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Anna Spada, Lucia Vallar and Giovanni Faglia

Spada A, Vallar L, Faglia G. Cellular alterations in pituitary tumors. Eur J Endocrinol 1994;130:43–52. ISSN 0804–4643

In the last few years, molecular studies on pituitary adenomas have yielded evidence supporting a primary pituitary origin of these tumors. Although the existence of genomic alterations in tumoral cells is strongly suggested by the fact that almost all pituitary adenomas are monoclonal in origin, structural genetic abnormalities such as rearrangement, deletion or mutation, which could result in transcriptional activation, have been identified in a minority of tumors. As far as the possible loss of anti-oncogenes in pituitary tumors is concerned, gene alterations have not been found in the p53 nor in the retinoblastoma gene, while loss of chromosome 1 1q13 sequences, which contain the deduced location of the yet uncloned MEN-1 gene, has been reported in a subset of GH-secreting adenomas. With regard to the activation of dominant oncogenes in the process of tumor formation, activating mutations of either the Gs α-subunit or the ras gene have been identified in a large proportion of GH-secreting adenomas and in individual particularly invasive tumours, respectively. Promoting agents such as hypothalamic neurohormones and growth factors may be required for the selective growth of genetically altered cells. In this respect, it is worth noting that receptor/postreceptor alterations occurring in pituitary tumors may cause an increased action of stimulatory neurohormones with growth promoting properties as well as defective action of inhibitory inputs.

Anna Spada, Institute of Endocrine Sciences, Pad. Granelli Ospedale Maggiore IRCCS, via F Sforza 35, Milano 20122, Italy

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Paloma Gil-del-Alamo, Katia Saccomanno, Andrea Lania, Kim SI Pettersson, Paolo Beck-Peccoz and Anna Spada

Gil-del-Alamo P, Saccomanno K, Lania A, Pettersson KSI, Beck-Peccoz P, Spada A. Serum levels of β-subunit of chorionic gonadotropin in patients with pituitary tumors. Eur J Endocrinol 1995;133:33–7. ISSN 0804–4643

Many studies have shown that normal and tumoral pituitary is able to synthesize chorionic gonadotropin (CG). The aim of the present work was to investigate the circulating levels of free β-subunit of CG (CG-β) in a large number of patients with pituitary tumors in basal conditions and after thyrotropin-releasing hormone (TRH) injection. The study includes 27 healthy subjects, 23 patients with prolactinoma, 20 with growth hormone-secreting adenoma and 77 with non-functioning pituitary adenoma (NFPA). The CG-β was evaluated using a new one-step immunometric assay employing two monoclonal antibodies directed against epitopes present only on the free CG-β and showing a detection limit of 0.04 U/l and a cross-reactivity with complete CG < 0.01%. In basal conditions, serum CG-β was undetectable in healthy subjects and in the majority of patients, while in seven patients with NFPA and four with prolactinoma the CG-β values ranged between 0.05 and 0.72 U/l. In these 11 patients serum levels of intact CG were found within the normal range (normal range < 5 U/I), while two patients with NFPA and one with prolactinoma had levels of free α-subunit inappropriately high with respect to gonadotropins and thyrotropin. Injection of TRH caused CG-β to increase in two out of 16 patients with NFPA, whereas it was ineffective in 12 healthy subjects and 10 patients with prolactinoma. The present data indicate that detectable level of CG-β not associated with hypersecretion of the intact CG molecule may be observed in about 10% of patients with NFPA or prolactinoma, while abnormal CG-β responses to TRH are observed infrequently in individual patients with NFPA.

Paolo Beck-Peccoz, Institute of Endocrine Sciences, Ospedale Maggiore IRCCS, Pad. Granelli, Via F Sforza 35, 20122-Milano, Italy

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Antonio Stefano Salcuni, Valentina Morelli, Cristina Eller Vainicher, Serena Palmieri, Elisa Cairoli, Anna Spada, Alfredo Scillitani and Iacopo Chiodini

Objective

Subclinical hypercortisolism (SH) is associated with increased risk of vertebral fractures (VFx). The effect on bone following recovery from SH is unknown.

Design

Of the 605 subjects consecutively referred for monolateral adrenal incidentalomas (AIs) to our outpatient clinics, 55 SH patients (recruited on the basis of the exclusion criteria) were enrolled. We suggested to all patients to undergo adrenalectomy, which was accepted by 32 patients (surgical group, age 61.3±8.1 years) and refused by 23 patients, who were followed with a conservative management (non-surgical group, age 65.4±7.1 years).

Methods

We diagnosed SH in patients with serum cortisol after 1 mg dexamethasone suppression test (1 mg-DST) >5.0 μg/dl or with greater than or equal to two criteria among 1 mg-DST >3.0 μg/dl, urinary free cortisol >70 μg/24 h and ACTH <10 pg/ml. We assessed: bone mineral density (BMD) at lumbar spine (LS) and femoral neck (as Z-score) by dual-energy X-ray absorptiometry and the VFx presence by X-ray at baseline and at the end of follow up (surgical group 39.9±20.9 months and non-surgical group 27.7±11.1 months).

