OBJECTIVE: As circulating chromogranin A (CgA) has been claimed to be the best general neuroendocrine marker so far available, we evaluated the usefulness of CgA determination in the clinical assessment of patients with sporadic gastro-entero-pancreatic neuroendocrine tumors (GEP NETs) or multiple endocrine neoplasia type 1 (MEN 1). DESIGN AND METHODS: Plasma CgA levels were measured using a commercial enzyme-linked immunosorbent assay in 61 patients with sporadic GEP NET and in 25 with MEN 1 including 16 with GEP NET. Controls were 50 healthy volunteers, 46 patients with pituitary adenoma and 35 patients with primary hyperparathyroidism. RESULTS: The cutoff value for CgA established in our healthy subjects (as mean+2 s.d.) was 20 U/l. CgA levels were above the normal range in 71/77 patients with sporadic or MEN 1-related GEP NETs (92%), in four out of nine MEN 1 patients without GEP NETs (44%), and only in 22/81 control patients with pituitary or parathyroid disease (27%). Furthermore, CgA levels of over 100 U/l occurred in 36/77 patients with GEP NETs (47%) and only in one patient with a non-functioning pituitary adenoma. In the patients with GEP NETs, both tumor burden and secretory activity affected CgA levels, and successful surgical resection was associated with markedly decreased CgA values. CONCLUSIONS: Plasma CgA was confirmed to be a reliable marker for GEP NETs. Moreover, in MEN 1 patients the finding of very high CgA levels strongly suggests the presence of a GEP NET, as both primary hyperparathyroidism and pituitary adenomas rarely cause marked CgA increases.
M Peracchi, D Conte, C Gebbia, C Penati, S Pizzinelli, M Arosio, S Corbetta and A Spada
M Peracchi, S Porretti, C Gebbia, C Pagliari, P Bucciarelli, P Epaminonda, S Manenti and M Arosio
OBJECTIVE: Acromegaly is often associated with fasting and postprandial hyperinsulinemia, and the mechanisms involved are only partly understood. Hypersecretion of incretins such as glucose-dependent insulinotropic polypeptide (GIP) could play a role in determining hyperinsulinemia in acromegaly, but the available data are inconsistent. The aim of this study was to characterize the fasting and postprandial pattern of plasma GIP and insulin in a group of acromegalic patients. DESIGN AND METHODS: Eleven non-diabetic patients with newly diagnosed acromegaly and 11 sex- and age-matched healthy subjects were studied. Blood samples were taken at regular intervals in fasting conditions and for 3 h after a standard solid-liquid meal for growth hormone (GH), GIP and insulin measurements. RESULTS: Not only insulin, but also fasting and postprandial GIP levels were significantly higher in the patients with acromegaly than the healthy subjects (P<0.01). In the former group fasting GIP levels and the integrated GIP response to the meal correlated significantly with GH basal levels (r=0.83, P<0.01 and r=0.65, P<0.05, respectively). Moreover, multivariate linear regression analysis showed that the presence of acromegalic status was associated with higher fasting and postprandial GIP levels independently of sex, age, fasting and postprandial plasma glucose and insulin levels, and the occurrence of normal or impaired glucose tolerance. CONCLUSION: This study provides evidence that in patients with acromegaly fasting and postprandial GIP levels are abnormally high. GIP hypersecretion in turn might play a role in the pathogenesis of hyperinsulinemia that characterizes acromegaly.
