Renato Cozzi

Clinical characteristics and therapeutic responses in patients with Germ-line AIP mutations and pituitary adenomas : An international collaborative study

CONTEXT AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. OBJECTIVE The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. DESIGN This study was an international, multicenter, retrospective case collection/database analysis. SETTING The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. PATIENTS Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. RESULTS The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. CONCLUSIONS AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.

Cabergoline addition to depot somatostatin analogues in resistant acromegalic patients: Efficacy and lack of predictive value of prolactin status

background  Somatostatin analogues (SA) are currently the mainstay in the medical treatment of acromegaly. However, even high doses of depot SA for prolonged periods do not achieve GH–IGF‐I normalization in some patients. Even though some data were reported about the addition of cabergoline, a long‐acting dopamine agonist (DA), to SA in resistant patients, definite data are still lacking.

Low Doses of Dopamine Agonists in the Long-Term Treatment of Macroprolactinomas

To evaluate the long-term effects of dopamine agonists in the treatment of macroprolactinoma, we studied prolactin levels and tumor size for 30 to 88 months (57 +/- 14, mean +/- S.D.) in 38 patients treated with bromocriptine or lisuride. Elevated prolactin levels became normal in 30 patients, and the tumor shrank in 29. After two years of treatment, we attempted to reduce the maintenance dose (5 to 20 mg of bromocriptine per day or 0.4 to 0.8 mg of lisuride per day); in 21 patients no changes in prolactin levels or tumor size were observed over 6 to 52 months with 0.625 to 10 mg of bromocriptine per day or 0.05 mg of lisuride per day. However, it was possible to withdraw the drug in only one patient. We conclude that dopamine agonists are usually effective treatments for macroprolactinoma and that after a response has been obtained, it can be maintained in many patients with a greatly reduced dose.

High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas

BACKGROUND Aryl hydrocarbon receptor interacting protein (AIP) mutations (AIPmut) cause aggressive pituitary adenomas in young patients, usually in the setting of familial isolated pituitary adenomas. The prevalence of AIPmut among sporadic pituitary adenoma patients appears to be low; studies have not addressed prevalence in the most clinically relevant population. Hence, we undertook an international, multicenter, prospective genetic, and clinical analysis at 21 tertiary referral endocrine departments. METHODS We included 163 sporadic pituitary macroadenoma patients irrespective of clinical phenotype diagnosed at <30 years of age. RESULTS Overall, 19/163 (11.7%) patients had germline AIPmut; a further nine patients had sequence changes of uncertain significance or polymorphisms. AIPmut were identified in 8/39 (20.5%) pediatric patients. Ten AIPmut were identified in 11/83 (13.3%) sporadic somatotropinoma patients, in 7/61 (11.5%) prolactinoma patients, and in 1/16 non-functioning pituitary adenoma patients. Large genetic deletions were not seen using multiplex ligation-dependent probe amplification. Familial screening was possible in the relatives of seven patients with AIPmut and carriers were found in six of the seven families. In total, pituitary adenomas were diagnosed in 2/21 AIPmut-screened carriers; both had asymptomatic microadenomas. CONCLUSION Germline AIPmut occur in 11.7% of patients <30 years with sporadic pituitary macroadenomas and in 20.5% of pediatric patients. AIPmut mutation testing in this population should be considered in order to optimize clinical genetic investigation and management.

High-dose intramuscular octreotide in patients with acromegaly inadequately controlled on conventional somatostatin analogue therapy: a randomised controlled trial

OBJECTIVE In acromegaly, 25-50% of patients respond inadequately to conventional long-acting somatostatin analogue (SSA) therapy. Response may be improved by increasing SSA frequency or dose. This study evaluated the biochemical efficacy and safety of high-dose octreotide in patients with acromegaly. DESIGN A 24-week prospective, multicentre, randomised, open-label trial conducted from 12 December 2005 to 23 October 2007 in patients with persistently uncontrolled acromegaly despite > or =6 month conventional SSA therapy. METHODS Patients with > or =50% reduction in GH levels during previous SSA treatment were randomised to high-dose (60 mg/28 days) or high-frequency (30 mg/21 days) octreotide i.m. injection. Primary end-points were week 12 and 24 reduction in serum IGF1 and GH from baseline. Secondary end points included IGF1 normalisation and tumour shrinkage rates, and safety/tolerability evaluations. RESULTS Significantly, more patients (10 out of 11) achieved week 24 IGF1 reduction in the high-dose than the high-frequency group (8 out of 15; P<0.05). In the high-dose group only, week-24 IGF1 values were significantly reduced (P=0.02) versus baseline. Normalisation of IGF1 occurred only with the high-dose regimen (4/11; P=0.02). Out of 14 patients experiencing adverse events, 5 reported drug-related gastrointestinal effects. No dose-response relationship was seen. Safety parameters were similar between treatment groups, apart from a slight decrease in HbA1c in the high-dose group only. CONCLUSION High-dose octreotide treatment is safe and effective (normalisation of IGF1 levels) in a subset of patients with active acromegaly inadequately controlled with long-term SSA. Individualised octreotide doses up to 60 mg/28 days may improve outcomes of SSA therapy.

