Biomedical subjects

D Ferone

Publications and source records attributed to D Ferone.

At least 19 recordsLinked to original sources

PubMed2000

Hormone levels and tumour size response to quinagolide and cabergoline in patients with prolactin-secreting and clinically non-functioning pituitary adenomas: predictive value of pituitary scintigraphy with 123I-methoxybenzamide.

BACKGROUND: Dopamine agonists are indicated as primary therapy for PRL-secreting pituitary adenomas, while controversial results have been reported in nonfunctioning adenomas (NFA). OBJECTIVE: To evaluate whether the in vivo visualization of dopamine D2 receptor expression detected by pituitary scintigraphy using 123I-methoxybenzamide (123I-IBZM) was correlated with the response to chronic treatment with quinagolide or cabergoline. PATIENTS: 10 patients affected with NFA (5 men and 5 women, age ranging between 25 and 50 years), and 10 with PRL-secreting naive macroadenomas (3 men and 7 women, age ranging between 22 and 59 years), serving as control. STUDY DESIGN: All patients underwent an acute test with quinagolide: at 3-day intervals and in random order all patients received the drug (0.075 mg at 0800 h), or placebo. Blood samples were taken 15 and 5 minutes before and every 30 minutes for 6 h after drug or placebo administration. The test was considered positive when PRL and/or alpha-subunit levels decreased >/=50% as compared to baseline levels. After 6 months of treatment, 10 patients were randomised to continue the treatment with quinagolide and the remaining 10 received cabergoline for the remaining 6 months. The doses of quinagolide and cabergoline ranged from 0.075 to 0.6 mg/day and from 0.5 to 3 mg/week, respectively. At study entry, a magnetic resonance imaging (MR) study of the pituitary region and 123I-IBZM pituitary scintigraphy were performed. MR was repeated after 12 months of treatment to evaluate tumour shrinkage: reduction of tumour volume = 80% in prolactinomas and = 50% in NFA was considered significant. Basal PRL levels were 9495.0 +/- 1131.6 mU/l in prolactinomas and 602.4 +/- 50.5 mU/l in NFA. RESULTS: The scintigraphy was negative in 6 out of 10 patients with NFA. Moderate uptake was observed in 3 patients with prolactinoma and 2 patients with NFA whereas intense uptake was observed in the remaining 7 patients with prolactinoma and 2 patients with NFA. Among the 8 patients with NFA and high circulating alpha-subunit levels, the acute test was negative in 5 while it was positive in the remaining 3 patients. The acute test was positive in all 10 patients with prolactinoma. After 12 months of treatment with quinagolide and cabergoline, circulating PRL levels were decreased in all 10 patients with prolactinoma (571.8 +/- 255.9 mU/l), being normalized in 7 patients. Suppression of PRL levels was found in all 10 patients with NFA (89.5 +/- 2.3 mU/l). A significant reduction of alpha-subunit levels was obtained in 9 out of 10 patients with NFA: in 4 out of 8 patients alpha-subunit levels were normalized. Significant adenoma shrinkage was recorded in 4 patients with prolactinoma among the 7 with intense pituitary uptake of 123I-IBZM. Significant adenoma shrinkage was recorded only in the 2 out of 10 patients with NFA with intense pituitary uptake of 123I-IBZM. A significant positive correlation was found between the degree of uptake (considered as score) and the response to quinagolide or cabergoline treatment (considered as percent hormone suppression) either in patients affected with PRL-secreting adenoma (r = 0.856, P < 0.005) or in those affected with NFA (r = 0.787, P < 0.05). CONCLUSIONS: An intense 123I-IBZM uptake in patients with non-functioning adenomas was predictive of a good response to a chronic treatment with quinagolide and cabergoline. This result suggests that a pituitary 123I-IBZM scintigraphy could be considered in selected patients with non-functioning adenomas before starting medical treatment with dopamine agonists.

Adenoma↗

PubMed2000

Increased prevalence of thyroid autoimmunity in patients successfully treated for Cushing's disease.

BACKGROUND: Cushing's disease is characterized by abnormalities of immune function. OBJECTIVE: To evaluate the prevalence of autoimmune thyroid diseases in patients with Cushing's disease (CD), after successful treatment and the possible association between previous nodular goitre or positive thyroid autoantibodies during the active phase of CD and the subsequent development of autoimmune thyroid diseases after cure. SUBJECTS AND METHODS: Twenty patients with CD and 40 sex- and age-matched healthy controls were considered for the study. In CD patients, thyroid ultrasonography and measurement of circulating free thyroxine (fT4), free triiodothyronine (fT3), thyroid stimulating hormone (TSH), antithyroglobulin (anti-Tg) and antithyroperoxidase (anti-TPO) antibodies were performed at diagnosis and 6 months after disease cure while in controls they were performed only at study entry. RESULTS: Serum fT3, and fT4 levels were similar in patients, either during the active phase or after cure of the disease, and controls. Conversely, in the patients, serum TSH levels were significantly lower during active disease (0. 4 +/- 0.05 mU/l, P = 0.001) and significantly higher after disease cure (4.7 +/- 0.1 mU/l, P < 0.001) than in controls (2.3 +/- 0.4 mU/l). Four patients (20%) and 11 controls (27.5%) had positive anti-Tg and/or anti-TPO titre at study entry, while eight patients (40%) developed positive anti-Tg and/or anti-TPO titre after disease cure. The prevalence of positive antithyroid antibodies titre in cured CD patients was significantly higher than that observed in the same patients during the active disease (P = 0.008) and in controls (P = 0.031). A significantly higher prevalence of autoimmune thyroiditis was found in patients cured from CD (35%) than in patients with active CD (0%) (P = 0.016) and in controls (10%) (P = 0.031). A significant association was found between the presence of autoimmune thyroiditis after CD cure and the presence of a previous nodular goitre (P = 0.017) or positive thyroid autoantibodies titre (P = 0.007) during the active phase of the disease. CONCLUSION: Patients successfully treated for Cushing's disease have an increased prevalence of thyroid autoimmunity and autoimmune thyroiditis as compared to a control population. Therefore, patients with hypercortisolism need an accurate evaluation of thyroid function after remission of the disease in order to prevent the eventual onset of subclinical or overt post-thyroiditis hypothyroidism.

