Paolo Marzullo

Increased arterial intima‐media thickness by B‐M mode echodoppler ultrasonography in acromegaly

BACKGROUND Patients with acromegaly have an increased morbidity and mortality for cardiovascular diseases. Despite the increasing evidence for the existence of a specific cardiomyopathy in acromegaly, the presence of vascular abnormalities has been never investigated.

The effect of quinagolide and cabergoline, two selective dopamine receptor type 2 agonists, in the treatment of prolactinomas

To compare effectiveness and tolerability of quinagolide (CV 205–502) and cabergoline (CAB) treatments in 39 patients with prolactinoma.

Circulating insulin-like growth factor-I levels are correlated with the atherosclerotic profile in healthy subjects independently of age

To investigate the relationships between the GH-IGF-I axis and the atherosclerotic profile, we designed this open, observational, prospective study. Peak GH after GHRH+arginine (ARG) test, serum IGF-I and IGF binding protein-3 (IGFBP-3), lipid profile, homeostasis model assessment (HOMA) index and intima-media thickness (IMT) at common carotid arteries were measured in 174 healthy individuals (92 women, 82 men, aged 18–80 yr). Exclusion criteria for this study were: 1) body mass index (BMI) ≥30 kg/m2; 2) personal history of cardiovascular diseases; 3) previous or current treatments of diabetes or hypertension; 4) previous corticosteroids treatment for longer than 2 weeks or estrogens for longer than 3 months; 5) smoking of more than 15 cigarettes/day and alcohol abuse. Subjects were divided according to age in decade groups from <20 to >70 yr. BMI increased with age, as did systolic and diastolic blood pressures, although they remained in the normal range. The GH peak after GHRH+ARG test was significantly higher in the subjects aged <20 yr than in all the other groups (p<0.01), but was similar in the remaining groups. An inverse correlation was found between the IGF-I z-score and total/HDL-cholesterol ratio (p=0.02) and mean IMT (p=0.0009); IGFBP-3 z-score and mean IMT (p=0.043); IGF: IGFBP-3 molar ratio and total/HDL-cholesterol ratio (p<0.0001) and mean IMT (p<0.0001). Atherosclerotic plaques were found in 7 out of 12 subjects (53.8%) with a z-IGF-I score from ≤−2 to −1, in 4 out of 63 (6.3%) with a z-IGF-I score from −0.99 to 0.1 out of 66 (1.5%) with a z-IGF-I score from 0.1 to 1 and none of the 33 subjects with an IGF-I z-score >1 (p=0.006). At multi-step regression analysis, age was the best predictor of HDL-cholesterol levels and mean IMT, IGF-I level was the best predictor of total cholesterol and total/HDL-cholesterol ratio, the IGF-I/IGFBP-3 molar ratio was the best predictor of triglycerides levels. The z-scores of IGF-I and IGFBP-3 were the second best predictors of mean IMT after age. In conclusion, IGF-I and IGFBP-3 were negatively correlated with common cardiovascular risk factors, studied as total/HDL-cholesterol ratio, and/or early atherosclerosis, studied as IMT at common carotid arteries. The prevalence of atherosclerotic plaques, though not hemodinamically significant, was higher in the subjects having a z-score of IGF-I of ≤−2 to −1. Our results support a role of the IGF/IGFBP-3 axis in the pathogenesis of atherosclerosis.

Effects of a Chronic Treatment with Octreotide in Patients with Functionless Pituitary Adenomas

The effects of a chronic treatment with octreotide were evaluated in 19 patients affected with functionless pituitary adenomas. Octreotide caused a significant decrease of GH and IGF-I levels in all the patients and no significant change in thyroid, adrenal and gonadal function. In contrast, during the therapy, the glucose response to an oral glucose tolerance test considerably increased and was delayed, while the insulin response decreased and was delayed. Serum alpha-subunit (alpha-SU) was above normal in 10 of 16 patients in which this evaluation was performed: octreotide caused a significant decrease (p < 0.01) of alpha-SU levels in 6 of these 10 patients. Octreotide did not induce any significant change in visual fields except in 1 patient, who had a great improvement of visual perimetry and a decrease of alpha-SU levels but unmodified CT scan features. In our series of patients, octreotide was ineffective in reducing tumor mass. The efficacy of octreotide might rely on the presence of somatostatin receptors on adenoma-cell membranes. Therefore patients with functionless adenomas to be treated with octreotide might be identified with pituitary scintiscan using the recently available labeled 111In-octreotide.

