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Maura Arosio, Marina Nissim, Maria Ballabio, Rita Orefice, Nicoletta Bazzoni, and Giovanni Faglia

Abstract.

Circulating GH consists of several molecular size species with different biological activity. A reduced sensitivity of some monoclonal antibodies towards high-molecular weight GH variants has been reported. The aim of the present work was to evaluate the molecular size species of circulating GH using Sephadex G-100 gel filtration chromatography in acromegalic patients and in normal subjects employing both RIA and an immunoradiometric assay for all GH determinations. In 6 normal subjects, studied under GHRH stimulation, little GH was 69.8±6% (mean ±sd), big GH (44 kD) 26.4±6% and big-big GH (>80 kD) 2.8±4%, in IRMA, with a good correspondence with RIA results (70.8±8, 27.0±4, and 3.2±2%, respectively). In 13 untreated acromegalic patients, studied in basal conditions, the little form constituted 76.2±7%, the big form 18.3±4%, which is significantly lower than in normals (p<0.05), and the big-big form 5.5±7%. Similar results were obtained with RIA. A clear elevation of big-big GH (21% for both in IRMA, and 15.7 and 27.8% in RIA) was found in 2 patients with IGF-I levels lower than expected on the basis of mean GH concentrations. The study was extended to an additional acromegalic patient, previously operated and irradiated on, characterized by discrepant serum GH levels in RIA (4.6 μg/l), and in IRMA (1.4 μg/l), and by normal IGF-I levels. Serum GH showed a lack of parallelism to standard GH in RIA, but not in IRMA. RIA immunoreactivity was almost completely composed (92%) of a high molecular weight GH form (>90 kD), not recognized by IRMA. All IRMA immunoreactivity eluted with a Kav corresponding to 19–50 kD. In conclusion: a. the three main molecular size isomers of serum GH are similarly recognized by IRMA and RIA methods in normal subjects. b. in acromegaly, both quantitative and qualitative modifications of the GH chromatographic profile may be present. In particular, increased amounts of big-big forms, whether or not recognized by monoclonal antibodies, have been observed. Their lower bioactivity, suggested by the normal or lower than expected IGF-I levels, can account for the discrepancy between serum GH levels and the clinical picture or IGF-I levels sometimes observed in acromegaly.

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Maura Arosio, Marco Losa, Nicoletta Bazzoni, Domenico Bochicchio, Eva Palmieri, Claudio Nava, and Giovanni Faglia

Abstract.

The influence of β-adrenergic blockade by oral propranolol on the variability of GH responses to GHRH and on GH responsiveness to repeated GHRH administrations was investigated. Eight normal volunteers underwent three tests on three separate occasions. Each test consisted of two administrations of 80 μg GHRH at 2-h intervals without other medication (test 1) or combined with oral administration of 80 mg propranolol 90 min before the first (test 2) or the second GHRH injection (test 3). In test 1 GH levels increased significantly after the first, but not the second GHRH bolus (net incremental area under the curve [nAUC], mean ± sd: 1453 ± 974 and 178 ± 309 μg·l−1·(120 min)−1, respectively). In test 2 basal GH secretion was not influenced by propranolol administration, whereas the GH response to the first GHRH injection was significantly greater than in test 1 (2327 ± 1814 μg·l−1·(120 min)−1; p<0.05). However, individual subjects showed the same variability of GH response as in test 1. The GH response to the second GHRH bolus remained negligible. In test 3 administration of propranolol 90 min before the second GHRH bolus led to a clear GH increase (690±1002 μg·l−1·(120 min)−1), not significantly different from the GH response to the first bolus (1796±1375 μg·l−1·(120 min)−1). However, only 4 subjects showed a marked restoration of the GH responsiveness to the second GHRH administration. In conclusion, oral administration of propranolol is able to increase GH responsiveness to GHRH without changing the great individual variability. The response to a repeated GHRH stimulation is only partially restored by propranolol.