Results

The LS Z-score (ΔZ-score/year) tended to increase in the surgical group (0.10±0.20) compared with the non-surgical group (−0.01±0.27, P=0.08) and in the former, the percentage of patients with new VFx was lower (9.4%) than in the latter (52.2%, P<0.0001). Surgery in AI patients with SH was associated with a 30% VFx risk reduction (odds ratio 0.7, 95% CI 0.01–0.05, P=0.008) regardless of age, gender, follow up duration, 1 mg-DST, LS BMD, and presence of VFx at baseline.

Conclusion

In patients with monolateral AI and SH, adrenalectomy reduces the risk of VFx.

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Giovanna Mantovani, Ernesto De Menis, Giorgio Borretta, Giorgio Radetti, Sara Bondioni, Anna Spada, Luca Persani and Paolo Beck-Peccoz

Objective: Mutations in the gene coding for the orphan nuclear receptor DAX1 cause X-linked adrenal hypoplasia congenita (AHC). Affected boys usually present with primary adrenal failure in early infancy or childhood. Impaired sexual development due to hypogonadotropic hypogonadism becomes manifest at the time of puberty. Moreover, evidence from Dax1 knockout mice and a limited number of patients with AHC, suggests that mutations in DAX1 may directly cause abnormalities in spermatogenesis. The aim of this study was to characterize clinically and genetically five patients with AHC.

Design: DNA sequencing analysis, endocrine testing, testicular ultrasound and semen analysis with 1-year follow-up after gonadotropin treatment.

Methods: We report on five men with classic AHC manifestations. Genomic DNA was extracted from patients’ peripheral blood leukocytes and the coding region, splice sites, and promoter (−240 bp) region of DAX1 were directly sequenced.

Results: Three known and two novel mutations were detected in the DAX1 coding sequence in these patients. Semen analysis was performed in four of the five patients and showed azoospermia. Twelvemonth treatment with gonadotropins did not restore fertility in these patients. All patients showed a normal testicular Doppler ultrasound, in contrast with that observed in Dax1-deficient mice, which display abnormalities in the rete testis.

Conclusions: These cases further expand the number of DAX1 mutations reported in the literature, as well as our clinical knowledge of this rare disease.

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Angela Cecilia Pesatori, Andrea Baccarelli, Dario Consonni, Andrea Lania, Paolo Beck-Peccoz, Pier Alberto Bertazzi and Anna Spada

Objective

The pathogenesis of sporadic pituitary tumors is unknown. Loss-of-function mutations of aryl hydrocarbon receptor-interacting protein (AIP) have been identified in patients with familial pituitary tumors. AIP is a chaperone protein with multifunction properties, including modulation of the transcriptional activity of the aryl hydrocarbon receptor, which mediates toxicological and carcinogenic dioxin effects.

Design

We investigated the incidence of pituitary tumors in the Seveso population exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin following an industrial accident in 1976.

Methods

Through the hospital discharge registration system of Lombardy Region, we identified incident cases of pituitary adenomas between 1976 and 1996 in the Seveso population, subdivided in zone A (n=804), B (n=5.941), and R (n=38.624) according to high, intermediate, and low exposure to dioxin respectively, and in the surrounding non-contaminated area, as reference (n=232 745).

Results

We identified 42 pituitary adenomas in the reference area, 1 prolactinoma in zone A (rate ratio (RR) 6.2; 95% CI 0.9–45.5, P=0.07), 2 nonfuctioning pituitary tumors (NFPAs) in zone B (RR 1.9; 95% CI 0.5–7.7, P=0.39), and 3 prolactinomas and 2 NFPAs in zone R (RR 0.7; 95% CI 0.3–1.8, P=0.48).

Conclusions

The study is unique with regard to the availability of epidemiological and clinical data in an area of relatively pure dioxin exposure. The study indicates no statistically significant increase of incident pituitary tumors in this area, although the tendency toward a higher risk (three cases in zones A and B) of pituitary tumors in subjects exposed to high–intermediate dioxin concentrations in comparison with nonexposed population suggests the need for extended follow-up.

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Marcello Filopanti, Uberta Verga, Federica Ermetici, Luca Olgiati, Cristina Eller-Vainicher, Sabrina Corbetta, Luca Persani, Paolo Beck-Peccoz and Anna Spada

Objective

Primary hyperparathyroidism (PHPT) is a challenging problem in type 1 multiple endocrine neoplasia (MEN1) due to the high postsurgery recurrence rate. The aim was to evaluate the efficacy of cinacalcet in MEN1 patients in comparison with patients with sporadic PHPT (sPHPT) and the effect of Arg990Gly calcium-sensing receptor (CASR) polymorphism on the response to treatment.

Design

This is a randomized, crossover, double-blind study carried out in the University Hospitals.

Methods

Fifteen MEN1 patients with PHPT were randomized to two groups, one administered with 30 mg daily cinacalcet, titrated until calcium normalization, and one with placebo. After 3 months, patients were reassessed and after washout switched to the other treatment. For comparison, 20 sPHPT patients with similar calcium levels were administered with cinacalcet for 3 months. Ionized and total calcium, phosphate, and parathyroid hormone (PTH) were evaluated. CASR Arg990Gly was genotyped on blood DNA by direct sequencing.

