Efficacy of the new long-acting formulation of lanreotide (lanreotide Autogel) in somatostatin analogue-naive patients with acromegaly.

OBJECTIVE: To evaluate efficacy and safety of lanreotide autogel (ATG) 120 mg injections every 4-8 weeks in somatostatin analogue-naïve patients with acromegaly. DESIGN: Open, non-comparative, phase III, multicenter clinical study. METHODS: Fifty-one patients (28 women, aged 19-78 yr): 39 newly diagnosed (de novo) and 12 who had previously undergone unsuccessful surgery (post-op, 11 macro and 1 micro) were studied. ATG 120 mg was initially given every 8 weeks for 24 weeks and subsequently changed according to GH levels: if 5 microg/l every 4 weeks (group C, 19 patients). Treatment duration was 48-52 weeks. The primary objective was to control GH and IGF-I levels (GH

Clinical characterization of familial isolated pituitary adenomas.

CONTEXT: Familial pituitary adenomas occur rarely in the absence of multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). OBJECTIVE: Our objective was to characterize the clinical and genealogical features of non-MEN1/CNC familial isolated pituitary adenomas (FIPA). DESIGN AND SETTING: We conducted a retrospective study of clinical and genealogical characteristics of FIPA cases and performed a comparison with a sporadic population at 22 university hospitals in Belgium, Italy, France, and The Netherlands. RESULTS: Sixty-four FIPA families including 138 affected individuals were identified [55 prolactinomas, 47 somatotropinomas, 28 nonsecreting adenomas (NS), and eight ACTH-secreting tumors]. Cases were MEN1/PRKAR1A-mutation negative. First-degree relationships predominated (75.6%) among affected individuals. A single tumor phenotype occurred in 30 families (homogeneous), and heterogeneous phenotypes occurred in 34 families. FIPA cases were younger at diagnosis than sporadic cases (P = 0.015); tumors were diagnosed earlier in the first vs. the second generation of multigenerational families. Macroadenomas were more frequent in heterogeneous vs. homogeneous FIPA families (P = 0.036). Prolactinomas from heterogeneous families were larger and had more frequent suprasellar extension (P = 0.004) than sporadic cases. Somatotropinomas occurred as isolated familial somatotropinoma cases and within heterogeneous FIPA families; isolated familial somatotropinoma cases represented 18% of FIPA cases and were younger at diagnosis than patients with sporadic somatotropinomas. Familial NS cases were younger at diagnosis (P = 0.03) and had more frequently invasive tumors (P = 0.024) than sporadic cases. CONCLUSIONS: Homogeneous and heterogeneous expression of prolactinomas, somatotropinomas, NS, and Cushing's disease can occur within families in the absence of MEN1/CNC. FIPA and sporadic cases have differing clinical characteristics. FIPA may represent a novel endocrine neoplasia classification that requires further genetic characterization.

Thymic neuroendocrine carcinoma (carcinoid) in multiple endocrine neoplasia type 1 syndrome: the Italian series.

Neuroendocrine tumors may occur in the setting of multiple endocrine neoplasia type 1 (MEN1) syndrome. Among these, a probably underestimated prevalence of well differentiated neuroendocrine thymic carcinoma (carcinoid), a neoplasm characterized by very aggressive behavior, has been described. We report characterization of the seven Italian cases in which this association occurred among a series of 221 MEN1 patients (41 sporadic and 180 familial cases; prevalence, 3.1%). All of the patients were male, and six of seven (85%) were heavy smokers. No associated hormonal hypersecretion was detected. The first diagnosis was between the second and fifth decades. Familial clusters were present in three of seven (42.8%). No genotype-phenotype correlation was found. All seven cases were associated with hyperparathyroidism. In one patient, prophylactic thymectomy revealed a small nodular lesion suggestive of a thymic carcinoid, providing evidence that preventive thymectomy might prevent additional growth of an occult thymic carcinoid. These findings confirm that thymic carcinoids are associated with a very high lethality, with a near-total prevalence in smoker males. Therefore, prophylactic thymectomy should be considered at neck surgery for primary hyperparathyroidism in MEN1 male patients, especially for smokers, and, due to the frequent familial clusters distribution of this pathology, in subjects with affected relatives presenting this feature. Thus, we recommend screening every patient affected with a neuroendocrine thymic neoplasm for MEN1 syndrome.

