Search

Objective: This study aimed to assess the long-term outcome of patients with acromegaly. Design: This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up. Methods: Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population. Results: A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4–2.0, p< 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1–1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population. Conclusions: Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

In 2007, we published an opinion document to review the role of pegvisomant (PEG) in the treatment of acromegaly. Since then, new evidence emerged on the biochemical and clinical effects of PEG and on its long-term efficacy and safety. We here reviewed the emerging aspects of the use of PEG in clinical practice in the light of the most recent literature. The clinical use of PEG is still suboptimal, considering that it remains the most powerful tool to control IGF-I in acromegaly allowing to obtain, with a pharmacological treatment, the most important clinical effects in terms of signs and symptoms, quality of life and comorbidities. The number of patients with acromegaly exposed to PEG worldwide has become quite elevated and the prolonged follow-up allows now to deal quite satisfactorily with many clinical issues including major safety issues, such as the concerns about possible tumour (re)growth under PEG. The positive or neutral impact of PEG on glucose metabolism has been highlighted, and the clinical experience, although limited, with sleep apnoea and pregnancy has been reviewed. Finally, the current concept of somatostatin receptor ligands (SRL) resistance has been addressed, in order to better define the acromegaly patients to whom the PEG option may be offered. PEG increasingly appears to be an effective and safe medical option for many patients not controlled by SRL but its use still needs to be optimized.

ARMC5mutations have recently been identified as a common genetic cause of primary bilateral macronodular adrenal hyperplasia (PBMAH). We aimed to assess the prevalence of ARMC5germline mutations and correlate genotype with phenotype in a large cohort of PBMAH patients. A multicenter study was performed, collecting patients from different endocrinology units in Italy. Seventy-one PBMAH patients were screened for small mutations and large rearrangements in the ARMC5gene: 53 were cortisol-secreting (two with a family history of adrenal hyperplasia) and 18 were non-secreting cases of PBMAH. Non-mutated and mutated patients’ clinical phenotypes were compared and related to the type of mutation. A likely causative germline ARMC5mutation was only identified in cortisol-secreting PBMAH patients (one with a family history of adrenal hyperplasia and ten apparently sporadic cases). Screening in eight first-degree relatives of three index cases revealed four carriers of an ARMC5mutation. Evidence of a second hit at somatic level was identified in five nodules. Mutated patients had higher cortisol levels (p= 0.062), and more severe hypertension and diabetes (p< 0.05). Adrenal glands were significantly larger, with a multinodular phenotype, in the mutant group (p< 0.01). No correlation emerged between type of mutation and clinical parameters. ARMC5mutations are frequent in cortisol-secreting PBMAH and seem to be associated with a particular pattern of the adrenal masses. Their identification may have implications for the clinical care of PBMAH cases and their relatives.

This multicentric study aimed to investigate the prevalence of the G protein-coupled receptor 101 (GPR101)p.E308D variant and aryl hydrocarbon receptor interacting protein (AIP)gene mutations in a representative cohort of Italian patients with acromegaly. 215 patients with GH-secreting pituitary adenomas, referred to 4 Italian referral centres for pituitary diseases, have been included. Three cases of gigantism were present. Five cases were classified as FIPA. All the patients have been screened for germline AIPgene mutations and GPR101gene p.E308D variant. Heterozygous AIPgene variants have been found in 7 patients (3.2 %). Five patients carried an AIPmutation (2.3 %; 4 females): 3 patients harboured the p.R3O4Q mutation, one had the p.R304* mutation and the last one the IVS3+1G>A mutation. The prevalence of AIPmutations was 3.3 % and 2.8 % when considering only the patients diagnosed when they were <30 or <40-year old, respectively. Furthermore, 2.0 % of the patients with a pituitary macroadenoma and 4.2 % of patients resistant to somatostatin analogues treatment were found to harbour an AIPgene mutation. None of the patients was found to carry the GPR101p.E308D variant. The prevalence of AIPgene mutations among our sporadic and familial acromegaly cases was similar to that one reported in previous studies, but lower when considering only the cases diagnosed before 40 years of age. The GPR101 p.E308D change is unlikely to have a role in somatotroph adenomas tumorigenesis, since none of our sporadic or familial patients tested positive for this variant.