Adult↗

PubMed2000

Age-related decrease of somatostatin receptor number in the normal human thymus.

The thymus exhibits a pattern of aging oriented toward a physiological involution. The structural changes start with a steady decrease of thymocytes, whereas no major variations occur in the number of thymic epithelial cells (TEC). The data concerning the role of hormones and neuropeptides in thymic involution are equivocal. We recently demonstrated the presence of somatostatin (SS) and three different SS receptor (SSR) subtypes in the human thymus. TEC selectively expressed SSR subtype 1 (sst(1)) and sst(2A). In the present study we investigated whether SSR number is age related in the thymus. Binding of the sst(2)-preferring ligand (125)I-Tyr(3)-octreotide was evaluated in a large series of normal human thymuses of different age by SSR autoradiography and ligand binding on tissue homogenates. The score at autoradiography and the number of SSR at membrane homogenate binding (B(max)) were inversely correlated with the thymus age (r = -0.84, P < 0.001; r = -0.82, P < 0.001, respectively). The autoradiographic score was positively correlated with the B(max) values (r = 0.74, P < 0.001). Because the TEC number in the age range considered remains unchanged, the decrease of octreotide binding sites might be due to a reduction of sst(2A) receptor number on TEC. The age-related expression of a receptor involved mainly in controlling secretive processes is in line with the evidence that the major changes occurring in TEC with aging are related to their capabilities in producing thymic hormones. In conclusion, SS and SSR might play a role in the involution of the human thymus. These findings underline the links between the neuroendocrine and immune systems and support the concept that neuropeptides participate in development of cellular immunity in humans.

Adolescent↗

PubMed2000

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.

Acromegaly↗

PubMed2000

Effect of two years of growth hormone and insulin-like growth factor-I suppression on prostate diseases in acromegalic patients.

The insulin-like growth factors (IGFs) have mitogenic effects on normal and tumoral prostate epithelial cells and have been suggested to be involved in prostate cancer. Moreover, chronic GH and IGF-I excess causes prostate overgrowth in patients with acromegaly. This study was designed to investigate whether the suppression of GH and IGF-I levels by surgery or pharmacotherapy could induce the regression of prostatic hyperplasia in acromegalic patients. To this end, prostate volume (PV) as well as the occurrence of prostatic diseases were studied by transrectal ultrasonography in 23 untreated acromegalic patients (with elevated GH and IGF levels). None of the patients reported symptoms due to prostatic disorders or obstruction. At study entry, prostate hyperplasia was found in half patients. After 2 yr, GH, IGF-I, and IGFBP-3 levels were decreased, whereas prostate-specific antigen levels did not change. PV was decreased in the 16 patients who were well controlled. Among the 6 patients with prostate hyperplasia at study entry who achieved disease control, 4 regained a normal PV at the end of the 2 yr of treatment, whereas none of the 5 patients with prostate hyperplasia at study entry and not achieving disease control normalized their PV. When patients were divided according to age, prostate volume decreased after 2 yr only in the 8 controlled patients aged below 50 yr, but not in those controlled and with age above 50 yr despite similar decrease in GH, IGF-I, and IGFBP3 levels. No clinical, transrectal ultrasonography, or cytological evidence of prostate cancer was detected during the study period. These data suggest that hyperplasia, but not cancer, is frequent in acromegalic men, and that the GH-IGF axis and age are independently associated with the development of this process.

Acromegaly↗

PubMed2000

Cardiac effect of thyrotoxicosis in acromegaly.

Cardiac structure and function are affected both by acromegaly and hyperthyroidism. Whereas the former is mainly characterized by ventricular hypertrophy as well as diastolic and systolic impairment, the latter frequently leads to increased heart rate and enhancement of contractility and cardiac output. To further investigate this issue, we designed this two-arm study. In the first cross-sectional study, we compared echocardiography and radionuclide angiography results obtained in eight hyperthyroid acromegalic patients, eight hyperthyroid nonacromegalic patients, and eight healthy subjects. All acromegalic patients were receiving treatment for acromegaly at the onset of hyperthyroidism. In the second longitudinal study, performed in the group of acromegalic patients, we compared the cardiovascular results obtained during hyperthyroidism with the retrospective data obtained at the initial diagnosis of acromegaly and after 1-yr treatment for this disease and those prospective data obtained during the remission of hyperthyroidism. In the cross-sectional study, hyperthyroid acromegalic patients showed an increase in the left ventricular (LV) mass index (LVMi) compared to healthy and hyperthyroid controls (P < 0.05), with evidence of LVMi hypertrophy in five of them (62.5%). A significant correlation was found between LVMi and GH levels (r = 0.785; P < 0.05). The LV ejection fraction (LVEF) at rest was higher in the control hyperthyroid population than in healthy controls (P < 0.05), whereas the LVEF response to exercise was reduced in acromegalic patients (P < 0.05 vs. healthy controls). In acromegalics, the exercise-induced change in LVEF was significantly reduced compared to that in healthy controls (P < 0.001), but not to that in hyperthyroid controls (P < 0.07), being abnormal (<5% increase vs. baseline values) in six patients. Four of these six patients (66%) had elevated GH and insulin-like growth factor I levels during the treatment of acromegaly. An inverse correlation between GH and LVEF at rest (r = -0.896;P < 0.05) and at peak exercise (r = -0.950; P < 0.001) was recorded. The peak filling rate was reduced in hyperthyroid acromegalic patients compared to those in both control populations (P < 0.05). In the longitudinal study, acromegalic patients showed an increased LVMi during hyperthyroidism compared to that observed after successful treatment of acromegaly (P < 0.05); resting LVEF was increased compared to both basal (P < 0.001) and posttreatment values (P < 0.05). However, the exercise-induced change in LVEF was reduced (P < 0.05 vs. previous follow-up values). Remission of hyperthyroidism led to significant reduction of LVMi (P < 0.05) and resting LVEF (P < 0.05) and an increase in exercise-induced LVEF (P < 0.05). In light of these findings, hyperthyroidism produces a detrimental effect on the cardiovascular system of acromegalic patients, particularly in those with uncontrolled disease. Thus, control of GH and insulin-like growth factor I should be a major objective, as cardiovascular risk persists in patients with ineffective hormonal suppression, and constant endocrine and cardiovascular surveillance remain crucial steps in patient follow-up.