Expression of insulin/IGF-I hybrid receptors is increased in skeletal muscle of patients with chronic primary hyperinsulinemia.

The insulin receptor (IR) shares structural and functional homology with the IGF-I receptor (IGF-IR). Hybrid receptors composed of an IR alphabeta-heterodimer and an IGF-IR alphabeta-heterodimer are formed in tissues expressing both molecules. Hybrids behave as IGF-IR rather than IR with respect to ligand binding affinity, receptor autophosphorylation, and hormone internalization and degradation. Factors regulating hybrid formation in vivo are unknown. We recently reported that in skeletal muscle of NIDDM patients, expression of hybrids is increased and correlated with a decrease in IR number and an increase in fasting insulin levels. However, it is not clear whether increased expression of hybrid receptors is a primary defect specifically associated with NIDDM or a secondary event caused by hyperinsulinemia. To address this issue, we used a quantitative microwell-based immunoassay to measure hybrid receptor abundance in skeletal muscle of 11 normal subjects and 12 patients with insulinoma, a state of primary nongenetically determined hyperinsulinemia. Total insulin binding was lower in insulinoma patients than in normal subjects (0.70 +/- 0.18 vs. 4.59 +/- 0.77; P < 0.0001). Total IGF-I binding did not differ between the two groups (0.81 +/- 0.27 and 0.85 +/- 0.10, respectively). The amount of hybrids, expressed as bound/total (B/T), was higher in patients with insulinoma than in normal subjects (0.57 +/- 0.19 vs. 0.36 +/- 0.03; P < 0.0006) and was inversely correlated with total insulin binding (r = -0.64, P < 0.0004). Increased abundance of hybrid receptors was positively correlated with insulin levels (r = -0.82, P < 0.0009) and inversely correlated with insulin-mediated glucose uptake (r = -0.80, P < 0.01). No correlations were observed between insulin-mediated glucose uptake and maximal specific insulin binding (r = 0.19, P = 0.64). These results indicate that insulin-induced IR downregulation may lead to the formation of a higher proportion of hybrid receptors, whose abundance is negatively correlated with in vivo insulin sensitivity. These results, therefore, support a role for insulin in the regulation of hybrid receptors formation and suggest that increased expression of hybrids in NIDDM may be a secondary event caused by hyperinsulinemia rather than a primary defect.

Increased OB gene expression leads to elevated plasma leptin concentrations in patients with chronic primary hyperinsulinemia.

Leptin, a hormone secreted by adipocytes, decreases food intake and increases energy expenditure. The role of insulin in the regulation of leptin secretion is poorly understood and is still a topic of debate. Insulin increases leptin mRNA synthesis in rodents, but in humans, the available data are discordant. To investigate the role of chronic hyperinsulinemia in the regulation of plasma leptin concentrations, we studied 13 patients with surgically confirmed insulinoma before and after tumor removal, along with 15 healthy control subjects matched for sex, age, and BMI. Immunoreactive plasma leptin levels were measured by radioimmunoassay; leptin mRNA levels were also determined by reverse transcription-competitive polymerase chain reaction in a subgroup of six patients with insulinoma and six control subjects. All determinations were made with subjects in the fasting state. Plasma leptin concentrations correlated positively with leptin mRNA levels (r = 0.880, P < 0.001). Leptin levels, both plasma protein and mRNA, were significantly higher in the insulinoma patients than in the control subjects (plasma protein: 17.5 +/- 3.6 vs. 2.9 +/- 0.4 ng/ml, respectively, P < 0.001; mRNA: 0.98 +/- 0.33 vs. 0.19 +/- 0.064 amol/microg RNA, respectively, P < 0.05), and they correlated positively with fasting plasma insulin levels in the patients with insulinoma (plasma protein: r = 0.686, P < 0.01; mRNA: 0.796, P < 0.05). Finally, removal of the insulin-secreting tumor was followed by the normalization of plasma leptin levels. In summary, in patients with insulinoma, 1) plasma leptin levels and leptin mRNA are elevated; 2) a direct relationship exists between leptin, both circulating protein and mRNA, and insulin concentrations; and 3) plasma leptin returns to normal levels after tumor removal. These data, therefore, support a role for insulin in the chronic regulation of leptin gene expression.

