Biomedical subjects

R Pivonello

Publications and source records attributed to R Pivonello.

At least 19 recordsLinked to original sources

PubMed2006

Association of pelvic endometriosis with alopecia universalis, autoimmune thyroiditis and multiple sclerosis.

An adult Caucasian female developed a previously unreported association of pelvic endometriosis (PE) with the triad of alopecia universalis (AU), autoimmune thyroiditis (AT) and multiple sclerosis (MS). Molecular human leukocyte antigen (HLA)-tissue typing of this subject showed the presence of the DR(2) 15 and DR(3) 17 alleles, which are associated to an increased risk of MS and AT, respectively. Clinical onset of AT followed withdrawal of corticosteroid treatment for AU, whereas MS become clinically evident after withdrawal from long-term estroprogestin therapy for PE. This clinical case is presented to discuss the autoimmune origin of PE, its possible association with multiple autoimmune disorders as well as the effect of other factors, such as administration and/ or discontinuation of specific hormonal regimens, on genetic autoimmunity-prone background.

Adolescent↗

PubMed2005

Efficacy and safety of 48 weeks of treatment with octreotide LAR in newly diagnosed acromegalic patients with macroadenomas: an open-label, multicenter, non-comparative study.

The aim of the present multicentric, open-label, non-comparative study was to evaluate the role of octreotide long-acting repeatable (LAR) as primary therapy for the treatment of GH-secreting pituitary macroadenomas. The patients received octreotide LAR 20 mg every 4 weeks for 12 weeks; afterwards the dose was confirmed or adjusted at 30 mg every 4 weeks, for the remaining 12 weeks, for responder or non-responder patients, respectively. Responder patients continued the study until 48 weeks. Twenty-one naive active acromegalic patients were enrolled. In all patients, GH profile, IGF-I levels and magnetic resonance imaging (MRI) were evaluated at baseline and during treatment. The ability of octreotide LAR to decrease mean GH < 2.5 microg/I and/or normalize IGF-I levels, adjusted for age and gender, was defined respectively as total or partial success. Total success was achieved in 5/21 (23.8%), 6/20 (30%) and 4/14 (28.6%) patients after 12, 24 and 48 weeks; partial success in 7/21 (33.3%), 9/20 (45%) and 9/14 (64%) patients at 12, 24 and 48 weeks according to GH levels, while according to IGF-I levels in 7/21 (33.3%), 7/20 (35%) and 5/14 (35.7%) patients at 12, 24 and 48 week. Tumor size was notably decreased after treatment with octreotide LAR: in 16 macroadenoma patients completing the study, the tumor sizes were 1609 +/- 1288, 818 +/- 616 (49.1 +/- 23.7%) and 688 +/- 567 mm3 (54.6 +/- 24.4%) at baseline, 24 and 48 weeks. This study shows that octreotide LAR is effective in suppressing GH/IGF-I secretion and inducing tumor shrinkage in GH-secreting macroadenomas in a 48-week treatment. Octreotide LAR could be used as primary therapy in patients harbouring large pituitary tumors, who are less likely to be cured by neurosurgery.

Acromegaly↗

PubMed2005

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) > or = 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 < or = -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 < or = -2 to -1. Our results support a role of the IGF/IGFBP-3 axis in the pathogenesis of atherosclerosis.

Adolescent↗

PubMed2005

Severe systemic complications of acromegaly.

It is well accepted that mortality in acromegaly is increased because of cardiovascular and respiratory diseases while neoplastic complications account less to mortality. Amongst different cardiovascular complications the most frequent is biventricular hypertrophy, which occurs independently of hypertension and metabolic complications that, in turn, aggravate the cardiomyopathy. Diastolic and systolic dysfunction develops in a variable number of patients, depending on age and disease duration. Other cardiac disorders, such as arrhythmias, valve disease, hypertension, atherosclerosis and endothelial dysfunction have been less characterized but all appear to be present in acromegaly, depicting the so called "acromegalic cardiomyopathy". The best characterized respiratory disease is the sleep apnea. Ventilatory dysfunction recognizes bony changes of thoracic cage and lung overgrowth as relevant pathogenetic factors. Earlier evidences that patients with acromegaly have an increased risk of developing malignancies have become more realistic in recent years. Most studies have reported an increased risk of colonic polyps, which more frequently recur in patients not controlled after treatment. Malignancies in other organs have also been described, but less convincingly than at the gastrointestinal level and are not a main cause of mortality. Bone changes are also feature of the disease. They involve theoretically all bones and, particularly, the appendicular and the axial skeleton. Patients with long-standing disease are more prone to develop degenerative changes. Control of acromegaly by surgery or pharmacotherapy, especially by somatostatin analogs, improves cardiovascular morbidity and sleep apnea. There is still no demonstration that improvement of different complications corresponds a reduction in mortality.

Acromegaly↗

PubMed2005

The acromegalic arthropathy.