Lymphocyte subset pattern in acromegaly

Immune function in acromegalic patients has been poorly investigated. The aim of this study was to evaluate the main surface antigen clusters of circulating lymphocytes in acromegaly. One hundred patients with active acromegaly (55 women and 45 men, aged 20–70 yr) and 200 healthy subjects sex- and age-matched with the patients (110 women and 90 men, aged 20–70 yr) were enrolled in this study. All patients and controls were born and live in Southern Italy. No patient had received octreotide, bromocriptine or corticosteroids for at least 3 months before entering the study. The analysis of lymphocyte subset pattern was performed by flow cytometry and fluorescein isothiocyanate or phycoerythrin directly conjugated monoclonal antibodies specific for the cell surface antigen clusters (CD) representing T-cell population as a whole (CD3), T helpers (CD4), T suppressors (CD8), natural killer cells (CD16) and B-cell population as a whole (CD19). Acromegalics had significantly increased levels of CD3 (67.1±7.2 vs 64.3±8.8%; p=0.03) and CD4 (37.8±3.5 vs 36.4±4.3%; p=0.004) and decreased levels of CD8 (31.4±3.3 vs 33.7±8.2%; plt0.01) and CD19 (12.1±3.1 vs 15.2±5.1; p=0.01) without age-difference. The results of the current study demonstrate an increase in T-cell activity together with a decrease in B-cell activity in a very large series of patients with active acromegaly. These data further support the existence of abnormalities of the immune system in patients with chronic GH/IGF-I excess.

Percutaneous ethanol injection under Power Doppler ultrasound assistance in the treatment of autonomously functioning thyroid nodules

Power Doppler (PD) is a recent color- Doppler Ultrasound (US)-technique, which allows to detect the presence of flow even in very small vessels, providing a sort of angiographic micromap. The aim of this study was to evaluate whether percutaneous ethanol injection (PEI) outcome might be improved by injecting the ethanol into the nodule under PD assistance. Thus, 14 patients affected with pretoxic (PTA) and 8 with toxic adenoma (TA) were submitted to this alternative tool. Before PEI, all patients were submitted to a careful endocrinological study, including an US-guided fine-needle biopsy in order to exclude the presence of malignancy. In addition, all the nodules were evaluated at PD-US and their vascular patterns were recorded on videotape and compared with those obtained after treatment. The procedure consisted of slow injection of sterile ethanol under direct PD-US control. The number of PEI sessions was 2.3±0.1 in PTA and 3.0±0.3 in TA. All patients were also evaluated 3, 6, 12 and 18 months after PEI. Successful therapy was considered when normalization of thyroid hormones and TSH was achieved together with the disappearance of nodular hyperactivity and complete recovery of extra-nodular tracer uptake at scintigraphy. PEI was tolerated very well by all patients. The most common side effect was a transient local or irradiated pain. All patients with PTA and 6 out of 8 patients with TA were successfully treated. In these cases, PD-US showed the progressive reduction of the intranodular blood flow, up to its extinction after 6-12 months, with the presence of little perilesional vascular spots. Nodular shrinkage was obtained in all patients (from 4.7±0.7 to 1.1±0.4 ml in PTA and from 21.0±2.8 to 6.2±1.6 ml in TA). In conclusion, PD assistance improves PEI procedure, since it allows to guide the ethanol injection towards the principal afferent vessels of the nodules and to monitor the diffusion and the effects of ethanol on nodular vascularization.

Acromegaly and immune function

Abstract GH/IGF-I axes have long been supposed to play a major role in immunomodulation. They ensure ordered body growth and therefore are involved in complex interactions with most organ systems, tissues, and cell types. The homozygous Snell-Bagg dwarf mouse, GH-, PRL-, and thyroid hormones-deficient, has an associated poorly developed immune system including a marked spleen and thymus hypertrophy, a progressive loss of small lymphocytes in the thymic cortex, and a decreased number of peripheral blood lymphocytes. On the other hand, lymphoid cells themselves produce GH: 10% of unstimulated human peripheral blood mononuclear cells (PBMCs) were positive for GH, whereas after mitogen stimulation 20% were positive. A paracrine effect of thymocyte-secreted GH on human primary thymic epithelial cell (TEC) cultures has also been observed. Moreover, somatostatin and GH receptors are expressed in either human TEC or thymocytes. Both these types of receptor seem to be developmentally and differentially expressed on thymic cells, suggesting a crucial role of the local somatostatin-GH-IGF-I system in immune cell differentiation. Cytokines other than GH affect IGF-I synthesis in lymphoid tissues, e.g. in macrophages tumor necrosis factor-α (TNF-α) regulates IGF-I production, the colony-stimulating factors induce the expression of IGF-I mRNA, and the T cell-derived cytokine IFN-γ reduces IGF-I mRNA in a time- and dose-dependent manner. Therefore, the possibility that GH and IGF-I may have effects on immune responses in nonstressed, healthy animals that are compensated by the overlapping actions of other hormones or cytokines cannot be ruled out. Some changes in the lymphocyte subset pattern have been found in acromegaly, but whether these changes play a role in the increased prevalence of neo-plasms is still unknown.