Evidence for glucose/hexosamine in vivo regulation of insulin/IGF-I hybrid receptor assembly.

Hybrid receptors composed of an insulin alphabeta-hemireceptor and a type 1 IGF alphabeta-hemireceptor are formed in tissues expressing both molecules. We recently reported an increased hybrid receptor expression in skeletal muscle of type 2 diabetic patients that is inversely correlated with in vivo insulin sensitivity. It is unclear whether these changes were due to primary abnormalities or to secondary derangements acting in vivo, such as hyperglycemia. To address this, we determined abundance of hybrids in skeletal muscle from three groups of rats: controls, diabetic (90% pancreatectomy), and diabetic treated with phlorizin to normalize plasma glucose levels. We found that the abundance of hybrid receptors was higher in diabetic rats compared with control and phlorizin-treated diabetic rats (percentage of 125I-insulin bound versus total added radioactivity [B/T] = 1.8+/-0.11, 0.4+/-0.01, and 0.32+/-0.04, respectively; P < 0.0001). Fasting plasma glucose levels were positively correlated with hybrids abundance (r = 0.77, P < 0.002). Hybrid receptor protein content, assessed by immunoblotting, was 2.4-fold higher in diabetic rats as compared with control and phlorizin-treated diabetic rats. Because it has been shown that some of the regulatory effects of glucose may be mediated by the glucosamine pathway, we subsequently determined the effect of an in vivo glucosamine infusion on hybrid receptor formation. We found that abundance of hybrids was significantly higher in muscle from glucosamine-treated rats compared with control rats (B/T = 0.17+/-0.02 and 0.11+/-0.01, respectively; P < 0.009). Quantitation of hybrid content by immunoblotting revealed that their abundance was 1.9-fold higher in glucosamine-treated rats. The results demonstrate that 1) elevated glucose levels in diabetic rats are associated with increased expression of hybrid receptors in muscle, 2) correction of hyperglycemia with phlorizin completely reverses increased expression of hybrids, and 3) glucosamine infused into control rats mimics the effects of hyperglycemia on hybrid receptor formation. Thus, the results support the hypothesis that glucose acting, at least in part, through the glucosamine pathway may play an important role in regulating hybrid receptor assembly in vivo.

Evaluation of trans-sphenoidal surgery in pituitary GH-secreting micro- and macroadenomas: a comparison between microsurgical and endoscopic approach.

AIM: Acromegaly is caused by a GH-secreting pituitary adenoma, associated with many comorbidities and increased risk of mortality. Surgery is the first-line therapy. Success of therapy is measured by symptomatic improvement, preservation of pituitary function and biochemical control. Trans-sphenoidal surgery (TSS), endoscopic or microscopic, is the preferred treatment. To evaluate surgery effectiveness and individuate the technique associated with a higher remission rate, patients undergoing TSS were retrospectively selected. METHODS: Thirty-seven consecutive patients underwent surgery between 1996 and 2006. Tumors were classified into macroadenomas or microadenomas and into intrasellar, extrasellar and extrasellar with cavernous sinus invasion. Surgery was performed in 22 patients with endoscopic technique, in 15 patients with microsurgical approach. The hormonal assays were performed 6 months and yearly after surgery for an average of 5 years. RESULTS: Ten patients were affected by microadenoma, 27 by macroadenoma. In microadenomas remission rate was independent of the used technique. Within macroadenomas, remission percentage in endoscopic approach (68.75%) was significantly higher than in microscopic approach (18.18%) (P=0.018). Postsurgical biochemical remission was calculated combining the surgical technique and tumor extension: the endoscopic approach was associated with a significantly higher remission rate in extrasellar than both in intrasellar and extrasellar with cavernous sinus invasion. In the latter group, any technique had not reached biochemical remission. CONCLUSION: TSS is able to induce a long-term remission of acromegaly, with low risk of recurrence and complications. Endoscopic approach is more suitable than microscopic technique in macroadenomas and adenomas with suprasellar extension.