Since the initial definition of acromegaly over 100 yr ago, extraordinary efforts have been made to control GH levels and the pituitary tumor. Criteria of cure have been evolving constantly and all previous statements should be revised according to modern criteria of disease control. Arthropathy is undoubtedly the most important cause of morbidity and functional disability of acromegaly, and bone alterations are highly characteristic of this syndrome. They involve theoretically all bones and, particularly, the appendicular and the axial skeleton. Radiographic changes at different joint sites are more common than symptoms related to their involvement. There is a progression in the acromegalic arthropathy, resembling that described for the acromegalic cardiomyopathy or for the acromegalic features at other organs, such as thyroid, breast and prostate. At early stage, cartilage hypertrophy predominates, and then degenerative changes start until osteoarthritis features occur. Arthropathy can be reversed by normalizing GH and IGF-I levels only at the initial stage. If the disease is left untreated for long time, the osteo-articular sequelae cannot be modified by any treatment of acromegaly.

Acromegaly↗

PubMed2005

New perspectives in the medical treatment of acromegaly.

Currently available medical treatment of acromegaly includes dopamine agonists, slow release formulation of somatostatin analogues and pegvisomant, a GH-receptor antagonist. Dopamine agonists are well tolerated, not expensive but poorly effective. Somatostatin analogues are highly effective in 60-70% of patients based on the receptor profile of individual tumors. Pegvisomant is reported to normalize IGF-I levels in nearly the totality of the patients, but is devoted of tumor shrinking effect. In a preliminary study in patients with acromegaly, a new somatostatin analogue with affinity to four of the five somatostatin receptors (SOM230) was shown to be similarly effective as octreotide in some patients and more effective than octreotide in other patients. Moreover, new molecules with selective activity on the somatostatin receptor type 2, or 5, or 1 have been reported in vitro to strongly suppress GH secretion. Other new promising alternatives are the chimeric compounds with both somatostatin receptor and dopamine receptor binding. These drugs have been also shown to possess strong GH-inhibitory activity in primary cultures from GH-secreting adenomas. These drugs are the future perspectives in the treatment of patients with GH-secreting or GH/PRL-secreting tumors.

Acromegaly↗

PubMed2005

Potential indications for somatostatin analogues: immune system and limphoproliferative disorders.

Among hormones and neuropeptides influencing the immune system, somatostatin seems to play a key role not only in inhibiting specific immune cell activities, but also in promoting selected functions of particular immune cell subsets. Indeed, controversial effects have been observed in experimental conditions where somatostatin seems to stimulate certain cell functions, such as secretion of specific products (immunoglobulin, cytokines), cell migration and adhesion to extracellular matrix components. However, interestingly, cortistatin (CST), a neuropeptide that strongly resembles somatostatin, from both the structural and functional points of view, seems to have potential roles in regulating immune responses, as well as other lymphoid cell functions. The unexpected wide distribution of CST in a number of human organs, but particularly in immune cells, points to a broader physiological role of CST than previously presumed. The actions of somatostatin and its synthetic analogs (SSA) are mediated by five membrane G protein-coupled receptors subtypes (SSTR1-5), displaying a tissue specific distribution. The majority of somatostatin-target tissues, including lymphoid tissues, may co-express multiple somatostatin receptor (SSTR). The number of SSTRs in lymphoid cells is significantly lower compared to neuroendocrine tissues. However, the presence of receptors allowed the localization by in vivo SSTR scintigraphy of lymphoproliferative disorders, as well as granulomatous and autoimmune diseases. In specific cases, this technique may contribute to establishing the diagnosis and staging the disease. Recent studies evaluating the specific and quantitative SSTR distribution in lymphoid organs and cells, in both normal conditions and immune disorders, have largely contributed to better understand the phenomenology of in vivo receptor imaging and also the involvement of the different SSTR in determining the uptake of radiolabeled SSAs. Moreover, since lymphomas are highly radiosensitive malignancies, a promising approach in refractory patients with malignant lymphomas may be represented by radionuclide-targeted therapy with radioactive-coupled SSAs combined with gene therapy. This latter technique seems effective in inducing the expression or increasing the number of given SSTR in order to ameliorate the impact of radionuclide-targeted therapy. Medical treatment of lymphoproliferative diseases with currently available synthetic analogs have produced unsatisfactory and conflicting results. This might be due to the affinity of the current available SSAs for specific SSTR. However, the synthesis of new compounds with distinct properties has reopened a challenge in this field. The application of receptor-based localization and anti-tumor strategies should also be taking into account the new knowledge recently emerged on the physiopathology of neuropeptide receptors: firstly, neuropeptide receptor homo- and heterodimerization, which may involve different subtypes of SSTRs, as well as other neuropetide receptors, and secondly, the role of endogenous SSTR ligands, such as CST.

Humans↗

PubMed2004

Expression and function of somatostatin receptor subtype 1 in human growth hormone secreting pituitary tumors deriving from patients partially responsive or resistant to long-term treatment with somatostatin analogs.