Context:An increased prevalence of acromegaly was found some years ago in a highly polluted area in North-Eastern Sicily, where high concentration of nonmethane hydrocarbons, volatile organic compounds, and cadmium was found. Aryl hydrocarbon receptor (AHR) pathway has a key role in detoxification of these compounds and in tumorigenesis.Objective:We correlated the occurrence of AHRand/or AHR-interacting protein (AIP) gene variants with acromegaly severity according to pollution exposition.Design, Setting, and Patients:This was an observational, perspective study conducted over 7 years in four Italian referral centers for pituitary diseases in which 210 patients with acromegaly were enrolled between 2008 and 2015.Interventions:Genetic screening of patients for AHRand AIPvariants.Main Outcome Measures:Clinical, biochemical, and radiological data of patients with and without AIPand/or AHRgene variants, living in polluted (high-risk for health, [HR]) or nonpolluted (NP) areas of five Italian regions were evaluated and compared.Results:Among the 23 patients from HR areas, nine showed AHRor AIPvariants. Mean IGF-I levels and pituitary tumor diameter were significantly higher in these nine patients (HR/VAR+) than in the other 14 (HR/VAR−) and in the 187 from NP areas (44 NP/VAR+). Somatostatin analogs significantly decreased mean GH and IGF-I levels in patients from NP areas and in HR/VAR−(GH P< .05; IGF-I times the upper limit of normal P< .01) but not in HR/VAR+group.Conclusions:Genetic variants potentially inducing functional abnormalities of the aryl hydrocarbon receptor (AHR) pathway are associated with a more severe acromegaly, increased pituitary tumor size, and somatostatin analog resistance in patients living in HR areas.

In 2007 the Italian COM.E.T.A. (COMorbidities Evaluation and Treatment in Acromegaly) study group started to assess the application in a clinical setting of the Versailles criteria for management of acromegaly complications by a first questionnaire focusing on cardiovascular co-morbidities. A further questionnaire on sleep apnea syndrome (SAS) was delivered by the COM.E.T.A. study group to 107 endocrine centers in Italy. The results of our survey suggest that SAS is a well-known comorbidity even if its estimated prevalence is lower than in the literature. Polysomnography is the preferred tool for diagnosis. Control of SAS is considered relevant both for quality of life and co-morbidities. Continuous positive airway pressure is the cornerstone of therapy, but patients’ acceptance may be critical. Control of GH/IGF-I secretion is important to improve SAS. Management of SAS requires cooperation between specialists.

Background: Mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene have been described in about 15% of kindreds with familial isolated pituitary adenomas and in a minority of early onset sporadic pituitary adenomas (PA). Among the AIPmutations reported so far, the R304X (AIPR304X) represents, together with the “Finnish mutation” Q14X, the most common one. Methods: Three AIPR304XItalian families, including a newly reported kindred, have been genotyped for 12 genetic markers surrounding the AIPgene in order to look for a potential founder effect in Italy. Disease penetrance and genotype-phenotype correlations were also addressed. Results: Analysis of chromosome 11′ genetic markers revealed a common haplotype in 2 AIPR304Xkindreds originating from central Italy. Overall, 17 mutations carriers were identified, including 7 patients and 10 unaffected subjects, respectively, arguing in this case for a disease penetrance of 41%. Mean age at diagnosis was 19.1±6.7 yr old, with females tending to be older than males. Though most PA were somatotropinomas (6/7), a great variability in disease severity was observed, even between subjects sharing the same at-risk haplotype. Conclusion: These data provide strong evidence for a new founder effect of the AIPR304Xmutation in central Italy and the observed variations in disease severity point out the role of additional genetic or environmental factors in such kindreds.