Evolving criteria for post-operative biochemical remission of acromegaly: can we achieve a definitive cure? An audit of surgical results on a large series and a review of the literature.

Criteria to define the biochemical remission of acromegaly following surgery have changed over the years, and the current use of stringent criteria needs a critical re-evaluation of the surgical results. On the other hand, few data are currently available concerning the possible impact of pituitary surgery on the quality of life of operated acromegalic patients. In this prospective study, we wished to evaluate the initial outcome and long-term recurrence rate in a large series of acromegalic patients operated on by transsphenoidal surgery (TSS), to carefully analyse predictive factors for surgical outcome and to point out possible additional effects of surgery in these patients. Ninety-two out of 98 operated patients could be considered for follow-up. Biochemical remission was strictly defined as plasma GH levels <1 ng/ml during an oral glucose tolerance test (OGTT) and normalisation of age-related IGF-I levels. Hormonal assessment, including an OGTT, was performed 6 months following surgery and then annually to evaluate pituitary function. Fifty-five per cent of patients achieved a biochemical remission of acromegaly. The remission rate at 6 months was 80% for patients with microadenoma and 50% for macroadenoma. Univariate analysis showed that a large extrasellar extension, preoperative high GH levels and dural invasion were correlated with a poor outcome of surgery while, according to multivariate analysis, only invasion of cavernous sinus and preoperative GH levels > 10 ng/ml were independent negative predictors. Mortality was 0% and the overall complication rate was about 10%. Pituitary function worsened in five patients but improved in 16 out of 30 patients with preoperative pituitary defects. No recurrence was observed during a median follow-up of about 8 years. We conclude that TSS is able to achieve a biochemical remission in more than half of acromegalic patients, and that the current criteria for remission seem to indicate a cure in most cases.

Regulation of rat insulin receptor tyrosine kinase by hypoglycemia.

To investigate the effect of hypoglycemia on the regulation of muscle-derived insulin receptor tyrosine kinase activity, four groups of Sprague-Dawley rats were studied: two groups in which either insulin (4 mU/kg.min) or phloridzin (3 mg/kg.min) was infused to acutely reach hypoglycemia (mean, 3.2-3.5 mM); and two control groups in which either saline or phloridzin (3 mg/kg.min) was infused, while maintaining euglycemia. Plasma glucose was maintained constant for 40 min in the hypoglycemic group and for 60 min in the phloridzin-infused euglycemic groups by a variable glucose infusion. Insulin receptors were isolated under conditions designed to preserve their in vivo phosphorylation state, and their tyrosine kinase activity toward poly(Glu-Tyr) was measured in the absence and presence of in vitro exposure to insulin. Insulin infusion resulted in an enhanced in vivo tyrosine kinase activity. Surprising was the finding of a slight increase of the in vivo tyrosine kinase activity in the phloridzin-infused hypoglycemic rats. The in vitro insulin dose-response curves of tyrosine kinase activity showed no significant differences between insulin-infused and control rats. In contrast, there was a marked increase of the insulin-stimulated kinase activity in phloridzin-infused hypoglycemic rats; at 100 nM insulin, tyrosine kinase activity was 1.8-fold more responsive when compared with either insulin-infused rats or control groups. Moreover, in phloridzin-infused hypoglycemic rats, the half-maximal stimulation of tyrosine kinase activity was greater than 10-fold (0.36 +/- 0.01 nM) more sensitive to insulin than both insulin-infused (3.8 +/- 0.03 nM, mean +/- SE) and control groups (4.2 +/- 0.05 and 4.1 +/- 0.04 nM in saline- and phloridzin-infused euglycemic rats, respectively, mean +/- SE). In conclusion, hypoglycemia associated with low plasma insulin concentrations determines a hypersensitization of the intrinsic tyrosine kinase of the insulin receptor.

Effects of alcohol on growth hormone secretion in acromegaly.

In 3 normal subjects and in 4 acromegalic patients pretreatment with an alcohol infusion for 4 hours at a constant rate reduced the GH response to Arginine, when comparison was made with pretreatment with saline. The reduction in acromegalics was more marked and sustained than in normals. Though it is likely that the effect of alcohol is exerted on hypothalamic centers, a direct influence on the pituitary cannot be excluded.

