Pituitary tumours express both somatostatin and dopamine receptors. Medical treatment with somatostatin analogues is a cornerstone of GH- and TSH-secreting tumours, while treatment with dopamine agonists is a cornerstone of prolactin-secreting tumours. Dopamine agonists have also demonstrated some efficacy in patients with GH- and TSH-secreting adenomas. Neither ACTH-secreting nor clinically non-functioning tumours have a well-established medical treatment. Nevertheless, some recent results have indicated a potential usefulness of the dopamine agonist cabergoline in patients with pituitary-dependent Cushing’s disease. Combination treatment with both somatostatin analogues and dopamine agonists has been poorly investigated. Some studies conducted in small series have documented an additive effect of both drugs in patients with GH-secreting adenomas. Of mention is that none of the studies were randomised and cross-sectional so that the results should be confirmed by other well-designed studies. No data are available in other pituitary tumour histotypes. Preliminary observations in patients with clinically non-functioning adenomas are very promising.
Annamaria Colao, Mariagiovanna Filippella, Rosario Pivonello, Carolina Di Somma, Antongiulio Faggiano, and Gaetano Lombardi
Annamaria Colao, Rosario Pivonello, Renata S Auriemma, Mariano Galdiero, Silvia Savastano, and Gaetano Lombardi
To evaluate the efficacy of dose escalation of Octreotide-long-acting repeatable (LAR) up to 40 mg/month we studied 56 newly diagnosed patients with acromegaly (24 women, 32 men; age 20–82 years).
Analytical, observational, open and prospective.
Three months after LAR treatment beginning with a dose of 20 mg /q28d (every 28 days), 24 patients maintained the same dose (Group A), while 32 required a dose of 30 mg/q28d (Group B). The dose was further increased to 40 mg/q28d in 17 out of the 32 patients of Group B for another 12 months (Group C).
After 24 months, serum GH and IGF-I levels decreased by 93.1±8.6% (95% confidence limit (CL) 90.8–95.4%) and 62.7±13.4% (95% CL 59.1–66.3%) respectively. Control of GH and IGF-I levels was achieved in 45 patients (80.3%). Tumor shrinkage after 12 months was 49.8±23%; the relative tumor shrinkage during the second 12 months of treatment was 35.3±13.1% and overall tumor volume was 68.1±16.5% (95% CL 63.7–72.5%). Glucose tolerance impaired in eight patients (14.3%): four in Group A and four in Group C (16.7% vs 36.4%, P=0.39).
The final dose was predicted by the patient's age at diagnosis (t=−2.2; P=0.032) and baseline tumor volume (t=2.1; P=0.043).
An increase of the LAR dose up to 40 mg/q28d in patients resistant to 30 mg/q28d is followed by greater suppression of GH and IGF-I levels and tumor shrinkage without further significant impairment of glucose tolerance when compared with lower doses. These results suggest that a new dosage schedule of 40 mg every 28 days is applied in patients with acromegaly mostly of young age and with bigger tumors who are likely to be poorly responsive to standard doses of Octreotide-LAR.
Annamaria Colao, Rosario Pivonello, Ludovica Francesca Stella Grasso, Renata Simona Auriemma, Mariano Galdiero, Silvia Savastano, and Gaetano Lombardi
The most frequent cause of death in acromegaly is cardiomyopathy.
To evaluate determinants of acromegalic cardiomyopathy.
Observational, open, controlled, retrospective study.
Two hundred and five patients with newly diagnosed active acromegaly (108 women and 97 men; median age 44 years) and 410 non-acromegalic subjects sex- and age-matched with the patients.
Main outcome measures
Left ventricular (LV) mass index (LVMi), transmitral inflow early-to-atrial (E/A) peak velocity ratio, and LV ejection fraction (LVEF) were measured by Doppler echocardiography to determine the prevalence of LV hypertrophy (LVH), diastolic and systolic dysfunction. The role of age, estimated disease duration, body mass index, GH and IGF1 levels, systolic and diastolic blood pressure, lipid profile and glucose tolerance in determining different features of the acromegalic cardiomyopathy was investigated.