The role of somatostatin (SS) receptor subtype 1 (SSTR(1)) in mediating the inhibitory effect of SS on growth hormone (GH) secreting pituitary tumors has been recently demonstrated. In the present study, we evaluated the effect of the selective SSTR(1) agonist BIM-23745 on in vitro GH secretion in GH-secreting pituitary tumor cells, deriving from patients resistant or partially responsive to octreotide long-acting release (octreotide-LAR) or lanreotide therapy in vivo and expressing SSTR(1) mRNA. In addition, the inhibiting effect of BIM-23745 on the GH secretion was compared with that of octreotide. Our data demonstrate that (1) SSTR(1) receptor was present in 56.25% (9/16) of the GH-secreting adenomas examined; (2) in all GH-secreting pituitary tumors that expressed SSTR(1), BIM-23745 significantly inhibited GH secretion in vitro, and (3) when SSTR(1) subtype was present in tumors from patients resistant to octreotide-LAR or lanreotide therapy, BIM-23745 was able to inhibit the in vitro GH secretion. In conclusion, the results of the current study suggest that SS analogs selective for the SSTR(1) may represent a further useful approach for the treatment of acromegaly in patients resistant or partially responsive to octreotide-LAR or lanreotide treatment in vivo.

Acromegaly↗

PubMed2004

The role of somatostatin receptors in the medical treatment of acromegaly.

Somatostatin is a hypothalamic inhibitor of pituitary growth hormone secretion and cell proliferation, binding to five distinct receptor subtypes (sstr1-5). Since native somatostatin has a short half-life, somatostatin analogues with a longer half-life have been developed for therapeutic purposes. Octreotide and lanreotide are currently available for treatment of acromegaly, binding with high-affinity sstr2 and sstr5. Octreotide, the first somatostatin analogue used in the medical therapy of acromegaly, was initially given subcutaneously at doses of 100-500 microg three times daily. The introduction of new depot formulations, such as octreotide long-acting release, slow-release lanreotide and lanreotide-autogel, improved patients compliance of long-term therapy, overcoming the inconvenience of multiple daily administration. The treatment with somatostatin analogues induces biochemical control and tumour shrinkage in about 50-70% and 30-60% of patients with acromegaly, respectively. However, the efficacy of this therapy lies on an adequate expression of sstr2 and sstr5 on tumor cells. In the past, somatostatin receptor expression was tested in vivo by (111)In-diethylenetriaminepentaacetate-D-Phe-octreotide scintigraphy: this method has been abandoned since normal pituitary tissue can be visualised by (111)In-diethylenetriaminepentaacetate-D-Phe-octreotide scintigraphy. Currently, the somatostatin receptorial profile can be characterised by autoradiography, molecular biology techniques and immunohistochemistry on surgically removed tumor tissue. These methods may offer an individualised approach sparing patients from unnecessary treatment.

Acromegaly↗

PubMed2004

The heart: an end-organ of GH action.

Several experimental and clinical studies have indicate that the heart is an end-organ of GH action. Patients with either childhood- or adulthood-onset GH deficiency (GHD) have abnormalities of cardiac structure and function, such as reduced cardiac mass, impaired diastolic filling and reduced left ventricular response at peak exercise. These cardiovascular abnormalities can be reversed, at least partially, after GH replacement therapy. On the other hand, the chronic overproduction of GH and IGF-I in acromegaly leads to the development of a specific cardiomyopathy. Concentric cardiac hypertrophy occurs in more than two-thirds of patients at diagnosis and is commonly associated with diastolic dysfunction. In later stages, impaired systolic function ending in heart failure can occur if GH/IGF-I excess is not controlled. Additionally, acromegalic cardiomyopathy is complicated by abnormalities of cardiac rhythm and cardiac valves. Successful control of acromegaly is accompanied by a decrease of the left ventricular mass and improvement of cardiac function. These beneficial effects appear earlier in young patients with short disease duration than in elderly patients. In conclusion, GH and IGF-I play a main role in the regulation of cardiac development and performance.

Acromegaly↗

PubMed2004

Cardiovascular complications in acromegaly.

Cardiovascular morbidity and mortality are increased in acromegaly. In fact, GH and IGF-I excess induces a specific cardiomyopathy. The early stage of acromegaly is characterized by the hyperkinetic syndrome (high heart rate and increased systolic output). Frequently, concentric biventricular hypertrophy and diastolic dysfunction occur in acromegaly, leading to an impaired systolic function ending in heart failure if the disease is untreated or unsuccessfully untreated. Besides, abnormalities of cardiac rhythm and of valves have been also described in acromegaly. The coexistence of other complications, such as arterial hypertension and diabetes, aggravates the acromegalic cardiomyopathy. The suppression of GH/IGF-I following an efficacious therapy could decrease left ventricular mass and improve cardiac function. In conclusion, a careful evaluation of cardiac function, morphology and activity seems to be mandatory in acromegaly.

Acromegaly↗

PubMed2003