tumors is generally unsuccessful in controlling the activated GH axis. Somatostatin analogs provide an effective option for medical management of carcinoid patients, especially those with recurrent disease. In fact, long-acting somatostatin analogs may be able to control not only the ectopic hormonal secretion syndrome, but also, in some instances, tumor growth. Therefore, although cytotoxic chemotherapy, pituitary surgery, or irradiation still remain available therapeutic options, long-acting somatostatin analogs are now preferred as a second-line therapy in patients with carcinoid tumors and ectopic GHRH-syndrome.

We reported a case of a 26-year-old female who was referred to our clinic with the diagnosis of possible acromegaly. She was born from a term pregnancy by forceps delivery. The patient was diagnosed as having hip luxation at one month and spoke her first word at 15 months. She had been diagnosed at the age of 9 years old as having perinatal encephalopathy with intellectual and motor affectation. Since this period of time she has undergone an insidious change in her appearance, mainly comprising progressive coarsening of the face. For this reason she was submitted to our clinic with presumed acromegaly. Dynamic tests of growth hormone secretion ruled out such a diagnosis. The Patient was considered as having "acromegaloidism", a term used for patients whom manifest clinical features of acromegaly but do not present a demonstrable growth hormone hypersecretion. Subsequently cytogenetic evaluation revealed an infrequent chromosome pattern: X-Tetrasomy. In the present article a differential diagnosis of acromegaloidism and the potential role of genes present on X-chromosome involved in human growth such as SHOX gene are discussed. Overdosification of SHOX gene might explain tall stature of girls with X-tetrasomy. Our observation suggested that X-tetrasomy should be considered in the differential diagnosis of acromegaloidism. Furthermore, this may lead to the identification of new genes in the X-chromosome that are important for growth of facial structures.

We describe four acromegalic patients with persisting typical symptoms - excessive sweating, lack of suppleness of hands, joint pains - despite the achievement of normal serum IGF-1 levels after pituitary surgery. In three patients there was a clear improvement in symptoms when lower IGF-1 levels within the normal range were achieved with pegvisomant treatment. In the fourth patient IGF-1 levels have fluctuated within the normal range with persistence of abnormal sweating, particularly at night. Two of three patients who had an oral glucose tolerance test when serum IGF-1 was in the normal range failed to suppress GH levels to less than 1 ng/ml. We conclude that, in the treated acromegalic patient, IGF-1 levels within the normal range need to be looked at critically to determine what is truly normal for that individual. Relief of symptoms seems a reasonable yardstick, in addition to population norms, by which to judge whether the prevailing IGF-1 level is appropriate; in some cases the aim should be an IGF-1 level in the lower half of the normal range, or perhaps even the lowest quartile.

Objective: Somatostatin analogues are an established treatment in acromegaly. This study was designed to evaluate whether the acute serum growth hormone (GH) response to a test dose of octreotide in acromegaly predicts longer-term response to the drug at 3 years., Design and Methods: In 23 patients, GH responses across 8 h to a subcutaneous test dose (50 microg) of octreotide were compared with GH levels after 3 years of therapy. The majority had pituitary surgery as primary therapy and at 3 years were receiving at least 600 microg octreotide daily subcutaneously or 20 mg LAR monthly intramuscularly., Results: Seven had a test day GH Nadir of 5 mU/l or less of whom 4 achieved GH < 5 mU/l at 3 years. Sixteen had a test day nadir GH of 10 mU/l or less and of these 8 achieved GH < 5 mU/l at 3 years. Seven of the 23 had a GH Nadir >10 mU/l and of these 3 had achieved GH <5 mU/l at 3 years. However all of these 3 had received external pituitary irradiation within 4 years of the 3 year assessment, as compared with 3 of the <5 mU/l nadir group and 5 of the <10 mU/l nadir group., Conclusions: In patients on optimal long-term doses of octreotide for acromegaly, absence of a nadir GH <10 mU/l in the 8 h after a test dose was associated with failure to achieve GH levels associated with a normal life expectancy (5 mU/l or less) unless adjunctive external pituitary irradiation was given. As well as testing tolerability a test dose of octreotide may help in determining which patients should be offered early external pituitary irradiation or therapy with a GH receptor antagonist if surgery has failed to achieve 'safe' GH levels.