Compared with controls, the patients had lower E/A, LVEF, high-density lipoprotein (HDL)-cholesterol levels and higher LVMi, total- and low-density lipoprotein (LDL)-cholesterol, triglycerides, glucose and insulin levels, homeostatic model assessment of insulin resistance (HOMA-R) and HOMA-β. The relative risk to develop mild (odds ratio (OR)=1.67 (1.05–2.66); P=0.027) or severe hypertension (OR=1.58 (1.04–2.32); P=0.027), arrhythmias (OR=4.93 (1.74–15.9); P=0.001), impaired fasting glucose/impaired glucose tolerance (OR=2.65 (1.70–4.13); P<0.0001), diabetes (OR=2.14 (1.34–3.40); P=0.0009), LVH (OR=11.9 (7.4–19.5); P<0.0001), diastolic (OR=3.32 (2.09–5.31); P<0.0001) and systolic dysfunction (OR=14.2 (6.95–32.2); P<0.0001), was higher in acromegaly. The most important predictor of LVH (t=2.4, P=0.02) and systolic dysfunction (t=−2.77, P=0.006) was disease duration and that of diastolic dysfunction was patient's age (t=−3.3, P=0.001). Patients with an estimated disease duration of >10 years had a relative risk to present cardiac complications three times higher than patients with estimated disease duration ≤5 years.
The prevalence of different features of cardiomyopathy is 3.3–14.2 times higher in the acromegalic than in the non-acromegalic population. The major determinant of cardiomyopathy is disease duration.
Alberto Tagliafico, Massimo Calabrese, Giulio Tagliafico, Eugenia Resmini, Carlo Martinoli, Alberto Rebora, Annamaria Colao, Rosario Pivonello, and Diego Ferone
Mammographic density is a strong independent risk factor for breast cancer, whose prevalence in acromegaly is still controversial.
To compare breast density in premenopausal acromegalic patients and controls and to determine whether density correlated with disease duration, GH, and IGF1 levels.
Design, setting and participants
A prospective study involving 30 patients and 60 controls matched for age and body mass index.
A quantitative computer-aided mammographic density estimation (MDEST) and a qualitative blind evaluation by two experienced radiologists using the breast imaging reporting and data system (BI-RADS) was performed. Totally, 60 (acromegaly) and 120 (controls) craniocaudal and mediolateral oblique mammograms were evaluated in both patients and controls.
Main outcome measures
Patients showed a significantly (P<0.01) increased mammographic breast density with both methods (MDEST: 0.33±0.21% and BI-RADS category: 2.81±0.78) in comparison with controls (MDEST: 0.26±0.19% and BI-RADS category: 2.35±0.61). The agreement between the two methods and inter-observer agreement between the two radiologists were excellent (k=0.63 and k=0.85). In patients grouped according to disease activity (17 controlled and 13 uncontrolled) and medical therapy (15 treated and 15 untreated), no differences were found. All these groups had significantly increased mammographic breast density compared with controls (P<0.01).
A positive correlation was found between mammographic breast density, IGF1 values and disease duration (r=0.29 and r=0.39), whereas it was not found with GH (r=−0.02).
Mammographic breast density in premenopausal acromegalic patients is significantly higher than controls and positively correlated with IGF1 and disease duration.
Annamaria Colao, Carolina Di Somma, Teresa Cascella, Rosario Pivonello, Giovanni Vitale, Ludovica F S Grasso, Gaetano Lombardi, and Silvia Savastano
In the general population, low IGF1 has been associated with higher prevalence of cardiovascular disease and mortality.
To investigate the relationships between IGF1 levels, blood pressure (BP), and glucose tolerance (GT).
Four-hundred and four subjects (200 men aged 18–80 years). Exclusion criteria: personal history of pituitary or cardiovascular diseases; previous or current treatments with drugs interfering with BP, GT, or lipids, corticosteroids (>2 weeks), estrogens, or testosterone (>12 weeks); smoking of >15 cigarettes/day and alcohol abuse (>3 glasses of wine/day).
Two hundred and ninety-six had normal BP (73.3%), 86 had mild (21.3%), and 22 had severe (5.4%) hypertension; 322 had normal GT (NGT (79.7%)), 53 had impaired glucose tolerance (IGT (13.1%)), 29 had diabetes mellitus (7.2%). Normotensive subjects had significantly higher IGF1 levels (0.11±0.94 SDS) than those with mild (−0.62±1.16 SDS, P<0.0001) or severe (−1.01±1.07 SDS, P<0.0001) hypertension. IGF1 SDS (t=−3.41, P=0.001) independently predicted systolic and diastolic BP (t=−2.77, P=0.006) values. NGT subjects had significantly higher IGF1 levels (0.13±0.90 SDS) than those with IGT (−0.86±1.14 SDS, P<0.0001) or diabetes mellitus (−1.31±1.13 SDS, P<0.0001). IGF1 SDS independently predicted fasting glucose (t=−3.49, P=0.0005) and homeostatic model assessment (HOMA)-R (t=−2.15, P=0.033) but not insulin (t=−1.92, P=0.055) and HOMA-β (t=−0.19, P=0.85).