Electroencephalography and visually evoked potentials during moderate hypoglycemia.

The effects of hypoglycemia per se on the electroencephalogram (EEG) and visually evoked potentials (VEPs) were studied in eight normal young adults. The EEG and VEPs were recorded before and during hypoglycemic clamp studies, carried out at plasma insulin and glucose concentrations of about 287 pmol/L and 2.38 mmol/L, respectively. From the mean power EEG spectra obtained during each testing condition, several parameters in each frequency band considered were compared statistically. During the eyes closed recording, the mean frequency of the alpha-band (8-13 Hz) decreased from 10.1 +/- 0.2 (+/- SE) Hz in both the right and left frontal leads during euglycemia to 8.8 +/- 0.2 and 8.8 +/- 0.1 Hz (left and right frontal leads, respectively; P less than 0.05) during hypoglycemia. In the same leads, the peak frequency decreased from 10.6 +/- 0.4 and 10.3 +/- 0.4 Hz to 9.6 +/- 0.4 and 9.5 +/- 0.3 Hz, respectively (P less than 0.05). A similar pattern of variation was found during the eyes open recording. In contrast, mean VEP latencies did not vary significantly; they were 118 +/- 3 ms (smallest image size; square wave signals subtending 30 min of arc) and 116 +/- 3 ms (largest image size; square wave signals subtending 60 min of arc) during euglycemia to 121 +/- 3 and 119 +/- 3 ms, respectively, during hypoglycemia. This study demonstrates that the earliest hypoglycemia-induced EEG alterations occur in the frontal regions and can be quantified in terms of decreased mean and peak frequencies of the alpha-band. VEP latency is less sensitive. If confirmed in diabetic patients, these data may provide a theoretical basis for developing a portable device to detect early hypoglycemia in those patients who lack warning symptoms.

Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism.

As there are few data on the evaluation of the adequacy of levothyroxine (L-T4) therapy in patients with central hypothyroidism (CH), a prospective study was performed to assess the accuracy of various parameters in the follow-up of 37 CH patients. Total and free thyroid hormones, TSH, and a series of clinical and biochemical indexes of peripheral thyroid hormone action have been evaluated off and on L-T4 therapy. Samples were taken before the daily administration of L-T4. In all patients off therapy, clinical hypothyroidism and low levels of free T4 (FT4) were observed, whereas values of FT3, total T4, and total T3 were below the normal range in 73%, 57%, and 19% of cases, respectively. Most of the indexes of thyroid hormone action were significantly modified after L-T4 withdrawal and exhibited significant correlation with free thyroid hormone levels. During L-T4 replacement therapy, 32 patients had circulating levels of FT4 and FT3 and indexes within the normal range with a mean L-T4 daily dose of 1.5 +/- 0.3 microg/kg BW. Despite normal serum FT4, 3 patients had borderline high values of FT3 and a clear elevation of serum-soluble interleukin-2 receptor concentrations, suggesting overtreatment. Low or borderline low FT4/FT3 levels indicated undertreatment in 2 patients. The clinical parameters lack the required specificity for the diagnosis or follow-up of CH patients. The L-T4 daily dose should be established, taking into account the weight, the age, and the presence of other hormone deficiencies or pharmacological treatment of CH patients. In conclusion, our results indicate that the diagnosis of CH is reached at best by measuring TSH and FT4 concentrations. In the evaluation of the adequacy of L-T4 replacement therapy, both FT4 and FT3 serum levels together with some biochemical indexes of thyroid hormone action are all necessary to a more accurate disclosure of over- or undertreated patients.

Growth hormone does not inhibit its own secretion during prolonged hypoglycemia in man.