Efficacy and tolerability of gamma knife radiosurgery in acromegaly: a 10‐year follow‐up study

Objective  The long‐term efficacy and safety of stereotactic radiosurgery by gamma knife (GK) still remain unknown. The aim of the study was to investigate the long‐term efficacy and tolerability of GK in acromegalic patients.

Screening of Cushing's Syndrome in Outpatients with Type 2 Diabetes: Results of a Prospective Multicentric Study in Italy

CONTEXT Cushings syndrome may remain unrecognized among patients referred for metabolic syndrome; thus, a proactive screening has been suggested in certain patient populations with features of the disorder. However, conflicting data have been reported on the prevalence of Cushings syndrome in patients with type 2 diabetes. OBJECTIVE Our aim was to evaluate the prevalence of unsuspected Cushings syndrome among outpatients with type 2 diabetes. DESIGN AND SETTING This was a cross-sectional prospective study in 24 diabetes clinics across Italy. PATIENTS Between June 2006 and April 2008, 813 patients with known type 2 diabetes without clinically overt hypercortisolism were evaluated. Follow-up of the study was closed in September 2010. Patients were not selected for characteristics conferring a higher pretest probability of hypercortisolism. Patients underwent a first screening step with the 1-mg overnight dexamethasone suppression test. RESULTS Forty patients failed to suppress serum cortisol less than 5.0 μg/dl (138 nmol/liter) and underwent a standard 2-d, 2-mg dexamethasone suppression test, after which six patients (0.6% of the overall series) failed to suppress cortisol less than 1.8 μg/dl (50 nmol/liter), receiving a definitive diagnosis of Cushings syndrome that was adrenal dependent in five patients. Four patients were cured, being able to discontinue, or reduce, the glucose-lowering agents. CONCLUSIONS The present data do not support widespread screening of patients with type 2 diabetes for Cushings syndrome; however, the disorder is less rare than previously thought when considering epidemiology of type 2 diabetes. Our results support a case-finding approach in patients with uncontrolled diabetes and hypertension despite appropriate treatment.

Differential Inhibition of Growth Hormone Secretion by Analogs Selective for Somatostatin Receptor Subtypes 2 and 5 in Human Growth-Hormone-Secreting Adenoma Cells in vitro

Somatostatin (SRIH), a cyclic tetradecapeptide hormone originally isolated from mammalian hypothalamus, is a potent suppressor of pituitary growth hormone (GH) secretion. SRIH acts through a family of G-protein-coupled membrane receptors containing seven transmembrane domains. Five genes encoding distinct SRIH receptor (SSTR) subtypes have so far been cloned in human and other species and termed SSTR1–5. In human somatotrophe pituitary adenomas GH secretion is controlled by both SSTR2 and SSTR5. However, in clinical practice only somatostatin analogs selective for SSTR2 (octreotide and lanreotide) are available. This may explain why clinical and in vitro responses to these analogs in acromegaly are only partial. In this study, we investigated the inhibitory effect of two new SRIH analogs with high selectivity for SSTR2 (NC-4-28B) and SSTR5 (BIM-23268) and compared it to that of native somatostatin (SRIH-14) on a large number of GH-secreting adenomas obtained by transphenoidal neurosurgery. Tissues from 16 adenomas were enzymatically dispersed and plated in 24-well dishes at 50,000 cells/well. After 3 days, groups of three wells were incubated for 4 h with medium alone, SRIH-14 or analogs NC-4-28B or BIM-23268, at the concentrations of 0.01, 0.1 and 1 µM. Our results show that 9 out of 16 adenomas were responsive (GH suppression: 20–40% vs. control, p < 0.05) to SRIH. In this group only 4 adenomas showed similar responses to both selective analogs, with 2 nonresponders (expression of other SRIH receptor subtypes) and 2 responders (concomitant expression of SSTR2 and SSTR5) to both analogs. GH release was selectively inhibited by NC-4-28B in 3 adenomas and by BIM-23268 in the remaining 2 adenomas, suggesting predominant expression of SSTR2 and SSTR5, respectively. SRIH failed to inhibit GH release in 7 adenomas (43%). Interestingly, in that group a better inhibitory effect was obtained with BIM-23268 (5 out of 7 adenomas) than with NC-4-28B, suggesting expression of a few SSTR5 receptors only, or of both SSTR2 and SSTR5, respectively. We conclude that the availability of somatostatin analogs selective for SSTR5 will enhance the treatment potency and spectrum in acromegaly.