Acromegaly↗

PubMed2000

Somatostatin receptor subtypes in human thymoma and inhibition of cell proliferation by octreotide in vitro.

Somatostatin (SS) and SS receptor (SSR) subtypes, code-named sst1-5, are heterogeneously expressed in the normal human thymus. This suggests their involvement in controlling the immune and/or neuroendocrine functions in this organ. Moreover, recently a high in vivo uptake of [111In-DTPA-D-Phe1]octreotide has been reported in patients bearing thymoma. The present study characterizes in vivo and in vitro, functional SS-binding sites in a human thymoma. A high uptake of [111In-DTPA-D-Phe1]octreotide was observed in the chest of a patient with myasthenia gravis due to a cortical thymoma. Specific binding of [125I-Tyr11] SS-14 was found on a membrane preparation of the surgically removed thymoma. Scatchard analysis showed high affinity binding sites (Kd, 47.5 +/- 2.5 pmol/L) with low maximum binding capacity (23.5 +/- 2.5 fmol/mg membrane protein). RT-PCR analysis showed the presence of sst1, sst2A, and a predominant sst3 messenger RNA (mRNA) expression in the tumor tissue. Primary cultured tumor cells expressed sst3 mRNA only. In contrast to the normal thymus, SS mRNA was not expressed. By immunohistochemistry, the tumor cells highly expressed sst3 receptors, weakly expressed sst1 receptors, and showed no immunostaining for sst2A receptors. sst2A immunoreactivity was found in the stromal compartment of the tumor, particularly on the endothelium of small intratumoral blood vessels. In primary cultured tumor cells, both SS and octreotide (10 nmol/L) significantly inhibited [3H]thymidine incorporation by 40.6% and 43.2%, respectively. The following conclusions were reached. 1) As this tumor displayed a high immunoreactivity for sst3 and the cultured tumor cells expressed the sst3 mRNA only, this SSR may be the subtype involved in the inhibition of epithelial tumor cell proliferation by octreotide in vitro. 2) A loss of endogenous SS production in this thymoma might be implicated in the uncontrolled cell growth. 3) In this case, the sst3 may play a role in determining the uptake of [111In-DTPA-D-Phe1]octreotide by in vivo SS receptor scintigraphy.

Antineoplastic Agents, Hormonal↗

PubMed2000

Cardiovascular effects of depot long-acting somatostatin analog Sandostatin LAR in acromegaly.

Cardiovascular disease is the most severe complication of acromegaly accounting for the increased mortality of these patients. Recently, the slow-release form of octreotide (OCT; Sandostatin LAR, OCT-LAR), for im injection every 28 days, was reported to induce suppression of GH levels below 7.5 mU/L (2.5 microg/L) in 39-75% of patients, and normalization of insulin-like growth factor (IGF)-I levels for age in 64-88% of patients, with an excellent patients' compliance. The aim of the present study was to investigate the early effect of OCT-LAR treatment on the left ventricular (LV) structure and performance in 15 somatostatin analog-naive patients with acromegaly (GH, 94.8 +/- 24.9 mU/L; IGF-I, 757.9 +/- 66.6 microg/L), focusing on the early effect of GH and IGF-I suppression on the heart. Cardiac structure was investigated by echocardiography, whereas LV performance was investigated by gated-blood-pool scintigraphy, before and after 3 and 6 months of treatment with OCT-LAR. OCT-LAR was initially administered im, at a dose of 20 mg every 28 days, for 3 months. In six patients, the dose was then increased to 30 mg every 28 days to achieve disease control, which was considered when fasting and/or glucose-suppressed GH values were below 7.5 and 3.0 mU/L, respectively, together with IGF-I values within the normal range for age. The treatment with OCT-LAR for 6 months induced a significant decrease of GH (to 12.9 +/- 3.0 mU/L) and IGF-I levels (to 340.3 +/- 40.2 microg/L) in all 15 patients. After 6 months of treatment, the percent IGF-I suppression was 52.8 +/- 4.4%, and serum GH/IGF-I levels were normalized in 9 patients. A significant decrease of LV mass index (LVMi), interventricular septum thickness, and LV posterior wall thickness was observed in all 15 patients after 3 and 6 months of OCT-LAR treatment: LVMi was decreased by 19.1 +/- 2.0% without any difference in patients with (19.9 +/- 2.7%) or without disease control (17.8 +/- 3.3%). Among the 11 patients with LV hypertrophy, 6 normalized their LVMi after treatment. At study entry, an inadequate LV ejection fraction (LVEF) at rest (<50%) was found in 5 patients (33.3%), whereas an impaired response of LVEF at peak exercise (<5% increase of basal value) was found in 9 patients (60%). A significant increase in LVEF, both at rest (from 51.6 +/- 2.6 to 58.1 +/- 1.7%, P < 0.01) and at peak exercise (from 51.6 +/- 2.3 to 60.2 +/- 2.4%, P < 0.001) was found in patients with (as compared with those without) disease control (from 55.2 +/- 3.8 to 58.0 +/- 4% and from 61.8 +/- 4.6 to 61.8 +/- 3.4%, respectively). Among the 5 patients with inadequate LVEF at rest, all but 1 regained a normal LVEF after 6 months of treatment; whereas, among the 9 patients with an impaired response of the LVEF at peak exercise, 3 patients normalized, 4 improved, and 2 impaired their responses after treatment. The percent of IGF-I suppression was significantly correlated with the percent increase of resting LVEF (r = 0.644, P < 0.01). Exercise duration (from 6.0 +/- 0.7 to 7.3 +/- 0.7 min) and capacity (from 69.0 +/- 8.2 to 80 +/- 7.8 watts) were increased in the 15 patients considered as a whole, but the improvement in the exercise response was significant only in patients with disease control (P < 0.01 and P < 0.05, respectively) who also had an increase in the peak ejection rate (P = 0.03). No change in hemodynamic parameters, either at rest or at peak exercise, was found after treatment with OCT-LAR in the 15 patients. In conclusion, the results of the present study demonstrate that OCT-LAR im injections every 28 days induces a sustained suppression of GH levels and IGF-I levels in all acromegalic patients, allowing achievement of disease control in 60% of patients after 6 months of treatment. The sustained suppression of IGF-I levels was followed by a significant reduction of LVMi in all patients already after 3 months of treatment, with recovery of LV hypertrophy in 6 of 11 patients. (ABSTRACT TRUN