In man, continuous infusion of GH-releasing hormone (GHRH) does not sustain GH secretion, unlike prolonged hypoglycemia. To further evaluate this difference in the stimulation of GH release we measured GH concentrations for 3 h during prolonged insulin-induced hypoglycemia and GHRH-(1-29)NH2 (100 micrograms/h) infusion in normal individuals. We also assessed the GH response to combined and separate administration of insulin and GHRH. Plasma GH levels increased during prolonged hypoglycemia and remained elevated for the third hour (22-24 micrograms/L). GH concentrations increased during GHRH infusion, peaked at 60 min (23.5 micrograms/L), and rapidly declined. Thus, our findings confirmed that prolonged hypoglycemia, unlike GHRH infusion, sustained elevated GH levels and that these high levels did not appear to influence GH secretion from the pituitary. Changes in FFA did not account for the sustained GH secretion. FFA levels initially declined during insulin infusion, but after 3 h of hypoglycemia they returned to near-basal values (basal, 0.1 +/- 0.02 g/L; 180 min, 0.09 +/- 0.02). The maximal GH concentration attained during the combined insulin and GHRH test was significantly higher than that with the insulin tolerance test or GHRH test (insulin plus GHRH, 71.9 +/- 13.5; insulin tolerance test, 34.2 +/- 2.9; P less than 0.025; GHRH test, 27.9 +/- 3.2; P less than 0.02), indicating an additive effect on GH secretion. These data suggest that insulin-induced hypoglycemia stimulates GH secretion through a mechanism partly independent of GHRH. The release from somatostatin inhibition and stimulation through other neuropeptides (e.g. galanin) is suggested as possible causes of hypoglycemia-induced GH secretion.

Increased insulin sensitivity in patients with idiopathic reactive hypoglycemia.

We performed a euglycemic hyperinsulinemic glucose clamp in 20 patients selected from a large number of subjects referred to our clinic with symptoms suggesting reactive hypoglycemia. Diagnosis was made on the basis of blood glucose measurements during symptoms in their daily life and confirmed by a 5-h oral glucose tolerance test. The patients were divided into the following groups: 8 patients with idiopathic reactive hypoglycemia (IRH), i.e. biochemical hypoglycemia associated with symptoms and plasma insulin concentrations in the normal range; 6 patients with nonhypoglycemia (NH), i.e. patients experiencing the symptoms evoking hypoglycemia at essentially normal plasma glucose levels; and 6 patients with alimentary hypoglycemia secondary to previous gastric surgery (GS). Eight normal volunteers formed the control group (N). Hypoglycemia in this study was considered to be present when plasma glucose concentrations were below 2.5 mmol/L. The peak cortisol levels after glycemic nadir were higher (2P less than 0.05) in IRH compared to GS and N. In the same group, a partially deficient glucagon response to hypoglycemia was noted. During the euglycemic clamp, the glucose uptake appeared to be significantly greater in the IRH group than in NH, GS, and N groups (8.13 +/- 0.49 vs. 7.02 +/- 0.35, 6.48 +/- 0.22, and 6.66 +/- 0.42 mg/kg.min, respectively; 2P less than 0.05). Therefore, our data suggest that increased insulin sensitivity represents a feature of idiopathic reactive hypoglycemia.

Two-year follow-up of acromegalic patients treated with slow release lanreotide (30 mg).

Pharmacotherapy of acromegaly has been improved in recent years as new long-acting somatostatin analogs have became available; they have been suggested as an alternative treatment to pituitary surgery and radiotherapy. To avoid the inconvenience of multiple daily injections during long-term therapy, a slow release formulation of lanreotide (LAN), to be administered im at a dose of 30 mg every 7-14 days, has been introduced in the therapeutic management. The suppressive effects of a short-term LAN treatment on GH and insulin-like growth factor I (IGF-I) hypersecretion were shown to be similar to those obtained with sc octreotide. However, scant data have been reported concerning a long-term treatment with this drug. In the present study the efficacy and tolerability of a 24-month LAN treatment were evaluated in 118 active acromegalic patients; 71 had been previously operated on and treated with s.c. octreotide (operated patients), 24 previously operated on had been irradiated and treated with s.c. octreotide (irradiated patients), and the remaining 23 were newly diagnosed (de novo patients). The efficacy was considered on the basis of controlled GH (fasting, <7.5 mU/L; glucose-suppressed, <3.0 mU/L) and IGF-I (age-adjusted normal values) secretion. In the 118 patients as a whole, circulating GH and IGF-I levels were significantly decreased during the 24-month LAN treatment (P < 0.0005 at all time points vs. basal value). After 24 months of therapy, controlled GH and IGF-I levels were achieved in 64%, 37%, and 78% and in 51%, 37%, and 70% of operated, irradiated, and de novo patients, respectively. A reduction in tumor size was documented in 5 of 23 de novo patients (22%). Among the 84 operated/irradiated with evident tumor remnant, significant shrinkage was documented in 5 patients (5.9%). Treatment was well tolerated by the majority of patients. Only 2 patients (1.7%) withdrew from LAN treatment due to severe side effects. In conclusion, a 24-month treatment with slow release lanreotide (30 mg) is effective in reducing GH and IGF-I levels; furthermore, in de novo patients it induces disease control in 70% of patients and causes tumor shrinkage in 22% of them, with excellent compliance. These data suggest that LAN can be used in long-term treatment of acromegalic patients.