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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

Open access

Giulia Carosi, Alessandra Mangone, Elisa Sala, Giulia Del Sindaco, Roberta Mungari, Arianna Cremaschi, Emanuele Ferrante, Maura Arosio, and Giovanna Mantovani

Objective: high IGF-1 and unsuppressed GH levels after glucose load confirm the diagnosis of acromegaly. Management of patients with conflicting results could be challenging. Our aim was to evaluate the clinical and hormonal evolution over a long follow-up in patients with high IGF-1 but normal GH nadir (GHn<0.4 μg/L according to the latest guidelines).

Design: retrospective cohort study.

Methods: we enrolled 53 patients presenting high IGF-1 and GHn<0.4 μg/L, assessed because of clinical suspicion of acromegaly or in other endocrinological contexts (e.g., pituitary incidentaloma). Clinical and hormonal data collected at the first and last visit were analyzed.

Results: at the first evaluation, the mean age was 54.1±15.4 years, 34/53 were females, median IGF-1 and GHn were +3.1 SDS and 0.06 μg/L, respectively. In the whole group, over a median time of 6 years, IGF-1 and GHn levels did not significantly change (IGF-1 mean of differences -0.58, p=0.15; GHn +0.03, p=0.29). In patients with clinical features of acromegaly, the prevalence of acromegalic comorbidities was higher than in the others (median of 3 vs 1 comorbidities per patient, p=0.005), especially malignancies (36% vs 6%, p=0.03), and the clinical worsening overtime was more pronounced (4 vs 1 comorbidities at the last visit).

Conclusions: in patients presenting high IGF-1 but GHn<0.4 μg/L, a hormonal progression is improbable, likely excluding classical acromegaly on its early stage. However, despite persistently low GH nadir values, patients with acromegalic features present more acromegalic comorbidities whose rate increases over time. Close clinical surveillance in this group is advised.

Free access

Valentina Morelli, Serena Palmieri, Andrea Lania, Alberto Tresoldi, Sabrina Corbetta, Elisa Cairoli, Cristina Eller-Vainicher, Maura Arosio, Massimiliano Copetti, Enzo Grossi, and Iacopo Chiodini

Background

The independent role of mild autonomous cortisol secretion (ACS) in influencing the cardiovascular event (CVE) occurrence is a topic of interest. We investigated the role of mild ACS in the CVE occurrence in patients with adrenal incidentaloma (AI) by standard statistics and artificial neural networks (ANNs).

Methods

We analyzed a retrospective record of 518 AI patients. Data regarding cortisol levels after 1 mg dexamethasone suppression (1 mg DST) and the presence of obesity (OB), hypertension (AH), type-2 diabetes (T2DM), dyslipidemia (DL), familial CVE history, smoking habit and CVE were collected.

Results

The receiver-operating characteristic curve analysis suggested that 1 mg DST, at a cut-off of 1.8 µg/dL, had the best accuracy for detecting patients with increased CVE risk. In patients with 1 mg-DST ≥1.8 µg/dL (DST+, n = 223), age and prevalence of AH, T2DM, DL and CVE (66 years, 74.5, 25.9, 41.4 and 26.8% respectively) were higher than that of patients with 1 mg-DST ≤1.8 µg/dL (61.9 years, 60.7, 18.5, 32.9 and 10%, respectively, P < 0.05 for all). The CVE were associated with DST+ (OR: 2.46, 95% CI: 1.5–4.1, P = 0.01), regardless of T2DM, AH, DL, smoking habit, gender, observation period and age. The presence of at least two among AH, T2DM, DL and OB plus DST+ had 61.1% sensitivity in detecting patients with CVE. By using the variables selected by ANNs (familial CVE history, age, T2DM, AH, DL and DST+) 78.7% sensitivity was reached.

Conclusions

Cortisol after 1 mg-DST is independently associated with the CVE occurrence. The ANNs might help for assessing the CVE risk in AI patients.