Acromegaly↗

PubMed2000

Pharmacotherapy or surgery as primary treatment for acromegaly?

In recent years important progress has been made in the management of acromegaly due to the availability of effective and well tolerated drugs and to improved surgical techniques, resulting in a broader choice of therapeutic interventions. Although surgery in the hands of an experienced surgeon still represents the primary option for the majority of patients, the new formulations of somatostatin analogues and dopamine agonists have partially modified the primary therapeutic approach to this severe and disabling chronic disease. Therapy with somatostatin analogues has been shown to reduce morbidity and the mortality rate in patients with acromegaly, and currently in some patients this medical approach may be preferable to surgery. Although in selected patients individualised pharmacotherapy might represent the primary therapy, trans-sphenoidal surgery of microadenomas and noninvasive macroadenomas remains the primary option, since the remission rate is very high and the costs are relatively low in comparison with lifelong therapy with somatostatin analogues. However, the treatment schedule in acromegaly should consider criteria additional to tumour size and invasiveness, such as the age and the general clinical condition of the patient. Presurgical treatment with somatostatin analogues has been reported to reduce surgical complications and time of hospitalisation after the operation. Moreover, a multidisciplinary team of well trained specialists is needed in order to guarantee the most optimal quality of life and life expectancy for patients with acromegaly.

Acromegaly↗

PubMed1999

The pituitary uptake of (111)In-DTPA-D-Phe1-octreotide in the normal pituitary and in pituitary adenomas.

The aim of this study was to compare the pituitary (111)In-DTPA-D-Phe1-octreotide uptake measured in 49 patients subjected to the scintigraphy for SS-R expressing tumors not located in the sellar region with that measured in 38 patients with pituitary adenomas. The 87 subjects enrolled in this study were divided into two groups: the first included SSR-expressing tumors (SS-ET), 10 thymomas, 13 differentiated thyroid carcinomas, 4 carcinoids, 5 neuroendocrine tumors, 5 insulinomas, 6 melanomas, 2 renal carcinomas, 2 pheocromocytomas, and 2 parathyroid tumors, while the second included pituitary adenomas, 25 GH-secreting, 4 GH/PRL-mixed and 9 clinically nonfunctioning adenomas (NFA). Planar and single-photon-emission tomography images of the head were obtained 2-4 and 24 hours after the injection of 77-103 MBq of (111)In-DTPA-D-Phe1-octreotide and pituitary uptake was measured by the region of interest method. A 4 point score was used to grade the pituitary-to-blood (T-to-B) ratios: 0=negative; 1 =faint (T-to-B=<1.5); 2=moderate (T-to-B=1.6-3.5); 3=intense (T-to-B=>3.5). In patients with pituitary adenomas, the percent suppression of GH and alpha-subunit levels after 6-12 months of octreotide treatment (0.3-0.6 mg/day) was correlated to T-to-B ratios. After 2-4 hr from injection, pituitary (111)In-DTPA-D-Phe1-octreotide uptake was moderate/intense in 2 out of 49 SS-ET (4%), 18 out of 29 acromegalics (62%) and 6 NFA (66.6%), while a faint uptake was detected in 4 SS-ET (8%), 8 GH-secreting adenomas (27.5%) and 3 NFA (33.3%). Negative scan was detected in the remaining 43 SS-ET (87.7%) and 3 GH-secreting microadenomas (10.3%). 24 hr after injection, pituitary (111)In-DTPA-D-Phe1-octreotide uptake was moderate/intense in SS-ET (10.2%), 21 GH-secreting adenomas (72.4%), and 9 NFA (100%) while a faint uptake was detectable in 15 SS-ET (30.6%), and 6 GH-secreting adenomas (20.7%). No uptake was visualized in 29 SS-ET, and 2 GH-secreting adenomas. By MRI a pituitary tumor was shown in the 2 SS-ET with early moderate tracer uptake. Normalization of circulating GH/IGF-I levels and suppression of alpha-subunit levels was achieved in 16 of 18 acromegalics (88.9%) and 5 of 6 NFA-bearing patients, respectively, with scan scored 2-3 at early images. Eleven acromegalics (37.9%) and 2 NFA (22.2%) displayed significant tumor shrinkage (> or =30% of baseline size) during long-term octreotide therapy. Both in GH-secreting and in NFA, a significant correlation was found between percent GH or alpha-subunit suppression after 6-12 months of octreotide therapy and T-to-B ratios both in early (r=0.626; p<0.0001 and r=0.738, p=0.003, respectively) and late images (r=0.569; p=0.002 and r=0.8, p=0.01, respectively). In conclusion, the (111)In-DTPA-D-Phe1-octreotide uptake in pituitary adenomas was significantly correlated to octreotide treatment. However, since pituitary (111)In-DTPA-D-Phe1-octreotide uptake was clearly detectable in 40% of patients with SS-ET not located in the pituitary region at 24 hr post-injection, (111)In-DTPA-D-Phe1-octreotide scintigraphy with late pituitary images can not be considered an useful method to predict the chronic responsiveness to octreotide in individual patients. Caution should also be taken in evaluating the results of the scintigraphy with early images in patients with scant uptake before excluding them from treatment.