Effect of bombesin on plasma insulin, pancreatic glucagon, and gut glucagon in man.

The effect of bombesin on insulin, pancreatic glucagon, and gut glucagon was investigated in eight healthy volunteers and two pancreatectomized patients. Bombesin, infused iv at the constant rate of 5 ng kg-1 min-1, produced a sharp and statistically significant rise in the plasma insulin concentration. The peak was reached at 5 min (26 +/- 2.17 microU/ml; P less than 0.005 vs. basal values), followed by a prolonged and statistically significant (P less than 0.05) decrease in blood glucose. Pancreatic glucagon rapidly rose to a maximal value of 80.5 +/- 7.6 pmol/liter (P less than 0.005 vs. basal values). In contrast with the prompt increase in insulin and glucagon plasma levels, the peak in gut glucagon concentration (55.8 +/- 4.6 pmol/liter; P less than 0.005 vs. basal values) was reached 30 min after bombesin infusion was discontinued. In the two pancreatectomized patients, bombesin induced an increase in gut glucagon concentrations only. The results presented indicate that bombesin acts directly on the A and B cells of the pancreas, influencing glucose homeostasis; however, more complex mechanisms seem to be involved in gut glucagon secretion.

Systemic hypertension and impaired glucose tolerance are independently correlated to the severity of the acromegalic cardiomyopathy.

Increased mortality from cardiovascular diseases has been reported in acromegaly. Our objective was to evaluate the impact of glucose tolerance abnormalities and/or systemic hypertension in further worsening the acromegalic cardiomyopathy. The study design was open transversal. The subjects studied were 130 consecutive naive acromegalic patients (74 women and 56 men; age, 17-80 yr). Interventricular septum (IST) and left ventricular (LV) posterior wall thickness (PWT), LV mass index (LVMi), maximal early to late diastolic flow velocity ratio (E/A), isovolumic relaxation time (IRT), and LV ejection fraction (EF) were measured by echocardiography. The results were analyzed in line with the presence of glucose tolerance abnormalities (normal in 60, impaired in 38, diabetes mellitus in 32) and the presence (in 46) or absence (in 84) of hypertension. Patients with impaired glucose tolerance and diabetes mellitus had significantly higher age (P = 0.01), and systolic (P = 0.01) and diastolic (P = 0.01) blood pressures and lower E/A (P = 0.01) and EF (P = 0.01) than those with normal glucose tolerance. Disease duration, circulating GH and insulin-like growth factor I (IGF-I) levels, IST, LVPWT, LVMi, and IRT were similar in the 3 groups. Normotensive patients had significantly lower age (P<0.001), LVPWT (P<0.001), IST (P = 0.003), LVMi (P<0.001), and IRT (P = 0.02) and significantly higher E/A (P<0.001) and EF (P<0.001) than hypertensive subjects. Disease duration, circulating GH, and IGF-I levels were similar in the 2 groups. Multiple regression analysis showed that systolic blood pressure was the strongest predictor of LVMi (P = 0.0004), followed by GH levels (P = 0.02), whereas diastolic blood pressure was the strongest predictor of LVEF reduction (P<0.0001), followed by glucose tolerance status (P = 0.02). Age was the strongest predictor of both E/A impairment (P<0.0001) and IRT (P = 0.01), followed by IGF-I levels (P = 0.02). Compared to patients with uncomplicated acromegaly, those with hypertension but without abnormalities of glucose tolerance had an increased prevalence of LV hypertrophy (75% vs. 37.2%) as well as of impaired diastolic (50% vs. 7.8%) and systolic function (18.7% vs. 3.9%), whereas patients with glucose tolerance abnormalities but without hypertension had only an increased prevalence of impaired diastolic (39.7%) and systolic function (31.7%). The subgroup of acromegalic patients suffering from hypertension and diabetes mellitus had the highest prevalence of LV hypertrophy (84.6%), diastolic filling abnormalities (69.2%), and impaired systolic function at rest (53.9%). A careful cardiac investigation should thus be performed in all acromegalic patients showing these complications.

