Francesco Minuto

Insulin-like growth factor-1 and angiographically documented coronary artery disease☆

In conclusion, we have reported an association between low IGF-I concentrations and CAD in relatively young men. This observation raises the possibility that IGF-I deficiency could be part of the polymetabolic syndrome. Whether a subnormal IGF-I production is due to growth hormone secretory abnormalities or to other metabolic reasons (e.g., insulin resistance or fat distribution, or both) is still unknown.

Correlation of in Vitro and in Vivo Somatotropic Adenoma Responsiveness to Somatostatin Analogs and Dopamine Agonists with Immunohistochemical Evaluation of Somatostatin and Dopamine Receptors and Electron Microscopy

OBJECTIVE AND PATIENTS Twenty-four pituitary adenomas from acromegalic patients (13 females, 11 males; age range 19-65 yr) were characterized for somatostatin receptor subtype 2A (sst(2A)), dopamine D(2) receptor (D(2)R), GH, and prolactin (PRL) expression by immunohistochemistry, and results correlated with the in vitro and in vivo hormone responses to octreotide and quinagolide. In nine cases, GH and PRL content was further studied by immunoelectron microscopy. RESULTS Immunoreactivity was semiquantitatively scored as 2 (>50% stained cells), 1 (10-50% stained cells), and 0 (<10% stained cells). Sst(2A) was scored as 2 in 13 cases, 1 in 10, and 0 in one; D(2)R was scored as 2 in 13 cases, 1 in nine, and 0 in 2; GH was 2 in 15 cases and 1 in nine; PRL was 2 in six cases, 1 in 13, and 0 in 5. Sst(2A) was positively correlated with in vitro (P = 0.003) and in vivo (P = 0.006) percent GH suppression by octreotide and with the chronic suppression of IGF-I by somatostatin analogs (P =0.008). D(2)R was positively correlated with in vitro percent GH (P =0.000) and PRL (P =0.005) suppression by quinagolide. Electron microscopy revealed two pure somatotroph adenomas, five somatomammotrophs with a variable coexpression of GH and PRL in the same cells, and two tumors consisting of mixed cell types, which were less sensitive to quinagolide and octreotide. CONCLUSION Sst(2A) and D(2)R are frequently coexpressed in adenomas from acromegalic patients, and immunohistochemistry may be helpful in characterizing receptor expression in pituitary adenomas to select patients responsive to different treatments.

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.

Predictors of morbidity and mortality in acromegaly: an Italian survey

OBJECTIVE To describe demographic and hormonal characteristics, comorbidities (diabetes mellitus and hypertension), therapeutic procedures and their effectiveness, as well as predictors of morbidity and mortality in a nationwide survey of Italian acromegalic patients. DESIGN Retrospective multicenter epidemiological study endorsed by the Italian Society of Endocrinology and performed in 24 tertiary referral Italian centers. The mean follow-up time was 120 months. RESULTS A total of 1512 patients, 41% male, mean age: 45±13 years, mean GH: 31±37 μg/l, IGF1: 744±318 ng/ml, were included. Diabetes mellitus was reported in 16% of cases and hypertension in 33%. Older age and higher IGF1 levels at diagnosis were significant predictors of diabetes and hypertension. At the last follow-up, 65% of patients had a controlled disease, of whom 55% were off medical therapy. Observed deaths were 61, with a standardized mortality ratio of 1.13 95% (confidence interval (CI): 0.87-1.46). Mortality was significantly higher in the patients with persistently active disease (1.93; 95% CI: 1.34-2.70). Main causes of death were vascular diseases and malignancies with similar prevalence. A multivariate analysis showed that older age, higher GH at the last follow-up, higher IGF1 levels at diagnosis, malignancy, and radiotherapy were independent predictors of mortality. CONCLUSIONS Pretreatment IGF1 levels are important predictors of morbidity and mortality in acromegaly. The full hormonal control of the disease, nowadays reached in the majority of patients with modern management, reduces greatly the disease-related mortality.