Adenoma↗

PubMed1999

Effectiveness and tolerability of slow release lanreotide treatment in active acromegaly.

This single-center open sequential study aimed at comparing the efficacy of a 6-month treatment with lanreotide (LAN) (60-90 mg/month i.m.), to that of octreotide (OCT) (0.3-0.6 mg/day s.c.) in 45 patients with active acromegaly (GH, 63.2+/-12.1 ng/ml, IGF-I, 757+/-67.1 ng/ml). After 6 months of OCT treatment, safe GH (fasting <2.5, glucose suppressed <1 ng/ml) and IGF-I (normalized for age) levels were achieved in 23 patients. After treatment withdrawal, GH levels significantly increased in all patients, though remaining slightly lower than pre-OCT therapy (39.2+/-5.8 ng/ml) while plasma IGF-I levels were unchanged (654+/-59.4 ng/ml). After 6 months of LAN treatment, safe GH and IGF-I levels were achieved in 26 patients (57.7%). After OCT or LAN treatments, no significant difference was found between nadir GH (6+/-1 vs 5.9+/-1.1 ng/ml) and IGF-I levels (281+/-23.3 vs 262+/-20.6 ng/ml). Four out of the 20 patients poorly responsive to OCT achieved safe GH and IGF-I levels after LAN treatment. Among the 20 non-operated patients, a significant tumor shrinkage was documented by CT and/or MRI in 5 patients after OCT and in 1 patient after LAN treatment. All patients referred a notable improvement of soft tissue swelling, arthralgia, headache and weakness, both after OCT and LAN treatments. During the first days of OCT treatment, abdominal discomfort was referred by 12 patients and steatorrhea by 5 patients: side effects disappeared spontaneously in 6 cases while during treatment with pancreatic enzymes in the remaining ones. After the first injections of LAN, abdominal discomfort was referred by 10 patients and steatorrhea by 2 of them. No difference in the prevalence of both early and late side effects was noted after treatment with OCT and LAN (chi2, 0.49). The majority of these poorly tolerant patients had side effects with both compounds. During LAN treatment, side effects were mild and spontaneously disappeared but recurred after the injection of the drug in six patients. Gallstones were detected in one patient during OCT and in another during LAN, sludge was noted in 6 patients after OCT and in 2 after LAN treatment. In conclusion, the treatment with LAN allowed to achieve safe GH and IGF-I levels in 57.7% of acromegalics with an excellent patients' compliance. LAN treatment possessed similar efficacy and caused side effects with a similar incidence of OCT treatment. The recurrence of side effects after LAN injection suggests the necessity of a careful monitoring of adverse reactions.

Acromegaly↗

PubMed1999

Comparison of six months therapy with octreotide versus lanreotide in acromegalic patients: a retrospective study.

OBJECTIVE: We analysed the effects of 6-months' treatment with octreotide s.c. and lanreotide-SR on circulating GH and IGF-I levels in acromegaly. DESIGN: Open retrospective study. PATIENTS: Thirty-eight patients with active acromegaly (plasma IGF-I levels greater than 2 standard deviations for age-matched controls and increased serum GH levels not suppressible by oral glucose load) were studied. All patients received s.c. octreotide at a dose of 150-600 microg/day for six months as first therapy and subsequently, lanreotide i.m., 30-60 mg either at 14 or 10 day intervals, for 6 months. A 3 months' washout was applied before starting lanreotide treatment. MEASUREMENTS: Mean serum GH levels (from three samples), IGF-I, and clinical examination were performed before and 30, 60, 90 and 180 days after octreotide and lanreotide treatments. Safety tests, HbA1c and, thyroid function were evaluated every three months. RESULTS: Circulating GH and IGF-I levels were significantly reduced (P < 0.001) after one, three and six months of both octreotide and lanreotide treatment. The absolute values were lower and the percent decrease in serum GH levels obtained after octreotide treatment was significantly greater, at all scheduled assessments, than after lanreotide (P < 0.01). Serum IGF-I levels during octreotide were significantly lower only after the first month of therapy (P < 0.01). CONCLUSIONS: Our study shows that octreotide s.c. is able to induce an earlier reduction in IGF-I levels and a more marked reduction in GH levels than lanreotide. However, after six months of therapy the number of patients with safe GH levels and normal IGF-I age-matched levels, was similar with both drugs. Therefore we suggest that octreotide treatment be preferentially used in the short-term presurgical treatment, while lanreotide can be used in chronic therapy when better compliance is necessary.

Acromegaly↗

PubMed1999

Ultrasonographic evidence of joint thickening reversibility in acromegalic patients treated with lanreotide for 12 months.