IGF1 levels in the low normal range are associated with hypertension and diabetes in subjects without pituitary and cardiovascular diseases.
Carla Giordano, Valentina Guarnotta, Rosario Pivonello, Marco Calogero Amato, Chiara Simeoli, Alessandro Ciresi, Alessia Cozzolino, and Annamaria Colao
Diabetes mellitus (DM) is one of the most frequent complications of Cushing's syndrome (CS). The aim of this study was to define the changes in insulin sensitivity and/or secretion in relation to glucose tolerance categories in newly diagnosed CS patients.
Cross-sectional study on 140 patients with CS.
A total of 113 women (80 with pituitary disease and 33 with adrenal disease, aged 41.7±15.7 years) and 27 men (19 with pituitary disease and eight with adrenal disease, aged 38.1±20.01 years) at diagnosis were divided according to glucose tolerance into normal glucose tolerance (CS/NGT), impaired fasting glucose and/or impaired glucose tolerance (CS/prediabetes), and diabetes (CS/DM) groups.
Seventy-one patients had CS/NGT (49.3%), 26 (18.5%) had CS/prediabetes and 43 (30.8%) had CS/DM. Significant increasing trends in the prevalence of family history of diabetes (P<0.001), metabolic syndrome (P<0.001), age (P<0.001) and waist circumference (P=0.043) and decreasing trends in HOMA-β (P<0.001) and oral disposition index (DIo) (P<0.002) were observed among the groups. No significant trends in fasting insulin levels, area under the curve for insulin (AUCINS), Matsuda index of insulin sensitivity (ISI-Matsuda) and visceral adiposity index were detected.
Impairment of glucose tolerance is characterized by the inability of β-cells to adequately compensate for insulin resistance through increased insulin secretion. Age, genetic predisposition and lifestyle, in combination with the duration and degree of hypercortisolism, strongly contribute to the impairment of glucose tolerance in patients with a natural history of CS. A careful phenotypic evaluation of glucose tolerance defects in patients with CS proves useful for the identification of those at a high risk of metabolic complications.
Annamaria Colao, Silvia Vandeva, Rosario Pivonello, Ludovica Francesca Stella Grasso, Emil Nachev, Renata S Auriemma, Krasimir Kalinov, and Sabina Zacharieva
Mortality in acromegaly strictly depends on optimal control of GH and IGF1 levels. Modern medical therapy with somatostatin analogs (SSAs) and GH receptor antagonists (GHRAs) is not available in many countries due to funding restrictions. This retrospective, comparative, cohort study investigated the impact of different treatment modalities on disease control (GH and IGF1) and mortality in acromegaly patients.
Two cohorts of patients with acromegaly from Bulgaria (n=407) and Campania, Italy (n=220), were compared, and mortality rates were evaluated during a 10-year period (1999–2008).
The major difference in treatment approach between cohorts was the higher utilization of SSAs and GHRAs in Italy, leading to a decreased requirement for radiotherapy. Significantly more Italian than Bulgarian patients had achieved disease control (50.1 vs 39.1%, P=0.005) at the last follow-up. Compared with the general population, the Bulgarian cohort had a decreased life expectancy with a standardized mortality ratio (SMR) of 2.0 (95% CI 1.54–2.47) that was restored to normal in patients with disease control – SMR 1.25 (95% CI 0.68–1.81). Irradiated patients had a higher cerebrovascular mortality – SMR 7.15 (95% CI 2.92–11.37). Internal analysis revealed an independent role of age at diagnosis and last GH value on all-cause mortality and radiotherapy on cerebrovascular mortality. Normal survival rates were observed in the Italian cohort: SMR 0.66 (95% CI 0.27–1.36).
Suboptimal biochemical control was associated with a higher mortality in the Bulgarian cohort. Modern treatment options that induce a strict biochemical control and reduce the necessity of radiotherapy might influence the life expectancy. Other factors, possibly management of comorbidities, could contribute to survival rates.