Free access

Iacopo Chiodini, Massimo Torlontano, Alfredo Scillitani, Maura Arosio, Simonetta Bacci, Sergio Di Lembo, Paolo Epaminonda, Giovanni Augello, Riccardo Enrini, Bruno Ambrosi, Guido Adda, and Vincenzo Trischitta

Objective: Subclinical hypercortisolism (SH) may play a role in several metabolic disorders, including diabetes. No data are available on the relative prevalence of SH in type 2 diabetes (T2D). In order to compare the prevalence of SH in T2D and matched non-diabetic control individuals, we performed a case-controlled, multicenter, 12-month study, enrolling 294 consecutive T2D inpatients (1.7% dropped out the study) with no evidence of clinical hypercortisolism and 189 consecutive age- and body mass index-matched non-diabetic inpatients (none of whom dropped out).

Design and methods: Ascertained SH (ASH) was diagnosed in individuals (i) with plasma cortisol after 1 mg overnight dexamethasone suppression >1.8 μg/dl (50 nmol/l), (ii) with more than one of the following: (a) urinary free cortisol >60.0 μg/24 h (165.6 nmol/24 h), (b) plasma ACTH <10.0 pg/ml (2.2 pmol/l) or (c) plasma cortisol >7.5 μg/dl (207 nmol/l) at 24:00 h or >1.4 μg/dl (38.6 nmol/l) after dexamethasone-CRH (serum cortisol after corticotrophin-releasing hormone stimulus during dexamethasone administration) test, and (iii) in whom the source of glucocorticoid excess was suggested by imaging and by additional biochemical tests (for ACTH-dependent ASH).

Results: Prevalence of ASH was higher in diabetic individuals than in controls (9.4 versus 2.1%; adjusted odds ratio, 4.8; 95% confidence interval, 1.6–14.1; P = 0.004). In our population the proportion of T2D which is statistically attributable to ASH was approx. 7%. Among diabetic patients, the presence of severe diabetes (as defined by the coexistence of hypertension, dyslipidaemia and insulin treatment) was significantly associated with SH (adjusted odds ratio, 3.8; 95% confidence interval, 1.4–10.2; P = 0.017).

Conclusions: In hospitalized patients, SH is associated with T2D.

Free access

Cristina L Ronchi, Erica Rizzo, Andrea G Lania, Rosario Pivonello, Silvia Grottoli, Annamaria Colao, Ezio Ghigo, Anna Spada, Maura Arosio, and Paolo Beck-Peccoz

Objective

It is still unknown whether prolonged treatment with somatostatin analogs (SSTa) may cause a long-lasting disease remission in GH-secreting adenomas after drug discontinuation. The aim of the present study was to investigate the evolution of GH/IGF-I secretion and tumor mass after SSTa withdrawal in patients affected by acromegaly.

Patients and Design

A total of 27 patients with acromegaly (12 de novo and 15 previously operated) were treated with SSTa for a median period of 48 months and considered optimally controlled in hormonal and neuroradiological terms. None of them were previously irradiated.

Methods

Basal GH, post-glucose GH nadir, IGF-I, clinical signs/symptoms, and metabolic parameters were evaluated after 12–16 weeks from drug withdrawal. Only patients who met the current criteria for disease remission remained in drug suspension being periodically re-evaluated for biochemical/clinical data and neuroradiological imaging.

Results

After 12–16 weeks withdrawal, 15 of the 27 patients had disease relapse and restarted SSTa, while 12 were considered ‘in disease remission’ (44% of total). Glucose metabolism improved in both euglycemic and diabetic patients after short-term SSTa discontinuation. Only one of the ten patients who reached 24 weeks withdrawal showed biochemical disease recurrence. On the whole, five of the patients still in remission after 6 months have already prolonged the follow-up over 12 months (median: 24 months), without clinical and biochemical/neuroradiological evidence of disease recurrence.

Conclusions

These preliminary data indicate a successful withdrawal of SSTa at least in a subset of well-responsive patients with acromegaly and challenge the previously held concept that medical therapy is always a lifelong requirement.

Free access

Cristina L Ronchi, Elisa Verrua, Emanuele Ferrante, Gwendolyn Bender, Elisa Sala, Andrea G Lania, Martin Fassnacht, Paolo Beck-Peccoz, Bruno Allolio, Anna Spada, and Maura Arosio

Objective

Radiation therapy (RT) is a useful adjuvant tool for acromegalic patients not cured by surgery and/or not responding to pharmacotherapy. However, its specific effects on cardio- and cerebrovascular morbidity are still on debate.