BACKGROUND: A major cause of morbidity and functional disability in acromegaly is represented by axial and peripheral arthropathy. OBJECTIVE: The effect of a 12-month treatment with lanreotide (LAN) on arthropathy in 12 untreated acromegalic patients has been evaluated. Twelve healthy subjects served as controls. STUDY DESIGN: Open prospective. STUDY PROTOCOL: Articular cartilage thickness of shoulder, wrist and knee, as well as the size of the heel tendons, was measured by ultrasonic (USG) examination before, monthly for the first 3 months and quarterly thereafter, during treatment with 60-90 mg/month of LAN. The achievement of safe GH and IGF-I levels was considered when fasting GH was below 5 mU/l and IGF-I levels were normalized for age. RESULTS: Before treatment, thickening of shoulder, wrist and knee cartilages, and of heel tendons, was found in all patients compared with controls (P < 0.01). During the first 3 months of LAN treatment, a significant decrease in circulating GH (from 86.8 +/- 19.8 to 25.6 +/- 9.8 mU/l) and IGF-I levels (from 624 +/- 47.8 to 412.2 +/- 44.5 microg/l) was observed. Overall, a slight decrease was noted in all the articular sites examined, but it reached statistical significance only at the right shoulder (P < 0. 001). However, a notable improvement of joint pain and active and passive articular mobility were recorded in all patients, as well as of weakness, soft tissue swelling, hyperhydrosis and headache. After 6 months of LAN treatment, a further significant decrease was observed at the level of the right shoulder (P < 0.01) and the right knee (P < 0.01). Eight patients achieved safe GH and IGF-I levels. After 12 months of LAN treatment, a significant decrease was observed at the level of all the articular sites examined (P < 0.01), as well as at the level of both heel tendons (P < 0.01). Safe GH and IGF-I levels were achieved in all but one of the patients who, similarly, had a significant decrease in shoulder, wrist and both heel tendon thicknesses. The thickness reduction of right shoulder cartilage, a non-weight-bearing joint, was significantly greater than that observed at the level of the right and left knee cartilages and heel tendons (37.4 +/- 4.4% vs. 18 +/- 6.1%, 19.3 +/- 4.4%, 16.5 +/- 4.2%, and 13.7 +/- 5.5%, respectively, P < 0.01). No difference was found in thickness decrease of all sites examined between the eight patients achieving safe GH levels after 3-6 months, and the remaining four patients, or between patients with estimated disease duration below (n = 6) or above 10 years (n = 6). CONCLUSIONS: Improvement in articular and periarticular soft tissue hypertrophy of the shoulder and wrist, two non-weight-bearing joints, but also of the knees, two weight-bearing joints, and heel tendons, was obtained by suppressing GH and IGF-I levels for 12 months with LAN treatment, although complete reversal of joint thickening was not achieved. Since no difference in the response to treatment, in terms of joint size decrease, was found between patients with short or long disease duration, treatment longer than 12 months may be needed to reverse the acromegalic arthropathy completely.

Acromegaly↗

PubMed1999

In vitro characterization of somatostatin receptors in the human thymus and effects of somatostatin and octreotide on cultured thymic epithelial cells.

Somatostatin (SS) and its analogs exert inhibitory effects on secretive and proliferative processes of various cells via high affinity SS receptors (SS-R). SS analogs bind with different affinity to the five cloned SS-R subtypes. Octreotide, an octapeptide SS analog, binds with high affinity to the SS-R subtype 2 (sst2). SS-R have been demonstrated in vivo and in vitro on cells from endocrine and immune systems. Among the lymphatic tissues, the thymus has been shown to contain the highest amount of SS, suggesting a local functional role of the peptide. We investigated the SS distribution and SS-R expression pattern in the normal human thymus using autoradiography, membrane homogenate binding studies, and RT-PCR. In addition, the effect of SS and octreotide on growth of cultured thymic epithelial cells (TEC) was studied. By autoradiography, binding of [125I-Tyr0]-SS-28 and [125I-Tyr3]-octreotide was detected in all seven thymuses studied. Specific [125I-Tyr3]-octreotide binding was shown on membrane preparations from thymuses, while not from cultured thymocytes. RT-PCR showed the expression of sst1, sst2A and sst3 messenger RNA (mRNA) in the thymic tissue, whereas sst1 and sst2A mRNAs were found in isolated TEC. SS mRNA was present in thymic tissue and in isolated TEC. SS and octreotide significantly inhibited 3H-thymidine incorporation in 3 of 3 and 6 of 6 TEC cultures, respectively. The percent inhibition ranged from 38.8 to 66.8% for SS and from 19.1 to 59.5% for octreotide. In conclusion, SS mRNA and sst1, sst2A, and sst3 mRNAs are expressed in the normal human thymus. Cultured TEC selectively express sst1 and sst2A mRNA and respond in vitro to SS and octreotide administration with an inhibition of cell proliferation. These data suggest a paracrine/autocrine role of SS and its receptors in the regulation of cell growth in thymic microenvironment.

Adolescent↗

PubMed1999

Effects of 1-year treatment with octreotide on cardiac performance in patients with acromegaly.