Overexpression of Stromal Cell–Derived Factor 1 and Its Receptor CXCR4 Induces Autocrine/Paracrine Cell Proliferation in Human Pituitary Adenomas

Purpose: Hypothalamic or locally produced growth factors and cytokines control pituitary development, functioning, and cell division. We evaluated the expression of the chemokine stromal cell–derived factor 1 (SDF1) and its receptor CXCR4 in human pituitary adenomas and normal pituitary tissues and their role in cell proliferation. Experimental Design: The expression of SDF1 and CXCR4 in 65 human pituitary adenomas and 4 human normal pituitaries was determined by reverse transcription-PCR, immunohistochemistry, and confocal immunofluorescence. The proliferative effect of SDF1 was evaluated in eight fibroblast-free human pituitary adenoma cell cultures. Results: CXCR4 mRNA was expressed in 92% of growth hormone (GH)-secreting pituitary adenomas (GHoma) and 81% of nonfunctioning pituitary adenomas (NFPA), whereas SDF1 was identified in 63% and 78% of GHomas and NFPAs, respectively. Immunostaining for CXCR4 and SDF1 showed a strong homogenous labeling in all tumoral cells in both GHomas and NFPAs. In normal tissues, CXCR4 and SDF1 were expressed only in a subset of anterior pituitary cells, with a lower expression of SDF1 compared with its cognate receptor. CXCR4 and SDF1 were not confined to a specific cell population in the anterior pituitary but colocalized with discrete subpopulations of GH-, prolactin-, and adrenocorticorticotropic hormone–secreting cells. Conversely, most of the SDF1-containing cells expressed CXCR4. In six of eight pituitary adenoma primary cultures, SDF1 induced a statistically significant increase in DNA synthesis that was prevented by the treatment with the CXCR4 antagonist AMD3100 or somatostatin. Conclusions: CXCR4 and SDF1 are overexpressed in human pituitary adenomas and CXCR4 activation may contribute to pituitary cell proliferation and, possibly, to adenoma development `in humans.

Immunoreactivity Score Using an Anti-sst2A Receptor Monoclonal Antibody Strongly Predicts the Biochemical Response to Adjuvant Treatment with Somatostatin Analogs in Acromegaly

CONTEXT Somatostatin receptor subtype 2 (sst2A) protein expression has been demonstrated to positively correlate with somatostatin analog treatment outcome in GH-secreting adenomas. Recently, a new rabbit monoclonal anti-sst2A antibody (clone UMB-1) has been validated as a reliable method to selectively detect sst2A protein levels in formalin-fixed tissues. OBJECTIVE The aim of the study was to establish whether the evaluation of sst2A protein levels, assessed with a routine reproducible immunohistochemistry protocol using UMB-1 antibody, may predict the successful adjuvant therapy with somatostatin analogs in acromegalic patients. DESIGN, SETTING, AND PATIENTS Thirty-six acromegalic patients from our referral hospital were evaluated retrospectively. Sst2A expression analysis was performed by immunohistochemistry in 25 patients and by quantitative RT-PCR in 26 patients. Sst2A immunoreactivity was evaluated using an immunoreactivity score (IRS), which takes into account both the percentage of positive cells and staining intensity. INTERVENTIONS Patients with persistent disease after surgery (n = 26) were treated with somatostatin analogs for a median duration of 6 months. MAIN OUTCOME MEASURE GH and IGF-I levels were measured before and after postoperative treatment. RESULTS Sst2A IRS showed a significant positive correlation with both GH (P = 0.039) and IGF-I (P = 0.001) suppression by octreotide. Sst2A IRS was negatively associated with IGF-I levels reached after treatment (P = 0.001), and patients that achieved IGF-I normalization showed significantly higher sst2A IRS compared to the group that was not normalized (P = 0.002). A sst2A IRS of at least 5 showed a sensitivity of 86% and a specificity of 91% in predicting IGF-I normalization during adjuvant octreotide treatment. CONCLUSION Sst2A IRS with the anti-sst2A antibody UMB-1 represents a valid tool in the clinical practice to identify acromegalic patients likely to be responders to adjuvant therapy with the currently available somatostatin analogs.