V Cappiello, C Ronchi, PS Morpurgo, P Epaminonda, M Arosio, P Beck-Peccoz and A Spada
BACKGROUND: Ghrelin exerts a wide range of metabolic functions. In contrast to the body of information accumulated on the role of ghrelin on energy balance, the possible relevance of the peptide on GH secretion in physiological and pathological conditions has so far been poorly investigated. AIM: The aim of the present study was to evaluate circulating ghrelin levels in acromegalic patients in basal conditions and in response to oral glucose tolerance test (OGTT). PATIENTS: Serum ghrelin, insulin and leptin levels were measured in 31 healthy normal weight subjects as controls, 25 patients with simple obesity and 17 non-diabetic acromegalic patients. Ghrelin and insulin response to OGTT was evaluated in six controls, four obese and six acromegalic patients. RESULTS: The acromegalic patients showed ghrelin levels lower than those observed in normal weight subjects (201+/-20 vs 329+/-32 pmol/l, P<0.05) and similar to those found in obese subjects (165+/-14 pmol/l, P=not significant). Both obese and acromegalic patients had insulin levels significantly higher than controls, while high levels of leptin were detected only in obese subjects. Serum ghrelin levels showed a significant negative correlation with insulin, leptin and body mass index (P<0.05) in normal and obese subjects. No correlation was observed in acromegalic patients, although those with severe insulin resistance showed the lowest ghrelin values (161+/-20 pmol/l). In controls and obese subjects, ghrelin levels showed a significant decrease (25-40%) during OGTT, while no effect was detectable in acromegalic patients. CONCLUSIONS: This study reports that patients with active acromegaly show low levels of circulating ghrelin that are not further reduced by OGTT, this pattern of secretion probably depending on both GH-induced insulin resistance and the putative GH/IGF-I negative feedback control on ghrelin secretion.
Maura Arosio, Sonia Macchelli, Cristina M Rossi, Giovanni Casati, Orietta Biella and Giovanni Faglia
Arosio M, Macchelli S, Rossi CM, Casati G, Biella 0, Faglia G, the Italian Multicenter Octreotide Study Group. Effects of treatment with octreotide in acromegalic patients—a multicenter Italian study. Eur J Endocrinol 1995:133:430–9. ISSN 0804–4643
Treatment of acromegaly is effective in reversing the reduced life-span of patients only when serum growth hormone (GH) concentrations are lowered to less than 2.5 μg/l. Usual treatments achieve this goal in no more than 50–60% of patients. The effects of octreotide were studied in a prospective, open label study with 68 acromegalic patients enrolled in 10 Italian centers. Octreotide was administered sc at a dose of 100 μg t.i.d. for 1 year. After 3 months of therapy, octreotide was effective in decreasing serum GH levels below 2.5 μg/l in 16 out of 64 acromegalic patients (25%). Fifteen of them had pretreatment GH levels below 25 μg/l. Insulin-like growth factor I (IGF-I) levels normalized in about 40% of patients. No further GH reduction was observed after 1 year of treatment. The presence of abnormal GH responses to thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone was reduced from 54 to 24% and from 16 to 12%, respectively. Tumor shrinkage was observed in 50% of 26 non-irradiated patients after 12 months of treatment. Both basal and TRH-stimulated serum prolactin levels significantly decreased in the 11 hyperprolactinemic patients. Although serum thyrotropin, free triiodothyronine and free thyroxine concentrations were not modified, a significant reduction of thyrotropin response to TRH was observed in the 9th month of therapy. In non-diabetic patients, an increase of mean blood glucose levels without modifications of fasting morning concentrations was found. About one-quarter of the patients with overt diabetes mellitus had an impairment of their metabolic control. Main clinical symptoms of acromegaly improved in 70–80% of patients. An 18% decrease of low-density-lipoprotein cholesterol and unchanged high-densitylipoprotein cholesterol levels were observed in 35 patients studied. Triglyceride levels decreased in patients with hypertriglyceridemia pretreatment. Regarding side effects, gallstones were newly diagnosed in five patients, three patients dropped out because of severe diarrhea and two diabetic patients dropped out due to worsening of their metabolic control. In conclusion, octreotide is an effective treatment of acromegaly, mainly in patients with moderate elevation of serum GH levels. The drug has also been proved to positively affect dyslipidemia.