The aim of the study was to investigate the effects of 1-yr treatment with octreotide (OCT) on left ventricular diastolic and systolic function, assessed at rest and during physical exercise by gated blood pool cardiac scintigraphy, in 30 patients with active acromegaly. OCT was initially given at a dose of 0.05-0.1 mg, 3 times daily, and the dose was subsequently increased to achieve GH/insulin-like growth factor I (IGF-I) normalization. Hormone normalization after treatment was considered when basal and/or oral glucose test-suppressed GH values were below 2.5 and 1 microg/L, respectively, and IGF-I values were within the normal range for age. To evaluate the response to OCT treatment in terms of cardiac performance, the 30 patients were divided into 2 groups on the basis of normalized (in 13 patients) or nonnormalized (in 17 patients) circulating GH and IGF-I levels. At study entry, hypertension was found in 6 patients (20%), abnormal left ventricular diastolic filling was found in 12 patients (40%), and impaired left ventricular ejection fraction was found in 2 patients at rest (6.6%) and in 18 patients at peak exercise (60%). Before OCT treatment, exercise duration ranged from 6-10 min, and exercise workload ranged from 50-125 watts. After 1-yr treatment with OCT, a significant decrease in circulating GH and IGF-I levels was achieved in all patients, but normalization was obtained only in 13 of 30 patients. In patients achieving circulating GH and IGF-I normalization after OCT treatment but not in those with persistently elevated hormone levels, a significant decrease in heart rate, both at rest (from 75.7 +/- 3.3 to 66.5 +/- 2.9 beats/min; P < 0.01) and after exercise (from 137.5 +/- 4.9 to 123.7 +/- 4.1 beats/min; P < 0.01), and a significant increase in left ventricular ejection fraction, both at rest (from 56.5 +/- 1.8% to 66.5 +/- 2.2%; P < 0.01) and after exercise (from 52.6 +/- 2.4% to 67.1 +/- 1.7%; P < 0.01), were found. In the 17 patients who had persistently high circulating GH and IGF-I levels after 1 yr of OCT treatment, left ventricular ejection fraction was unchanged at rest but was significantly reduced after exercise compared to the basal value (from 64.9 +/- 2.4% to 57.2 +/- 2.6%, P < 0.01); systolic blood pressure at rest was significantly increased (from 128.5 +/- 4.9 to 141.2 +/- 5.4 mm Hg; P < 0.05). In these 17 patients, the ejection fraction response to exercise was significantly impaired, mostly in those less than 40 yr of age (from 11.6 +/- 3.2% to -0.3 +/- 5.6%; P < 0.05). In particular, among 9 patients who had a normal response to exercise at study entry, 6 developed an abnormal response after 1 yr. Left ventricular diastolic filling was unchanged by OCT treatment in all patients. Exercise duration (only in young patients from 7.5 +/- 0.5 to 9.3 +/- 0.7 min; P < 0.05) and exercise workload (in all 13 patients from 80.8 +/- 6.4 to 92.3 +/- 5.9 watts; P < 0.05) were significantly increased in the group of patients with normalized GH and IGF levels, but not in the remaining 17 (from 7.6 +/- 0.4 to 7.5 +/- 0.4 min and from 89.9 +/- 5.5 to 84.4 +/- 4.5 watts, respectively). In conclusion, the results of the present study indicate that suppression of basal or glucose-suppressed GH levels below 2.5 or 1 microg/L, respectively, together with normalization of plasma IGF-I levels for 1 yr are followed by a significant improvement, but not complete normalization, of left ventricular ejection fraction either at rest or at peak exercise without significant changes in diastolic filling. By contrast, the persistence for 1 yr of elevated hormone levels caused a significant increase in systolic blood pressure and impaired cardiac performance. These data suggest that prolonged suppression of circulating GH and IGF-I levels could normalize cardiac performance and probably reverse the poor prognosis for cardiovascular disease in acromegaly.

Acromegaly↗

PubMed1999

Impact of patient's age and disease duration on cardiac performance in acromegaly: a radionuclide angiography study.

The aim of this study was to evaluate the impact of age and disease duration on cardiac performance in acromegaly. To address these issues, the left ventricular function at rest and during physical exercise was assessed by equilibrium radionuclide angiography in 40 rigorously selected patients with active acromegaly but without evidence of other complications able to affect heart function and in 32 healthy controls. Patients and controls were divided in two groups, on the basis of age below and above 40 yr. Circulating GH and insulin-like growth factor-I levels were significantly increased in patients, compared with controls, but were similar in the two groups of patients. At peak exercise, the systolic blood pressure was significantly higher in elderly patients (P < 0.001), whereas diastolic blood pressure was significantly higher in young patients than in age-matched controls (P < 0.01). Heart rate at peak exercise was significantly higher in young than in elderly patients and controls (P < 0.01), without any evidence of arrhythmia in both groups. The left ventricular ejection fraction at rest was normal (>50%) in all but 2 patients and in all controls. The left ventricular ejection fraction at peak exercise was significantly decreased in elderly, compared with young, patients (P < 0.01) and in age-matched controls (P < 0.001). A normal response of the left ventricular ejection fraction to exercise was found in 12 of 40 patients (30%) and in 28 of 32 controls (87.5%) (chi2, 5.764; P < 0.01). Exercise-induced changes in left ventricular ejection fraction were significantly decreased in young (+5.2 +/- 4.4% vs. +21.3 +/- 3.4%, P < 0.005) and elderly patients (-10.2 +/- 2.8% vs. +13.7 +/- 2.7%, P < 0.0001), as compared with age-matched controls. The peak rate of left ventricular filling was significantly higher in young, than in elderly, patients whether peak filling rate was normalized to end-diastolic volume (P < 0.001), or stroke volume (P < 0.0001), or expressed as the ratio of peak filling rate to peak ejection rate (P < 0.001). The peak rate of left ventricular filling was significantly decreased in elderly patients, compared with young patients and age-matched controls, whether peak filling rate was normalized to end-diastolic volume (P < 0.01), or stroke volume (P < 0.005), or expressed as the ratio of peak filling rate to peak ejection rate (P < 0.001). In the patient group, the left ventricular ejection fraction at peak exercise was significantly correlated with age (r = -0.33, P < 0.05), estimated disease duration (r = -0.34, P < 0.05), exercise-induced changes of the left ventricular ejection fraction (r = 0.34, P < 0.05), and the peak rate of left ventricular filling, whether peak filling rate was normalized to end-diastolic volume (r = 0.33, P < 0.05). Age and estimated disease duration were both significantly correlated with the peak rate of left ventricular filling, whether peak filling rate was normalized to end-diastolic volume (r = 0.55, P < 0.001 and r = -0.49, P < 0.001, respectively), or stroke volume (r = 0.5, P < 0.001 and r = -0.57, P < 0.001, respectively), or expressed as the ratio of peak filling rate to peak ejection rate (r = 0.56, P < 0.0001 and r = -0.52, P < 0.001, respectively). In the control group, the left ventricular ejection fraction at peak exercise was significantly correlated with the left ventricular ejection fraction at rest (r = 0.54, P < 0.01), exercise-induced changes of the left ventricular ejection fraction (r = 0.57, P < 0.001), but neither with age nor peak rate of left ventricular filling at all measurements. In conclusion, left ventricular performance is more frequently preserved in young patients with a short disease duration, although the left ventricular response to exercise was already reduced, as compared with controls. (ABSTRACT TRUNCATED)

Acromegaly↗

PubMed1999

Effect of growth hormone (GH) and insulin-like growth factor I on prostate diseases: an ultrasonographic and endocrine study in acromegaly, GH deficiency, and healthy subjects.