The clinical-molecular interface of somatostatin, dopamine and their receptors in pituitary pathophysiology

The role of somatostatin and dopamine receptors as molecular targets for the treatment of patients with pituitary adenomas is well established. Indeed, dopamine and somatostatin receptor agonists are considered milestones for the medical therapy of these tumours. However, in recent years, the knowledge of the expression of subtypes of somatostatin and dopamine receptors in pituitary adenomas, as well as of the coexpression of both types of receptors in tumour cells, has increased considerably. Moreover, recent insights suggest a functional interface of dopamine and somatostatin receptors, when coexpressed in the same cells. This interaction has been suggested to occur via dimerisation of these G-protein-coupled receptors. In addition, there was renewed interest around the concept of cell specificity in response to ligand-induced receptor activation. New experimental drugs, including novel somatostatin analogues, binding to multiple somatostatin receptor subtypes, as well as hybrid somatostatin-dopamine compounds have been generated, and recently a completely novel class of molecules has been developed. These advances have opened new perspectives for the medical treatment of patients with pituitary tumours poorly responsive to the present clinically available drugs, and perhaps also for the treatment of other categories of neuroendocrine tumours. The aim of the present review is to summarise the novel insights in somatostatin and dopamine receptor pathophysiology, and to bring these new insights into perspective for the future strategies in the medical treatment of patients with pituitary adenomas.

Insulin-Like Growth Factor-I in Human Malnutrition: Relationship with Some Body Composition and Nutritional Parameters

The insulin-like growth factor-I (IGF-I) plasma concentration was evaluated as a nutritional parameter in 18 patients affected with chronic malnutrition secondary to biliopancreatic bypass and compared with albumin, transferrin, and with body composition parameters: total body water (TBW), total body sodium (TBNa), total body potassium (TBK). Subjects were studied in malnutritional conditions and after 20 to 30 days of parenteral and enteral refeeding treatment. Immunoreactive IGF-I concentration was 0.35 U/ml +/- 0.07 (mean +/- SEM), significantly lower (p less than 0.01) than in age-matched controls (1.14 +/- 0.07 U/ml, n = 29) and rose significantly (0.84 +/- 0.12 U/ml; p less than 0.01) in parallel with the improvement of nutritional status. The ratios TBNa/TBW, TBNa/TBK, and TBK/TBW were then considered as reference parameters for definition of malnutritional state, and compared with IGF-I as well as with the most commonly used parameters, albumin and transferrin. Before treatment, IGF-I evidenced higher specificity (true negative ratios 0.63, 0.43, and 0.40 with regard to TBNa/TBW, TBNa/TBK, and TBK/TBW, respectively) than albumin (0.13, 0.14, and 0.10) and transferrin (0 in all cases), and slightly less sensitivity (true positive ratios for IGF-I 0.80, 0.67, and 0.67; always one for albumin and transferrin). Moreover, IGF-I resulted definitely more sensitive in assessing the effectiveness of the refeeding treatment and, on the basis of the likelihood ratio, it appeared a good discriminator of the nutritional status. The data indicate that different nutritional factors regulate IGF-I, albumin, and transferrin, and suggest that IGF-I can be used as a reliable and specific nutritional parameter, complementary to the others currently used.

Thyroid hormone stimulates the production of insulin-hke growth factor I (IGF-I) by immature rat Sertoli cells

The effects of thyroid hormone on insulin-like growth factor I (IGF-I) production by Sertoli cells isolated from immature rats have been investigated. In Sertoli cells from hypothyroid rats the production of IGF-I was significantly lower than in controls and was greatly stimulated by the administration of triiodothyronine (T3) in vivo. The in vitro addition of physiological doses of T3 (1 nmol/l) significantly increased the production of IGF-I by cultured Sertoli cells indicating a direct action of the hormone on local IGF-I production. Our results suggest the involvement of IGF-I in the thyroid hormone-dependent maturation of testicular function.

Significant tumour shrinkage after 12 months of lanreotide Autogel-120 mg treatment given first-line in acromegaly

Objective  To evaluate GH and IGF‐I control and tumour shrinkage in newly diagnosed patients with acromegaly treated first‐line with lanreotide‐Autogel (ATG) 120 mg.