Maura Arosio, Institute of Endocrine Sciences, Ospedale Maggiore IRCCS, Pad. Granelli, Via F Sforza 35, 20122 Milano, Italy
CL Ronchi, S Corbetta, V Cappiello, PS Morpurgo, C Giavoli, P Beck-Peccoz, M Arosio and A Spada
OBJECTIVE: Adiponectin (ApN) is an adipocytokine expressed in human adipose cells with anti-atherogenic and anti-inflammatory properties that plays a role in the pathophysiology of insulin resistance, metabolic syndrome and coronary artery disease. The aim of the study was to evaluate ApN secretion in patients with acromegaly, a chronic disease associated with insulin resistance and increased cardiovascular mortality, and to correlate ApN levels with hormonal, metabolic and cardiovascular parameters. DESIGN AND METHODS: The study included 32 patients with active acromegaly (11 male and 21 female, aged 48+/-11 years, duration of disease: 8+/-6 years, GH: 9.2+/-9.8 microg/l, IGF-I: 80+/-33 nmol/l (means+/-s.d.)) and 38 control subjects sex- and body mass index (BMI)-matched. In all subjects, serum ApN, leptin and ghrelin levels, BMI, waist circumference, insulin resistance (assessed by homeostasis model assessment and the quantitative insulin check index), lipid profile and blood pressure values were evaluated. RESULTS: Acromegalic patients and control subjects had similar ApN levels (9.4+/-3.5 vs 9.5+/-4.0 mg/l, NS), while when considering obese subjects acromegalic patients had ApN levels significantly higher than controls (10.2+/-4 vs 7.5+/-3 mg/l, P<0.05). No significant correlation between ApN and GH/IGF-I levels or duration of disease was found. ApN concentrations negatively correlated with BMI, waist circumference, glucose and diastolic blood pressure and positively with high-density lipoprotein cholesterol and ghrelin in controls, while all these correlations were lost in acromegalic patients. CONCLUSIONS: We provide evidence that, although metabolic and cardiovascular abnormalities are present in most acromegalic patients, in these subjects ApN levels are not reduced and, contrary to what is found in BMI-matched controls, do not correlate with cardiovascular risk factors. These data support the view that atherosclerosis is not the main determinant of cardiovascular mortality in acromegaly and suggest a permissive action of GH and/or IGF-I excess on ApN secretion.
C Giavoli, E Profka, E Sala, M Filopanti, A M Barbieri, S Bergamaschi, E Ferrante, M Arosio, B Ambrosi, A G Lania, A Spada and P Beck-Peccoz
A polymorphism in the promoter region of the IGF1 gene has been linked to serum IGF1 levels, risk of diabetes, and cardiovascular diseases with conflicting results. The aim of this study was to investigate the impact of this polymorphism on the short-term (1 year, n=98) and long-term (5 years, n=50) metabolic response to recombinant human GH (rhGH) in GH-deficient (GHD) adults.
Design and methods
Prospective study on GHD adults. Different genotypes were studied by microsatellite method. According to the most frequent 192 bp allele (19 cytosine–adenosine-repeats), subjects were divided into homozygous (19/19), heterozygous (19/X), and noncarriers (X/X).
Basal characteristics of patients as well as their response to rhGH in terms of decrease in body fat percentage and increase in IGF1 levels were not different in the three genotype-groups. Conversely, after 1-year rhGH, a significant worsening of insulin sensitivity (i.e. increase in fasting glucose levels and homeostasis model assessment of insulin resistance) and a significant improvement in lipid profile (i.e. reduction in total cholesterol and LDL-cholesterol) were recorded only in homozygous subjects. In the long-term, insulin sensitivity was restored in all the patients, while a significant improvement in lipid profile was observed in homozygous and heterozygous subjects, but not in noncarrier subjects. No difference in rhGH dose among groups was recorded throughout the study.
In GHD adults, the presence of the WT allele in the IGF1 gene promoter may enhance sensitivity to either negative or positive metabolic changes induced by rhGH.