The development of highly sensitive and specific GH assays has necessitated a critical re-evaluation of the biochemical criteria needed for the diagnosis of acromegaly. Use of these assays has revealed that GH levels after oral glucose in healthy subjects and postoperative patients with active acromegaly can be significantly less than previously recognized with older GH assays. In order to assess GH criteria for newly diagnosed acromegaly with a modern assay we have evaluated GH levels in 25 patients referred to our Neuroendocrine Unit for evaluation of untreated acromegaly. All patients underwent measurement of basal GH and IGF-I levels and 15 of these patients also underwent oral glucose tolerance testing for GH suppression (OGTT). Basal GH levels were < 1.0 microg/L at diagnosis in 5 of these 25 patients. Nadir GH levels were less than 1 microg/L also in 5 of 15 patients, and as low as 0.42 microg/L. All patients had elevated IGF-I levels preoperatively and pathological confirmation of a GH secreting pituitary tumor at the time of transsphenoidal surgery. The clinical presentations of these patients was variable. Most patients presented with classical manifestations of acromegaly, but 3 of the 5 patients with low nadir GH values had only very subtle signs of acromegaly. Although most newly diagnosed patients have classically elevated GH levels and obvious clinical features of acromegaly, early recognition of disease may uncover patients with milder biochemical and clinical abnormalities. The diagnosis should not be discounted in patients who have elevated IGF-I levels, but have basal or nadir GH levels less than 1 microg/L. Conventional GH criteria for the diagnosis of acromegaly cannot be applied to the use of modern sensitive and specific GH assays.

The biochemical assessment for newly recognized acromegaly is in most, but not all patients straightforward. Although significant improvements in the methods of biochemical testing for acromegaly have recently been made, major pitfalls to the assessment of this disease still exist. A number of different schemes have been employed for the assessment of GH secretion in clinical practice. Random GH levels have been often used, but remain unreliable for the assessment of acromegaly. Mean GH levels are also frequently used to assess GH status, but are not specific for the diagnosis of acromegaly. Measurement of glucose suppressed GH levels is the preferred method for assessing GH secretion in acromegaly. However, it is essential to recognize that when using highly sensitive and specific GH assays, nadir GH levels can be < 1 microg/L after oral glucose in some patients with newly diagnosed acromegaly and postoperative patients with active disease. On the other hand, when using most clinically available commercial GH assays which are less sensitive and specific than those used in research studies, failure of GH suppression into the normal range set in these studies is not alone diagnostic of active acromegaly. In order to diagnose acromegaly, documentation of GH excess should be accompanied by elevation in levels of the GH dependent peptide, insulin-like growth factor I (IGF-I). Consideration also needs to be given to the clinical context in which GH and IGF-I are being measured as both can be altered in a number of clinical settings other than acromegaly. Both IGF-I and GH evaluations are important and complimentary parts of the biochemical assessment of acromegaly.

Around fifteen percent of the deaths reported in acromegaly are attributable to malignancy (SM Melmed, J Clin Endocrinol Metab 2001;86:2929-2934; A Mestrón, SM Webb, In: Endocrine Society, San Francisco, June 2002 (abstract)), uncontrolled disease is associated with a growth advantage for concurrent neoplasms, which are more likely to be aggressive; however, there is no clear evidence of de novo cancer initiation in acromegaly and no proven causal relationship of acromegaly with malignant disease. Overall and cancer mortality in acromegaly have been shown to correlate with the degree of GH control; if post therapy GH is controlled, both the overall and cancer mortality do not appear to differ from that of the normal population (SM Orme et al., J Clin Endocrinol Metab 1998;83:2730-2734; JD Nabarro, Clin Endocrinol 1987;26:481-512). However, no long-term prospective evaluation of cancer prevalence or its relation to biochemical or clinical disease activity is available. IGF-1 appears to exert a permissive effect on tumorigenesis; there is no clear evidence that tumor initiation is triggered by IGF-1 in acromegaly; nevertheless, since IGF-1 may be higher in neoplasms, aggressive treatment aimed at controlling the disease activity will theoretically be advantageous for acromegalic patients with cancer. The prevalence of colon polyps and colon cancer appear to be incresed in acromegaly as is mortality for colon cancer (Orme et al., 1998), so regular colonoscopy screening and polypectomy would seem advisable, especially in older patients with active acromegaly. Surveillance for prostate cancer in elderly males with high IGF-1, especially if also receiving testosterone replacement therapy, is recommendable, by measurement of serum PSA, rectal examination and/or prostatic ultrasound. In women, mammography should be offered, especially after the age of 50 years, as in the normal population. Neither prostate nor breast cancer have been consistently shown to have an increased prevalence in acromegaly, but larger prospective epidemiological studies are required to study this further.