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Paolo Beck-Peccoz

The endocrinologist dedicated to the studies of pituitary adenomas is surprised when confronted by the highly variable biological appearance of pituitary tumours. By immunohistochemistry and in situ hybridization, pituitary tumours are frequently composed of cells able to co-secrete hormonal molecules with completely different biochemical and biological activities, such as GH/alpha-subunit, PRL/alpha-subunit or GH/TSH, together with normally differentiated cells. This phenomenon is particularly surprising taking into account the recent discovery that the great majority of pituitary tumours are monoclonal in origin. In addition, the frequent detection of allelic deletions of different chromosomes in sporadic pituitary adenomas suggests loss of tumour suppressor genes in these neoplasia. Recent findings also show mutations which result in the constitutive activation of GTP-binding proteins in subsets of pituitary adenomas and a pathogenetic role has been envisaged for gsp and ras oncogenes which are expressed in pituitary tumours with variable frequency.

The latest example of the above

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Paolo Beck-Peccoz and Luca Persani

Beck-Peccoz P, Persani L. Variable biological activity of thyroid-stimulating hormone. Eur J Endocrinol 1994;131:331–40. ISSN 0804–4643

Thyroid-stimulating hormone (TSH), like the other pituitary glycoprotein hormones, is produced and secreted as a mixture of isoforms, the majority of which represent differences in oligosaccharide structure and possess different bioactivity. When samples are quantified simultaneously by immunometric assay and bioassay, the ratio between bioactivity (B) and immunoreactivity (I) may serve as an index of the overall potency of TSH. Variations of the TSH B/I ratio have been documented in both physiological and pathological conditions associated with alteration of the two most important mechanisms controlling TSH synthesis and secretion, i.e. TRH release and the thyroid hormone feedback system. Major examples of this assumption are the low TSH bioactivity found in samples from patients lacking TRH and thus bearing a hypothalamic hypothyroidism, and the enhanced bioactivity that is invariably found in TSH from patients with thyroid hormone resistance. Moreover, variations of TSH bioactivity have been recorded in normal subjects during the nocturnal TSH surge, in normal fetuses during the last trimester of pregnancy, in patients with primary hypothyroidism and in patients with TSH-secreting pituitary adenoma and non-thyroidal illness. In conclusion, the secretion of TSH molecules with altered bioactivity plays an important pathogenetic role in various thyroid disorders, while in some particular physiological conditions the bioactivity of TSH may vary in order to adjust thyroid hormone secretion to temporary needs.

Paolo Beck-Peccoz, Istituto di Scienze Endocrine, Ospedale Maggiore IRCCS, Via F. Sforza 35, 1-20122 Milano, Italy

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Cristina Eller-Vainicher, Manuela Wally Ossola, Paolo Beck-Peccoz and Iacopo Chiodini

A 35-year-old oriental woman, who was 32 weeks pregnant, was hospitalized with suspected preeclampsia. Subsequently, she developed stupor and lethargia. Biochemical assessment showed severe hypercalcemia (21 mg/dl) with undetectable parathyroid hormone (PTH) and markedly elevated PTH-related peptide (PTHrP) levels (26 pmol/l, normal values <1.1 pmol/l). The patient was treated with i.v. fluid administration, which resulted in an unsatisfactory reduction in serum calcium. Therefore, a cesarean section was performed to deliver the baby. Serum calcium levels promptly normalized after delivery with undetectable PTHrP levels. She delivered a healthy infant only presenting with transient mild jaundice and slightly prolonged QT interval with serum calcium level of 7.8–8.4 mg/dl (corrected for albumin levels). In the subsequent days, the patient developed a transient ‘hungry bone’ syndrome (calcium 6.7 mg/dl, phosphorous 2.1 mg/dl, and PTH 100.4 pg/ml). In conclusion, this pregnant patient presented with PTHrP-associated hypercalcemia, presumably of placental origin. Delivery resulted in prompt reduction of serum calcium levels and a transient ‘hungry bone’ syndrome.

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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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Guia Vannucchi, Michela Perrino, Stefania Rossi, Carla Colombo, Leonardo Vicentini, Davide Dazzi, Paolo Beck-Peccoz and Laura Fugazzola

Objective

Pregnancy represents a favorable condition for the development of thyroid nodules, likely due to the secretion of hormones with stimulatory activity. In particular, differentiated thyroid cancer (DTC) represents the second most frequent tumor among those diagnosed during pregnancy. However, few and discordant data are available about the impact of pregnancy on tumor outcome.

Methods

A total of 123 women with DTC were divided into three groups according to the timing of tumor diagnosis (group 1, at least 1 year after the delivery; group 2, during pregnancy or in the first year after delivery; and group 3, before pregnancy or nulliparity) and evaluated according to the international guidelines. Furthermore, immunohistochemical studies of estrogen receptor α (ERα) were performed in 38 papillary thyroid cancer tissues from the three groups.