Cardiac effects of slow-release lanreotide, a slow-release somatostatin analog, in acromegalic patients.

Cardiac involvement, mostly characterized by left ventricular hypertrophy associated with various degrees of cardiac dysfunction, greatly contributes to the increased mortality and morbidity observed in acromegaly. Lanreotide is a new SRIF analog characterized by a slow-release (SR) formulation with the peculiarity of a 30-mg im administration every 10-14 days. In this study, 13 patients with postoperative active acromegaly (9 females, 4 males, 45.9 +/- 16.3 yr old) underwent an echo-Doppler and hormonal study before and during a 12-month period of treatment with SR-lanreotide. GH and insulin-like growth factor I plasma levels (mean +/- SD) decreased significantly throughout the study period (from 10.1 +/- 2.2 to 3.9 +/- 0.9 ng/mL for GH, P < 0.005; and from 511.0 +/- 33.0 to 305.0 +/- 34.2 ng/mL for insulin-like growth factor I, P < 0.0001). Left ventricular mass index (mean +/- SD, 137.1 +/- 7.5 g/m2 at baseline) decreased after 3 months (120.0 +/- 5.4 g/m2), 6 months (111.7 +/- 5.7 g/m2), and 12 months (110.3 +/- 5.2 g/m2) of treatment (P < 0.005 at each time-point). This reduction in left ventricular mass index was accompanied by an improvement in some indexes of left ventricular diastolic function, especially the isovolumetric relaxation time (mean +/- SD, 109.1 +/- 4.6 m/sec at baseline), which decreased after 3 months (91.9 +/- 2.8 m/sec), 6 months (92.3 +/- 3.2 m/sec), and 12 months (92.2 +/- 3.0 m/sec) of treatment (P < 0.005 at each time-point). We conclude that SR-lanreotide is able to improve cardiac morphology and functional abnormalities in acromegaly; whether such beneficial effects on cardiac parameters will contribute to improve life expectancy in these patients should be further investigated.

Effects of spontaneous chronic hypoglycemia on central and peripheral nervous system in insulinoma patients before and after surgery: a neurophysiological follow-up.

To investigate the effects of spontaneous chronic hypoglycemia on the peripheral and central nervous system, a multimodal neurophysiological evaluation [median somatosensory (mSEP), brain stem auditory (BAEP), and visual (VEP) evoked potentials recordings] was performed in seven insulinoma patients before and 3 and 6 months after surgical removal of tumor. Before surgery, mSEP findings showed abnormal reduction in peripheral wrist-Erb conduction velocity in three patients as well as a pathological increase in Erb-N13, N13-N20, and Erb-N20 conduction times in five cases. BAEP and VEP recordings gave pathological results in two patients. Moreover, during hypoglycemia, the III-V and I-V interpeak latencies of BAEPs were significantly prolonged (P < 0.01 and P < 0.005, respectively) compared to recordings in euglycemia. After 6 months, a mSEP recovery, even if partial was noted in four patients, BAEPs were normalized in one case, and VEPs were unmodified. Compared to presurgery data, these recordings showed a significant (P < 0.05), but incomplete, shortening of BAEPs (III-V and I-V interpeak latencies) and mSEPs (Erb-N13 and Erb-N20 conduction times). Our findings demonstrate that multiple and selective neurophysiological abnormalities are present in insulinoma patients, confirm that hypoglycemia impairs suddenly brain stem function, and show that after tumor removal, long recovery times for improvement of some neurophysiological anomalies are requested.

Guidelines for diagnosis and therapy of MEN type 1 and type 2.

This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.