Design

Retrospective analysis of 42 acromegalic patients cured after conventional radiotherapy (CRT, n=31) or radiosurgery by gamma-knife (GKRS, n=11) followed for a median period of 16.5 years (range: 2–40). Totally, 56 patients cured by surgery alone, with similar GH/IGF1 levels and duration of disease remission, served as control group.

Methods

Changes in cardiovascular risk factors, such as body mass index, glucose metabolism, insulin resistance, blood pressure, and lipid profile (pre-defined primary end point) and occurrence of new major cardio- and cerebrovascular events (secondary end point) during follow-up.

Results

The number of obese, hypertensive, and dyslipidemic subjects increased over time only in patients cured with RT. In contrast, the glucose response to the oral glucose tolerance test and the percentage of subjects with glucose alterations improved only in controls. As expected, the percentage of patients with pituitary failure was deeply higher among RT patients than among controls (86 vs 30%, P<0.0005). Despite these findings, a similar number of RT patients and controls developed major cardio- or cerebrovascular events (4/42 vs 3/56, P: NS). No differences were found between CRT and GKRS subgroups.

Conclusions

Previous RT seems to be associated with a worse metabolic profile in acromegalic patients studied after a long-term follow-up. Nevertheless, a direct link between RT and cardiovascular events remains to be proven.

Free access

Claudia Giavoli, Eriselda Profka, Noemi Giancola, Giulia Rodari, Federico Giacchetti, Emanuele Ferrante, Maura Arosio, and Giovanna Mantovani

Free access

Cristina Eller-Vainicher, Valentina Morelli, Antonio Stefano Salcuni, Massimo Torlontano, Francesca Coletti, Laura Iorio, Antonello Cuttitta, Angelo Ambrosio, Leonardo Vicentini, Vincenzo Carnevale, Paolo Beck-Peccoz, Maura Arosio, Bruno Ambrosi, Alfredo Scillitani, and Iacopo Chiodini

Objective

Few data are available regarding the need of steroid substitutive therapy after unilateral adrenalectomy for adrenal incidentaloma (AI). It is unknown whether, before surgery, the hypothalamic–pituitary–adrenal (HPA) axis secretion parameters can predict post-surgical hypocortisolism.

Aim

This study aimed to evaluate whether, in AI patients undergoing unilateral adrenalectomy, post-surgical hypocortisolism could be predicted by the parameters of HPA axis function.

Design

Prospective, multicenter.

Methods

A total of 60 patients underwent surgical removal of AI (surgical indication: 29 subclinical hypercortisolism (SH); 31 AI dimension). Before surgery, SH was diagnosed in patients presenting at least three criteria out of urinary free cortisol (UFC) levels>60 μg/24 h, cortisol after 1-mg dexamethasone suppression test (1 mg-DST)>3.0 μg/dl, ACTH levels<10 pg/ml, midnight serum cortisol (MSC)>5.4 μg/dl.

Two months after surgery, HPA axis function was assessed by low dose ACTH stimulation test or insulin tolerance test when needed: 39 patients were affected (Group B) and 21 were not affected (Group A) with hypocortisolism. The accuracy in predicting hypocortisolism of pre-surgical HPA axis parameters or their combinations was evaluated.

Results

The presence of >2 alterations among 1 mg-DST>5.0 μg/dl, ACTH<10 pg/ml, elevated UFC and MSC has the highest odds ratio (OR) for predicting post-surgical hypocortisolism (OR 10.45, 95% confidence interval, CI 2.54–42.95, P=0.001). Post-surgical hypocortisolism was predicted with 100% probability by elevated UFC plus MSC levels, but not ruled out even in the presence of the normality of all HPA axis parameters.

Conclusion

Post-surgical hypocortisolism cannot be pre-surgically ruled out. A steroid substitutive therapy is indicated after unilateral adrenalectomy for SH or size of the adenoma.