Background: During the course of acromegaly, cardiovascular, respiratory, and metabolic co-morbidities contribute to enhanced mortality. In 2002, the Pituitary Society and the European Neuroendocrine Association sponsored a Consensus Workshop in Versailles during which guidelines for diagnosis and treatment of co-morbidities in acromegaly were defined. However, as for other guidelines previously issued in the field, no data are available on their clinical application. Aim: The aim of this work coordinated by the Italian Study group on co-morbidities evaluation and treatment in acromegaly (COM.E.T.A.) was to assess, on a national basis, the application in the clinical practice of the Versailles criteria for diagnosis and treatment of cardiovascular comorbities in acromegaly. Materials and methods: In January 2007 an ad hocdesigned questionnaire was sent by mail to 130 endocrine Centers in Italy. Results: The guidelines have been generally well perceived and translated in clinical practice. Specifically: 1) echocardiography is considered the mainstay for the diagnosis and follow-up; 2) ambulatory blood pressure monitoring and blood lipid assessment are performed in most hypertensive patients; 3) most endocrinologists directly manage hypertension and are aware of the uncertainty of the effect of the control of the disease on blood pressure levels; 4) ACE inhibitors and angiotensin receptors blockers are first-choice anti-hypertensive treatment; 5) approximately half of the centers consider somatostatin analogues of paramount relevance for biochemical control of disease; 6) awareness that left ventricular hypertrophy and heart failure are the most relevant cardiovascular complications is high although the impact of ischemic, arrhythmic, and valvular complications on prognosis is less well perceived. Conclusion: The results of the present survey suggest that previuosly issued guidelines are generally carefully followed in the clinical practice. On the other side, a certain lack of awareness of emerging aspects of the cardiovascular comorbities of acromegaly confirms the necessity of periodically updating the guidelines based on the availability of new clinical information.

Acromegaly is associated with a greater morbidity and higher incidence of tumors, possibly due to the permissive role of elevated GH and IGF-I levels. In the general population, adrenal masses are frequently discovered (prevalence 1–5%) at computed tomography (CT). We evaluated the prevalence of adrenal lesions in patients with acromegaly. We studied 94 acromegalic patients, 54 females (mean age 55.0±16.0 yr) and 40 males (mean age 50±14 yr) referred to 5 Endocrinology Units between 2001–2003; 49 had active disease and 45 had been treated with surgery and/or were controlled with medical therapy. Abdominal CT showed adrenal lesions in 27 patients; 9 of them had unilateral masses (10%) with benign features (diameter 0.5–3 cm) and 18 had hyperplasia (14 monolateral and 4 bilateral), with no significant differences between patients with active vscontrolled disease, and with no correlation between prevalence of masses and duration of disease, GH and IGF-I levels. Hormone study (urinary free cortisol, catecholamines/metanephrines, upright plasma renin activity and aldosterone, morning plasma ACTH and low-dose dexamethasone suppression test) disclosed no major endocrine alterations. During a 1-yr follow-up, the adrenal masses increased in size in 3 cases and 1 patient also developed subclinical Cushing’s syndrome. Adrenal lesions seem more frequent in acromegaly than in the general population, but no single factor (GH/IGF-I levels or disease duration) predicts them. The masses appear to be benign and non-hypersecreting, but a longer follow-up is recommended to disclose any changes in their morphofunctional state

Anorexia nervosa (AN) is a psychosomatic disorder characterized by an alteration in body image, resulting in eating abnormalities that lead to malnutrition associated with secondary endocrinological disturbances. AN is associated with high levels of GH and low levels of IGF-I, suggestive of a nutritionally acquired lack of GH action or GH resistance and of an unbalanced hypothalamic GH neuroregulation with GHRH prevalence on SS tone. In this clinical report, we describe the development of acromegaly in a patient affected by AN and we discuss pathogenetic and diagnostic implications.

OBJECTIVE: Since Cushing's disease due to large pituitary tumors is rare, we evaluated biochemical characteristics at entry and the results of first surgical approach and of adjuvant therapeutic strategies during a long-term follow-up period. DESIGN: We studied 26 patients (nine male, 17 female; 42.5+/-12.7 years, mean+/-s.e.) with ACTH-secreting pituitary macroadenoma (tumor diameter: 11-40 mm). METHODS: At entry, plasma ACTH, serum cortisol and 24-h urinary free cortisol (UFC) levels were measured in all patients, a high-dose dexamethasone (dexa) suppression test was evaluated in 22 cases and a corticotrophin releasing hormone (CRH) test in 20 cases. Patients were re-evaluated after operation and, when not cured, they underwent second surgery, radiotherapy and/or ketoconazole treatment. The follow-up period was 78+/-10 months. RESULTS: Before surgery, dexa decreased ACTH (>50% of baseline) in only 14/22 patients. The CRH-stimulated ACTH/cortisol response was normal in six patients, impaired in six patients and exaggerated in eight patients. After operation eight patients were cured, nine had normalized cortisol levels and nine were not cured. Pre-surgery, mean ACTH values were significantly higher in the not cured patients than in those normalized (P<0.05) and cured (P<0.01); the ACTH response to CRH was impaired in only six patients of the not cured group. The tumour diameter was significantly less in cured patients (P<0.02) and in normalized patients (P<0.05) than in the not cured ones. Magnetic resonance imaging (MRI) showed invasion of the cavernous sinus in 2/9 normalized, and in 6/9 not cured patients. After surgery, ACTH, cortisol and UFC were significantly lower than at entry in cured and in normalized patients, but not in not cured patients. In the cured group, the disease recurred in one patient who was unsuccessfully treated with ketoconazole. In the normalized group, a relapse occurred in eight patients: radiotherapy and ketoconazole induced cortisol normalization in one case, hypoadrenalism in one case and were ineffective in another one, while five patients were lost at follow-up. In the not cured group, eight patients underwent second surgery, radiotherapy and/or ketoconazole, while one patient was lost at follow-up. These therapies induced cortisol normalization in two patients and hypoadrenalism in one. CONCLUSIONS: (i) A sub-set of patients with ACTH-secreting pituitary macroadenoma showed low sensitivity to high doses of dexamethasone and to CRH, (ii) pituitary surgery cured Cushing's disease in a minority of patients, (iii) high baseline ACTH levels, impaired ACTH response to CRH, increased tumor size or invasion of the cavernous sinus were unfavourable prognostic factors for surgical therapy, and (iv) second surgery, radiotherapy and/or ketaconazole cured or normalized hypercortisolism in half of the patients with recurrence or not cured.