M Arosio, CL Ronchi, C Gebbia, S Pizzinelli, D Conte, V Cappiello, P Epaminonda, BM Cesana, P Beck-Peccoz and M Peracchi
OBJECTIVE: Ghrelin, a gut-brain peptide involved in the control of energy homeostasis, affects antero-pituitary and gastro-entero-pancreatic (GEP) hormone secretion in healthy subjects. We aimed to verify whether such hormonal responses are retained in acromegaly, a disease characterized by high GH, subnormal ghrelin and abnormal GEP hormone levels. DESIGN AND METHODS: The effect of ghrelin (3.3 microg/kg given after overnight fasting as an i.v. bolus) on GH, prolactin (PRL), adrenocorticotropin (ACTH), cortisol, insulin, glucose, total somatostatin (SS) and pancreatic polypeptide (PP) circulating levels were evaluated in seven non-diabetic patients with newly diagnosed acromegaly and in nine healthy controls. RESULTS: Ghrelin elicited a prompt, marked increase of serum GH and PRL levels in all normal (from 1.6+/-0.6 to 52.9+/-7.8 and from 9.7+/-0.8 to 24.2+/-4.8 microg/l (means+/-S.E.M.), respectively) and acromegalic subjects (from 11.2+/-4.9 to 91.6+/-21.0 and from 42.9+/-26.1 to 113.8+/-79.0 microg/l, respectively). Both plasma ACTH and serum cortisol levels rose significantly in the controls, whereas the cortisol response was blunted in the acromegalic patients. Glucose levels rose earlier and insulin levels fell later in all subjects, with a significantly greater net insulin decrease in acromegalic than in healthy subjects (-80+/-21 vs -17+/-4 pmol/l, P<0.01). A prompt PP rise and a biphasic SS response occurred in all controls, whereas in the acromegalic group the PP response (from 26.1+/-5.0 to 92.2+/-39.0 pmol/l) and the SS response (from 11.9+/-3.0 to 19.7+/-4.0 ng/l) were quite variable. CONCLUSIONS: Ghrelin affects both pituitary and GEP hormones in acromegalic patients as in normal subjects. These findings suggest that ghrelin actions on the energy balance are mediated by complex interactive endocrine loops that involve also the gut and pancreas.
MM Ciulla, P Epaminonda, R Paliotti, MV Barelli, C Ronchi, V Cappiello, A Sartorio, V Buonamici, F Magrini, P Beck-Peccoz and M Arosio
OBJECTIVES: Cardiac echoreflectivity is a noninvasive tool for evaluating cardiac fibrosis. The present paper aimed to study the modifications of cardiac echoreflectivity in a group of acromegalic patients before and after therapy, and to assess possible correlations with serum levels of procollagen III (PIIINP), a peripheral index of collagen synthesis. DESIGN AND METHODS: Cardiac echoreflectivity (as assessed by analyzing 2-D echocardiograms digitized off-line onto a personal computer) and PIIINP levels were evaluated in 16 acromegalic patients of new diagnosis not affected by arterial hypertension (10 males, six females, age+/-s.d.: 38+/-10 years), and in a group of 16 sex- and age-matched healthy subjects. All the patients were re-evaluated after surgical and/or medical therapy for acromegaly. The echo patterns were analyzed by software that supplies the derived collagen volume fraction (dCVF), an index of fibrosis. RESULTS: At baseline, acromegalic patients showed significantly higher dCVF values and PIIINP levels than healthy controls (3.1+/-0.5% vs 1.6+/-0.3%, P<0.01 and 8.7+/-2.2 vs 3.1+/-1.1 ng/ml, P<0.05, respectively, by unpaired Student's t-test). After therapy, dCVF and PIIINP levels normalized in the six controlled patients (that is, GH of <2.5 microg/l and IGF-I within normal range) (dCVF from 2.8+/-0.4% to 1.4+/-0.2%, P<0.001; PIIINP from 8+/-2.7 to 3.3+/-1.9 ng/ml, P<0.05), while no significant changes were found in noncontrolled patients (dCVF from 3.3+/-0.6% to 2.9+/-1.2% and PIIINP from 9.1+/-1.9 to 7.9+/-3.5 ng/ml, P=NS). A positive correlation between dCVF and PIIINP (r=0.75, P<0.001) and between IGF-I and both dCVF and PIIINP (r=0.65 and 0.61 respectively, P<0.05) was found in acromegalic patients. CONCLUSIONS: Cardiac echoreflectivity, which may be a reflection of heart collagen content, is increased in patients with active acromegaly and correlates with PIIINP concentrations. After cure or adequate control of the disease, both parameters revert to normal. Echoreflectivity analysis could be a useful adjuvant parameter in the assessment of the activity of acromegalic disease.