The role of insulin-like growth factor I (IGF-I) in prostate development is currently under thorough investigation because it has been claimed that IGF-I is a positive predictor of prostate cancer. To assess the effect of GH and IGF-I levels on prostate pathophysiology, 46 acromegalic (30 in active disease, 10 cured from acromegaly, and 6 affected from GH deficiency) and 30 age-matched male controls, free from previous or concomitant prostate disorders, underwent pituitary, androgen, and prostate hormonal assessments and transrectal ultrasonography. Compared to control values, GH (P < 0.0001), IGF-I (P < 0.0001), and IGFBP-3 (P < 0.001) levels were increased, whereas testosterone (P < 0.0001) and dihydrotestosterone levels (P < 0.0001) were reduced in active acromegalic patients. Hypogonadism was present in 28 of the 46 acromegalic patients (60.8%). The anteroposterior (P < 0.05), and transverse (P < 0.0001) prostate diameters and the transitional zone volume (P < 0.05) were increased in acromegalic patients compared to those in controls. Prostate volume (PV) was significantly higher in untreated acromegalic patients than in controls (41.7 +/- 3.2 vs. 21.9 +/- 1.4 mL; P < 0.0001), cured patients (23.6 +/- 1.6 mL; P < 0.0001), and GH-deficient patients (17.5 +/- 1.1 mL; P < 0.0001). In the patients, PV was correlated with disease duration (r = 0.606; P < 0.0001) and age (r = 0.496; P < 0.0001), whereas in controls it was correlated with age (r = 0.476; P < 0.01) and IGF-I levels (r = -0.448; P < 0.05). Benign prostate hyperplasia (PV > or = 30 mL) was found in 58% of the acromegalics and 26.6% of the controls. When grouped by age (<40, 40-60, and >60 yr), PV was increased in elderly patients compared to younger patients (P < 0.05) and to controls (P < 0.01). The prevalence of structural abnormalities, including calcifications, nodules, cysts, and vesicle inflammation, was significantly increased in patients compared to controls (78.2% vs. 23.3%; chi2 = 5.856; P < 0.05). No clinical, transrectal ultrasonography, or cytological evidence of prostate cancer was detected in acromegalic or control subjects. In conclusion, chronic excess of GH and IGF-I cause prostate overgrowth and further phenomena of rearrangement, but not prostate cancer.

Acromegaly↗

PubMed1999

Persistence of increased cardiovascular risk in patients with Cushing's disease after five years of successful cure.

Patients with Cushing's disease (CD) mainly die because of cardiovascular accidents. The aim of this study was to evaluate whether patients with CD still have increased cardiovascular risk and suffer from premature atherosclerosis once cured. Fifteen patients cured from CD for a long term period (5 yr), 30 sex-and age-matched controls, and 30 body mass index (BMI)-matched controls were included in this study. BMI; waist to hip ratio (WHR); systolic (SBP) and diastolic (DBP) blood pressures; serum total, low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol; serum triglycerides, fibrinogen, and lipoprotein(a) levels; prothrombin time; activated partial thromboplastine time; and basal and glucose load-stimulated insulin and glucose levels were measured in patients and controls. By echo-Doppler ultrasonography, the intima media thickness (IMT), systolic and diastolic media-media distances, blood systolic (SPV) and diastolic (DPV) peak velocity, systolic (SLD) and diastolic (DLD) lumen diameter, and distensibility coefficient (DC) were measured at both common carotid arteries where the presence, size, and location of atherosclerotic plaques were also evaluated. Compared with a sex- and age-matched control population, CD patients had BMI (P < 0.001), WHR (P < 0.001), SBP (P < 0.005), DBP (P < 0.05), fasting glucose (P < 0.001) and insulin (P < 0.05), glucose load-stimulated glucose and insulin levels (P < 0.05), total cholesterol (P < 0.05), LDL cholesterol (P < 0.01), fibrinogen (P < 0.01), and lipoprotein(a) (P < 0.05) levels higher and HDL cholesterol levels (P < 0.05) lower than controls. At ultrasonography, in the patients, IMT (P < 0.05), SPV (P < 0.05) and DPV (P < 0.001) were significantly increased whereas SLD (P < 0.001), DLD (P < 0.001), and DC (P < 0.05) were significantly decreased compared to controls. In addition, CD patients had higher WHR (P < 0.05), DBP (P < 0.05), glucose load-stimulated glucose and insulin levels (P < 0.05), and fibrinogen levels (P < 0.01) and lower HDL cholesterol (P < 0.05) levels than BMI-matched controls. At ultrasonography, increased common carotid arteries IMT (P < 0.05) and DPV (P < 0.05) and decreased DLD (P < 0.05) and DC (P < 0.05) were measured in patients compared to those in BMI-matched controls. Atherosclerotic plaques were found in 26.7% of patients, in none of the sex- and age-matched controls, and in 3.3% of the BMI-matched controls. In CD patients, a significant correlation was found between both WHR and fasting serum insulin levels and DBP (r = 0.52 and r = 0.55; P < 0.05), triglycerides levels (r = 0.56 and r = 0.77; P < 0.05), and IMT (r = 0.64 and r = 0.56; P < 0.05). Right (r = -0.70; P < 0.005) and left (r = -0.65; P < 0.01) DC were inversely correlated to the duration of CD in the patient group. At the multiple regression analysis, WHR was the best predictor of fasting insulin levels (beta = 0.77; P < 0.05), and vice versa, fasting insulin level was the best predictor of WHR (beta = 1.20; P < 0.05). In conclusion, patients cured from CD for a long term period have a high prevalence of atherosclerosis and maintain increased several cardiovascular risk factors of the active disease, probably due to a residual abdominal obesity and/or insulin resistance syndrome.

Adolescent↗