Effects of lanreotide autogel on growth hormone, insulinlike growth factor 1, and tumor size in acromegaly: A 1-year prospective multicenter study

OBJECTIVE To evaluate the safety and effectiveness of lanreotide Autogel on growth hormone and insulinlike growth factor 1 (IGF-1) concentrations and tumor size in patients with acromegaly. METHODS Between September 2004 and March 2006, patients with active acromegaly who had not previously been treated with somatostatin analogues or received irradiation were enrolled in a 1-year, prospective, open, multicenter study. Lanreotide Autogel was injected subcutaneously starting with 90 mg every 4 weeks for 2 cycles and then individually titrated, aiming for safe growth hormone concentrations (<2.5 ng/mL) and normal age-matched IGF-1 concentrations. Tumor shrinkage, clinical score, pituitary function, and safety parameters were evaluated. RESULTS Twenty-seven patients (15 women, 12 men) were enrolled. One patient withdrew because of treatment intolerance, and 5 proceeded to neurosurgery 6 months into the study. Lanreotide Autogel was the primary treatment in 19 patients (4 with microadenoma, 15 with macroadenoma) and the adjuvant treatment in 8 patients in whom it followed a previous unsuccessful neurosurgery. In the 26 patients, safe growth hormone values were achieved in 11 (42%), normal IGF-1 values in 14 (54%), and both targets were achieved in 10 (38%). Tumors shrank in 16 of the 22 patients (73%) in whom tumor shrinkage could be evaluated. The maximal vertical diameter of the tumor decreased by a mean of 24% (range, 0% to 50%), from 14.4 +/- 8.4 mm to 10.4 +/- 7 mm, and tumor volume decreased by a mean of 44% (range, 0% to 76%), from 2536 mm3 (range, 115-7737 mm(3)) to 1461 mm(3) (range, 63-6217 mm(3)) (both P<.015). Symptom scores and lipid levels significantly improved. In the 26 patients, glucose metabolism deteriorated in 3 (12%) and improved in 4 (15%). New biliary alterations appeared in 26%. Pituitary function and safety parameters did not change. CONCLUSIONS Lanreotide Autogel treatment, titrated for optimal hormonal control, effectively controls IGF-1 and growth hormone levels, shrinks tumors, reduces acromegalic symptoms, and is well tolerated.

Somatostatin analogs and gallstones: a retrospective survey on a large series of acromegalic patients

Context: Development of gallstones (GS) is reported during the use of somatostatin analogs (SA) that are at present the mainstay for the medical treatment of acromegaly. Objective: To review the prevalence and clinical and biochemical correlates of GS in acromegalic patients. Design and seting: Retrospective survey on hospital records in acromegalic patients followed up in the last 20 yr in tertiary referral centers. Patients: Four hundred and fifty-nine patients (272 females). Main outcome measures: According to SA use and GS occurrence, patients were divided in 4 groups: 1) treated with SA without GS (SA+GS−), 2) GS developed while on SA (SA+GS+), 3) GS without SA use (SA−GS+), 4) neither GS nor SA (SA−GS−). Results: Patients were unevenly distributed in the 4 groups: 232, 125, 38, 64, respectively, pointing to a prevalence of GS in acromegaly of 8.3% at diagnosis with an additional 35% developing GS during SA. GS occurred after 3 months-18 yr (median 3 yr) of SA treatment, were diagnosed after symptoms in 17.6%, were associated to steatosis, ultrasound biliary dilation, and biochemical cholestasis, in 25.6%, 12.8%, and 4% of patients, respectively. Ursodehoxicolic acid was administered after GS occurrence, causing their dissolution in 39% of patients after 3–48 months (median 12). Cholecystectomy was performed in 16.8% of patients in group 2. At multivariate analysis obesity, dyslipidemia, and SA treatment were independent predictors of GS onset, whereas gender and age were not. Conclusions: GS are a frequent occurrence in acromegalic patients treated with SA, may occur at any time, but are seldom symptomatic or prompt acute surgery. Obesity and dyslipidemia appear to play a major role in the occurrence of GS in acromegalic patients on SA treatment.