B Ambrosi, C Dall'Asta, S Cannavo, R Libe, T Vigo, P Epaminonda, I Chiodini, S Ferrero, F Trimarchi, M Arosio and P Beck-Peccoz
OBJECTIVE: Rosiglitazone, a thiazolidinedione compound with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-binding affinity, is able to suppress adrenocorticotropic hormone (ACTH) secretion in treated mice and in AtT20 pituitary tumor cells. These observations suggested that thiazolidinediones may be effective as therapy for Cushing's disease (CD). PATIENTS AND METHODS: Rosiglitazone (8 mg/day) was administered to 14 patients with active CD (13 women, one man, 18-68 years). Plasma ACTH, serum cortisol (F) and urinary free cortisol (UFC) levels were measured before and then monthly during rosiglitazone administration. RESULTS: In six patients a reduction of ACTH and F levels and a normalization of UFC were observed 30-60 days after the beginning of rosiglitazone administration: there was a significant difference between basal and post-treatment values for UFC (1238+/-211 vs 154+/-40 nmol/24 h, P<0.03), but not for ACTH (15.9+/-3.7 vs 7.9+/-0.9 pmol/l) and F levels (531+/-73 vs 344+/-58 nmol/l). Two of six cases, followed up for 7 months, showed a mild clinical improvement. Eight patients were nonresponders after 30-60 days of rosiglitazone treatment: their ACTH, F and UFC levels did not differ before and during drug administration. Immunohistochemical analysis of pituitary tumors removed from two responder and two nonresponder patients showed a similar intense immunoreactivity for PPAR-gamma in about 50% of cells. CONCLUSIONS: The administration of rosiglitazone seems able to normalize cortisol secretion in some patients with CD, at least for short periods. Whether the activation of PPAR-gamma by rosiglitazone might be effective as chronic pharmacologic treatment of CD needs a more extensive investigation through a randomized and controlled study.
A Toini, A Dolci, E Ferrante, E Verrua, E Malchiodi, E Sala, A G Lania, I Chiodini, P Beck-Peccoz, M Arosio, A Spada and G Mantovani
Pituitary incidentalomas (PIs) are commonly encountered in clinical practice. The management of these asymptomatic pituitary lesions is still controversial. Systematic screening for subclinical or mild ACTH-dependent hypercortisolism (AH) is not presently recommended, due to the limited data available thus far on the epidemiological and clinical relevance of this condition in patients with PIs. As subclinical hypercortisolism (SH) was considered to be associated with chronic complications of overt cortisol excess, such as hypertension, diabetes, and osteoporosis, this disorder should be diagnosed at the early stage.
The objective of this study was to evaluate the prevalence of hypercortisolism in a population of subjects with PIs.
Design, subjects, and methods
A total of 68 consecutive patients (48 females and 20 males, aged 18–82 years) without clinically overt hypercortisolism, who were referred for evaluation of PIs between January 2010 and March 2013, were prospectively investigated for AH. Pituitary hypercortisolism was diagnosed in the presence of cortisol >50 nmol/l after 1 mg dexamethasone suppression test, non-suppressed ACTH, and the additional finding of one of the following: urinary free cortisol (UFC) >193 nmol/24 h, and midnight serum and salivary cortisol levels >207 and 2.8 nmol/l respectively.
Among patients with PIs, we found a 7.3% rate of pituitary hypercortisolism diagnosed with biochemical criteria and a 4.4% rate of histologically confirmed AH.
Subclinical or mild hypercortisolism may be more common than generally perceived in patients with PIs.