Results

Cinacalcet normalized calcium, increased phosphate, and reduced PTH levels in all patients. Cinacalcet dosage required to normalize calcium in MEN1 and sPHPT was not significantly different (45±21 vs 54±25 mg/day). Few mild adverse events, not requiring drug withdrawal, were observed in both the groups. No association between Arg990Gly CASR polymorphism and response to cinacalcet was found.

Conclusions

This short-term prospective study demonstrated that the efficacy profile of cinacalcet in patients with MEN1-related PHPT and in those with sPHPT was similar and was not influenced by the 990 CASR variant. Although long-term safety and efficacy data are required, cinacalcet might be considered a treatment option in MEN1 patients who have contraindications to surgery or persistent PHPT after surgery.

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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.

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Federica Ermetici, Marcello Filopanti, Uberta Verga, Elena Passeri, Giorgia Dito, Alexis Elias Malavazos, Chiara Mapelli, Maria Elisabetta Raggi, Anna Spada and Sabrina Corbetta

Objective

Patients with primary hyperparathyroidism (PHPT) are at risk of chronic kidney disease (CKD). Cystatin C (Cys-C) is considered a more reliable tool to assess glomerular filtration rate (GFR) than creatinine. The study aimed to assess circulating Cys-C and its relationships with biochemical PHPT and cardiometabolic parameters.

Design and methods

The present cross-sectional study was performed in academic endocrine units on PHPT patients (n=190) and non-hypertensive, non-diabetic, age- and sex-matched healthy controls (n=135) with no established CKD. The main outcomes were creatinine by alkaline picrate method, Cys-C by immunonephelometry and calculation of estimated GFR based on creatinine and Cys-C (eGFRcr-cys) using the CKD-EPI equation.

Results

In PHPT patients, circulating Cys-C ranged 0.45–3.13 mg/l and correlated with creatinine, age and BMI. Mean Cys-C level was higher in PHPT patients than in controls (0.93±0.02 vs 0.78±0.14 mg/l; P=0.03). Cys-C levels in PHPT patients were predicted by age, BMI, ionized calcium, hypertension and HDL-cholesterol, the most significant determinant being ionized calcium. Cys-C positively correlated with cardiovascular disease (CVD) occurrence. Overall, 18.4% of PHPT patients with eGFRcr >60 ml/min per 1.73 m2 (n=169) had Cys-C levels higher than the 95th percentile in controls (1.03 mg/l), consistent with a preclinical CKD, which was associated with hypertension and insulin resistance. Considering eGFRcr-cys, CKD (stages G3a, G3b, 4) was diagnosed in 13.7% of PHPT patients. Estimated GFRcr-cys, but not eGFR based on creatinine, was predicted by insulin resistance and hypertension and positively correlated with CVD.

Conclusions

Elevated Cys-C levels were associated with ionized calcium, cardiometabolic risk factors and CVD, and identified preclinical CKD in PHPT patients.

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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.

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Cristina L Ronchi, Erika Peverelli, Sabine Herterich, Isabel Weigand, Giovanna Mantovani, Thomas Schwarzmayr, Silviu Sbiera, Bruno Allolio, Jürgen Honegger, Silke Appenzeller, Andrea G Lania, Martin Reincke, Davide Calebiro, Anna Spada, Michael Buchfelder, Joerg Flitsch, Tim M Strom and Martin Fassnacht

Context

Alterations in the cAMP signaling pathway are common in hormonally active endocrine tumors. Somatic mutations at GNAS are causative in 30–40% of GH-secreting adenomas. Recently, mutations affecting the USP8 and PRKACA gene have been reported in ACTH-secreting pituitary adenomas and cortisol-secreting adrenocortical adenomas respectively. However, the pathogenesis of many GH-secreting adenomas remains unclear.

Aim

Comprehensive genetic characterization of sporadic GH-secreting adenomas and identification of new driver mutations.

Design

Screening for somatic mutations was performed in 67 GH-secreting adenomas by targeted sequencing for GNAS, PRKACA, and USP8 mutations (n=31) and next-generation exome sequencing (n=36).

Results

By targeted sequencing, known activating mutations in GNAS were detected in five cases (16.1%), while no somatic mutations were observed in both PRKACA and USP8. Whole-exome sequencing identified 132 protein-altering somatic mutations in 31/36 tumors with a median of three mutations per sample (range: 1–13). The only recurrent mutations have been observed in GNAS (31.4% of cases). However, seven genes involved in cAMP signaling pathway were affected in 14 of 36 samples and eight samples harbored variants in genes involved in the calcium signaling or metabolism. At the enrichment analysis, several altered genes resulted to be associated with developmental processes. No significant correlation between genetic alterations and the clinical data was observed.

Conclusion

This study provides a comprehensive analysis of somatic mutations in a large series of GH-secreting adenomas. No novel recurrent genetic alterations have been observed, but the data suggest that beside cAMP pathway, calcium signaling might be involved in the pathogenesis of these tumors.