Somatostatin receptors are highly expressed in almost all meningiomas but in this setting their functional role is not clear. A 59-yrold woman had been treated with octreotide after an unsuccessful operation for a GH-secreting pituitary adenoma. After 8 yr of treatment, a nuclear magnetic resonance (NMR) scan disclosed a 3 cm meningioma of the tentorium. Mean GH was 2.2 ng/ml and IGF-I 325 ng/ml. Meningioma was resected and tissue was digested to obtain tumor cell suspension. Aim of the study was to measure epidermal growth factor (EGF)-induced proliferation of cultured meningioma cells in the presence of either somatostatin or octreotide. Cells were grown to semiconfluency in Dolbecco’s modified eagle medium (D-MEM) supplemented with 10% fetal calf serum (FCS). After 48 h in D-MEM without serum, the medium was replaced by fresh medium plus recombinant EGF (10 ng/ml) and somatostatin or octreotide were added in the final concentrations of 1,10 and 100 nM. 20 h later 1 μcgCi of 3H-thymidine was added to each well. After 4 h, incorporated radioactivity was measured. While octreotide did not influence significantly cell growth at the three dose tested, somatostatin increased thymidine incorporation dose-dependently (peak 100nM: 150%±27% vs medium plus EGF, p<0.05). Octreotide effectively suppressed GH secretion in our acromegalic patient but is unlikely that its long-term use could have stimulated the growth of meningioma since it did not significantly influence the in vitroproliferation of the meningioma cells. These results suggest that somatostatin-mediated proliferative effect on meningioma cells is not mediated by the subtype 2 of the somatostatin receptor.

Pituitary adenomas in childhood and adolescence constitute 2–6% of all operated pituitary adenomas. We report the clinical features, treatment and follow-up of 10 pediatric patients affected by pituitary adenomas. All patients underwent clinical evaluation, endocrine tests, magnetic resonance imaging and visual field assessment. Follow-up ranged from 8 to 132 months (median 52.6). All patients were older than 10 years of age; 60% were males. In 50% the initial complaints were headache and/or visual impairment, all except one had clear evidence of endocrine dysfunction. Ninety percent were macroadenomas. According to hormone measurements and immunostaining 50% were prolactinomas, 20% were pure GH-se-creting and 30% were non-functioning adenomas. Prolactinomas in two females were successfully treated with cabergoline. The other patients un-derwent surgery: three prolactinomas are still being treated with dopamine agonists and a GH-secreting adenoma is being treated with octreotide LAR and cabergoline. Two patients were also treated with conventional radiotherapy. Treatments were completely successful in 50% of patients: these have normal hormone secretion, full pubertal development, no significant tumor mass and normal visual field. Hypersecretion of prolactin persists in two cases; partial or complete hypopituitarism is present in four, relevant tumor remnant in another four and impairment of visual field is present in two cases. In conclusion, pediatric adenomas occur mostly in pubertal age, are prevalently macroadenomas and clinically functioning. Medical therapy should be preferred for secreting adenomas, but in some cases, notably prolactinomas in males, surgery and eventual radiotherapy may be needed.