Results

Thyroid cancer diagnosed during pregnancy was associated with a poorer prognosis compared to tumors developed in nongravidic periods (P<0.0001). Accordingly, at the stepwise logistic regression analysis, the diagnosis of DTC during pregnancy or in the first year post partum was the most significant indicator of persistent disease (P=0.001). Interestingly, ERα expression significantly differed among tumors of the three groups, being detected in 31% of group 1, in 87.5% of group 2, and in 0% of group 3 (P=0.01).

Conclusions

Present data indicate that pregnancy has a negative impact on the outcome of thyroid cancer. The presence of ERα in the majority of tumors diagnosed during pregnancy indicates that the poorer outcome of these cases could be related to the estrogen-mediated growth stimulus.

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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 Eller-Vainicher, Elisa Cairoli, Volha V Zhukouskaya, Valentina Morelli, Serena Palmieri, Alfredo Scillitani, Paolo Beck-Peccoz and Iacopo Chiodini

Objective

The prevalence of subclinical contributors to low bone mineral density (BMD) and/or fragility fracture is debated. We evaluated the prevalence of subclinical contributors to low BMD and/or fragility fracture in the presence of normal 25-hydroxyvitamin D (25OHVitD) levels.

Design

Prospective observational study.

Methods

Among 1095 consecutive outpatients evaluated for low BMD and/or fragility fractures, 602 (563 females, age 65.4±10.0 years) with apparent primary osteoporosis were enrolled. A general chemistry profile, phosphate, 25OHVitD, cortisol after 1-mg overnight dexamethasone suppression test, antitissue transglutaminase and endomysial antibodies and testosterone (in males) were performed. Serum and urinary calcium and parathyroid hormone levels were also evaluated after 25OHVitD levels normalization. Vertebral deformities were assessed by radiograph.

Results

In total, 70.8% of patients had low 25OHVitD levels. Additional subclinical contributors to low BMD and/or fragility fracture were diagnosed in 45% of patients, with idiopathic hypercalciuria (IH, 34.1%) and primary hyperparathyroidism (PHPT, 4.5%) being the most frequent contributors, apart from hypovitaminosis D. Furthermore, 33.2% of IH and 18.5% of PHPT patients were diagnosed only after 25OHVitD levels normalization. The subclinical contributors to low BMD and/or fragility fracture besides hypovitaminosis D were associated inversely with age (odds ratio (OR) 1.02, 95% CI 1–1.04, P=0.04) and BMI (OR 1.1, 95% CI 1.05–1.17, P=0.0001) and directly with fragility fractures (OR 1.89, 95% CI 1.31–2.73, P=0.001), regardless of BMD.

Conclusions

Subclinical contributors to low BMD and/or fragility fracture besides hypovitaminosis D are present in more than 40% of the subjects with apparent primary osteoporosis. Hypovitaminosis D masks a substantial proportion of IH and PHPT patients.

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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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Guia Vannucchi, Danila Covelli, Irene Campi, Daniele Origo, Nicola Currò, Valentina Cirello, Davide Dazzi, Paolo Beck-Peccoz and Mario Salvi

Background

Glucocorticoids are the mainstay of immunosuppression for active moderate–severe Graves' orbitopathy (GO).

Aim

To analyze the response to therapy and the contribution of glucocorticoid receptor (GR) gene polymorphisms to the therapeutic outcome of intravenous glucocorticoids (IVGC) in active moderate–severe GO.

Methods

We have studied 58 patients treated with 7.5 g i.v. methylprednisolone (cumulative dose). Ophthalmological assessment was performed at baseline and at 6–8, 12–16, and 24–30 weeks after the first infusion. Three GR gene polymorphisms, ER22/23EK, N363S, and BCL1, which have been associated to variable sensitivity to steroids, were studied in 43/58 patients. The therapeutic outcomes defined as: i) reduction of the clinical activity score (CAS) ≥2 points or ii) reduction of proptosis ≥2 mm or iii) improvement of diplopia according to the Gorman score were also studied in relation to treatment schedule, age, gender, duration of thyroid or GO, smoking habits, and serum TSH-receptor autoantibodies levels.

Results

In total, 70% of patients responded and had GO inactivation (CAS <4) as early as 6–8 weeks. At 12–16 weeks, the proportion of patients who became inactive increased by another 10% up to a total of 80%. ER22/23EK and N363S polymorphisms were present only in about 7%, while the Bcl1 variant was present in 30% of patients; no significant association of any of the GR polymorphisms with either the therapeutic response or the occurrence of side effects was observed.

Conclusions

Most patients with active GO respond to IVGC as early as 6–8 weeks of therapy and the analyzed GR polymorphisms do not influence the therapeutic effect of steroids. Questions arise about the need of continuing therapy up to 12 weeks in nonresponders. We suggest that these patients may be switched to other treatments alone or in combination with steroids.

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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.