Renata S Auriemma, Mariano Galdiero, Ludovica F S Grasso, Pasquale Vitale, Alessia Cozzolino, Gaetano Lombardi, Annamaria Colao, and Rosario Pivonello
Somatostatin analogs (SA) are the cornerstone in the medical treatment of acromegaly, used as either primary or adjunctive therapy. In particular, SA are effective in inducing the biochemical remission of the disease and tumor shrinkage, although only few cases of complete disappearance of the pituitary tumor in patients treated with SA as long-acting formulations have been reported. SA withdrawal has been demonstrated to keep safe levels of GH and IGF1 at least in a small subset of patients well responsive to SA, although it is generally followed by disease recurrence after several months.
A 61-year-old female patient bearing a very large GH-secreting pituitary macroadenoma was treated with 12-month lanreotide Autogel (ATG), at the initial dose of 120 mg/28 days. After 3 months, GH and IGF1 levels were fully normalized, to prolong the administration interval from 28 to 56 days. After 6 months of treatment, a significant tumor shrinkage (90% of baseline size) was observed, whereas GH and IGF1 excess was still well controlled. After 12-month therapy, a complete disappearance of the pituitary tumor was observed, and the hormonal evaluation confirmed the complete biochemical remission of acromegaly. Lanreotide ATG treatment was withdrawn. The clinical, biochemical, and radiological remission of acromegaly was maintained 24 months after lanreotide ATG treatment discontinuation, without evidence of disease recurrence.
This report represents an exemplary case of the potentiality of treatment with lanreotide ATG in inducing a complete remission of acromegalic disease, persistent after a long period of time from treatment withdrawal.
Bartolomeo Merola, Salvatore Longobardi, Matteo Sofia, Rosario Pivonello, Assunta Micco, Francesca Di Rella, Vincenzo Esposito, Annamaria Colao, and Gaetano Lombardi
Merola B, Longobardi S, Sofia M, Pivonello R, Micco A, Di Rella F, Esposito V, Colao A, Lombardi G. Lung volumes and respiratory muscle strength in adult patients with childhood- or adult-onset growth hormone deficiency. Effect of 12 months' growth hormone replacement therapy. Eur J Endocrinol 1996;135:553–8. ISSN 0804–4643
We have described impairment of the respiratory function in adult patients with childhood-onset growth hormone (GH) deficiency. The aim of the present study was to evaluate lung volumes and respiratory muscle strength in patients diagnosed as GH deficient before and after 6 and 12 months of recombinant GH treatment. Ten adults diagnosed as GH deficient in childhood, ten adults diagnosed as GH deficient in adulthood and ten healthy subjects entered the study. For each subject, evaluation of respiratory function followed the same standard approach, consisting of respiratory muscle strength assessment, record of flow–volume curves, measurement of static lung volumes and lung diffusing capacity. Childhood-onset GH-deficient patients had a significant reduction of maximal inspiratory (p < 0.01) and maximal expiratory (p < 0.05) mouth pressures. Total lung capacity, vital capacity and functional residual capacity were significantly reduced compared to healthy subjects (p < 0.05). Conversely, residual volume and diffusing lung capacity did not show any significant change. No significant change of the ratio between the percentage forced expiratory volume in 1 s and the forced vital capacity was observed. The decrease of respiratory mouth pressures was not correlated to the decrease of lung volumes. Adult-onset GH-deficient patients had only a significant reduction of maximal expiratory pressure compared to healthy subjects (p < 0.05). After 6 months of treatment no significant differences in any of the evaluated parameters were found. After 12 months of treatment patients with childhood-onset GH deficiency show a significant improvement of lung volumes (p < 0.01) and maximal respiratory mouth pressures (p < 0.005), whereas adult-onset GH-deficient patients show a significant improvement of maximal expiratory pressure (p < 0.05). In conclusion, the results of this study showed that adult patients affected with childhood-onset GH deficiency suffer from an impairment of the ventilatory function due to a reduction of lung volumes and a decrease of respiratory pressures probably due to a reduction of respiratory muscle strength. This impairment was reversed after 12 months of treatment with recombinant GH. Conversely, adult-onset GH-deficient patients had only an impairment of the maximal expiratory pressure, probably due to respiratory muscle weakness re-established after 12 months of GH therapy.
Gaetano Lombardi, Via G. Santacroce 40/a, 80129 Naples, Italy
Cristina L Ronchi, Erica Rizzo, Andrea G Lania, Rosario Pivonello, Silvia Grottoli, Annamaria Colao, Ezio Ghigo, Anna Spada, Maura Arosio, and Paolo Beck-Peccoz
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.
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.
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.
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.