The effects of octreotide on biochemical markers of bone turnover were evaluated in patients with active acromegaly. Serum GH, IGF-I and serum and urinary markers of bone metabolism were measured before and after 4 months of treatment in 27 patients (short-term treatment) and after 12 and 24 months of treatment in 15 patients (long-term treatment). In the short-term, octreotide significantly decreased the levels of serum GH, IGF-I, calcium, osteocalcin, carboxyterminal propeptide of type I collagen and alkaline phosphatase plus urinary excretion of calcium. Short-term treatment significantly increased serum parathormone levels (before treatment 30.1 ±9.57 and at 4 months 46.1 ±24.98 ng/L, p<0.001) and urinary excretion of phosphate; urinary excretion of hydroxyproline was unchanged. The same results were observed during long-term treatment, except that there was no significant difference of serum calcium and alkaline phosphatase levels before and after treatment. Parathormone concentrations were still higher at 24 months compared with those prior to treatment (before treatment 31.9±9.74 and at 24 months 44.9±21.18 ng/L, p<0.05). The changes of most bone markers during octreotide therapy can be explained by the decrease of serum GH and IGF-I concentrations. On the other hand, the rise of parathormone concentrations suggests that octreotide has ulterior and long-standing actions on calcium homeostasis: intestinal malabsorption of calcium due to the octreotide could contribute to this secondary hyperparathyroidism. The clinical consequences of these alterations of bone metabolism need to be further clarified.

GH secreting pituitary adenomas are frequently visualized by scintigraphy with the somatostatin analogue 111Indium-pentetreotide. We studied 111Indium-pentetreotide scintigraphy and hormonal responses to octreotide in 12 acromegalic patients. Nine patients with active acromegaly were studied before pituitary adenomectomy; 6 of these and 3 other patients were studied after operation. GH was measured after a single sc dose of 100 µg of octreotide (acute test). The patients were preoperatively treated with 100 µg sc tid octreotide for 3 months as were patients who had been unsuccessfully operated; GH and IGF-I were measured at the end of this period (chronic treatment). A decrease of the hormones higher than 50% of basal values was considered a positive response in both acute test and chronic treatment. Eight/nine unoperated patients had a pituitary adenoma visualized by scintigraphy and a positive response to both the acute test and chronic treatment; one patient had no evidence of tumor at scintigraphy and he did not respond to octreotide. Scintigraphy was negative in all of the three patients cured by surgery. Six patients still had active disease after adenomectomy: scintigraphy was positive only in one case, although GH responded to octreotide treatment in all patients. Conclusions. 111In-pentetreotide scintigraphy frequently visualizes pituitary adenomas and predicts GH responses to octreotide in unoperated acromegalic patients. In unsuccessfully operated patients scintigraphy is infrequently positive and does not predict which patients will respond to octreotide. These data and the cost of 111In-pentetreotide scintigraphy do not warrant its extensive clinical use in acromegaly.

Endovesical administration of BCG is currently considered the most effective therapy and prophylaxis for bladder carcinoma in situ. Arthritis has been noted during this therapy, due to an immunitary type reaction rather than a localisation of the mycobacterium. We report the case of acute arthritis in a 52-year-old man undergoing endovesical treatment with BCG for multiple superficial carcinoma of the bladder, who presented a typical picture of spondyloarthritis. The positivity of the HLA-B27 histocompatibility of the antigen in the patient suggests that also with arthritis during BCG therapy, this antigen confers susceptibility at the onset of a spondyloarthritis, rather than other articular clinical pictures.

The pituitary-testicular axis and spermatogenesis, after puberty, have been evaluated in 93 patients, operated on for cryptorchidism and testicular ectopia, by the assessment of plasma testosterone, gonadotropins after GnRH stimulation and semen analysis. 12 healthy males formed the control group. Only bilateral cryptorchid patients showed abnormalities in the pituitary-Leydig cell axis with significantly higher basal and stimulated LH values than controls. Oligospermia was more frequent in cryptorchid cases (48%) than in ectopia (13%) and was accompanied by a significant increase of FSH concentration compared to controls. No relation was found between age at operation and sperm count. These data suggest that cryptorchidism and ectopia have different consequences on hormonal status and fertility.

Unfortunately, in page 584, second column, the first sentence under the heading “Type of switch” has been published incorrectly. The complete correct sentence is given below.