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I. Nicoletti, P. Filipponi, L. Fedeli, F. Ambrosi, G. Gregorini and F. Santeusanio

Abstract. A case of a patient with hypopituitarism due to a disturbance of hypothalamo-pituitary regulation is presented, who developed high-grade hyperprolactinaemia after the initiation of substitutive therapy with testosterone esthers.

The increase in serum Prl was strictly related to testosterone aromatization to oestradiol, since anti-oestrogen compounds were effective in reducing (clomiphene) or abolishing (tamoxifen) the enhanced Prl secretion. The oestrogen effect in raising Prl release was not attributable to a reduction in the dopamine inhibition of Prl-secreting cells, as the dopamine-antagonist domperidone failed to increase Prl serum levels in the same patient.

This suggests that, in man, the oestrogen effect in enhancing Prl release is mainly enacted directly on the pituitary lactotrophs rather than exerted through a reduction in the hypothalamic dopamine activity.

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G. Faglia, C. Ferrari, V. Neri, P. Beck-Peccoz, B. Ambrosi and F. Valentini

ABSTRACT

Out of 62 patients with pituitary tumours two (B. M.: vascular tumour and D. G.: chromophobe adenoma) showed symptoms and signs of hyperthyroidism and high plasma thyrotrophin (HTSH) values (mean values 24.0 and 8.4 μU/ml respectively). A parallelism was found between the Human Thyroid Stimulating Hormone Research Standard A (HTSH RSA) and the plasma dilution curves suggesting identity between immunoreactive material and authentic HTSH. The biological TSH activity was determined by McKenzie bioassay. Methimazole administration did not induce any significant modification in case B. M. while in case D. G. it caused a further increase in plasma HTSH. The triiodothyronine suppression test carried out in patient B. M. failed to produce a full inhibition, suggesting an autonomous function of the TSH secreting system. Lysine-vasopressin was ineffective in promoting HTSH increases in both cases, while insulin induced hypoglycaemia provoked in case B. M. a prompt fall in plasma HTSH levels, followed by an increase over the base line. The data obtained in case B. M. are compatible with a TSH-induced hyperthyroidism, while those found in patient D. G., though suggestive, are not completely consistent with this interpretation.

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S Cannavo, B Almoto, C Dall'Asta, S Corsello, RM Lovicu, E De Menis, F Trimarchi and B Ambrosi

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.

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S Asioli, A Righi, M Iommi, C Baldovini, F Ambrosi, F Guaraldi, M Zoli, D Mazzatenta, M Faustini-Fustini, P Rucci, C Giannini and M P Foschini

Objective and design

A clinicopathological score has been proposed by Trouillas et al. to predict the evolution of pituitary adenomas. Aim of our study was to perform an independent external validation of this score and identify other potential predictor of post-surgical outcome.

Methods

The study sample included 566 patients with pituitary adenomas, specifically 253 FSH/LH-secreting, 147 GH-secreting, 85 PRL-secreting, 72 ACTH-secreting and 9 TSH-secreting tumours with at least 3-year post-surgical follow-up.

Results

In 437 cases, pituitary adenomas were non-invasive, with low (grade 1a: 378 cases) or high (grade 1b: 59 cases) proliferative activity. In 129 cases, tumours were invasive, with low (grade 2a: 87 cases) or high (grade 2b: 42 cases) proliferative activity. During the follow-up (mean: 5.8 years), 60 patients developed disease recurrence or progression, with a total of 130 patients with pituitary disease at last follow-up. Univariate analysis demonstrated a significantly higher risk of disease persistence and recurrence/progression in patients with PRL-, ACTH- and FSH/LH-secreting tumours as compared to those with somatotroph tumours, and in those with high proliferative activity (grade 1b and 2b) or >1 cm diameter. Multivariate analysis confirmed tumour type and grade to be independent predictors of disease-free-survival. Tumour invasion, Ki-67 and tumour type were the only independent prognostic factors of disease-free survival.

Conclusions

Our data confirmed the validity of Trouillas’ score, being tumour type and grade independent predictors of disease evolution. Therefore, we recommend to always consider both features, together with tumour histological subtype, in the clinical setting to early identify patients at higher risk of recurrence.

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B Ambrosi, C Dall'Asta, S Cannavo, R Libe, T Vigo, P Epaminonda, I Chiodini, S Ferrero, F Trimarchi, M Arosio and P Beck-Peccoz

OBJECTIVE: Rosiglitazone, a thiazolidinedione compound with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-binding affinity, is able to suppress adrenocorticotropic hormone (ACTH) secretion in treated mice and in AtT20 pituitary tumor cells. These observations suggested that thiazolidinediones may be effective as therapy for Cushing's disease (CD). PATIENTS AND METHODS: Rosiglitazone (8 mg/day) was administered to 14 patients with active CD (13 women, one man, 18-68 years). Plasma ACTH, serum cortisol (F) and urinary free cortisol (UFC) levels were measured before and then monthly during rosiglitazone administration. RESULTS: In six patients a reduction of ACTH and F levels and a normalization of UFC were observed 30-60 days after the beginning of rosiglitazone administration: there was a significant difference between basal and post-treatment values for UFC (1238+/-211 vs 154+/-40 nmol/24 h, P<0.03), but not for ACTH (15.9+/-3.7 vs 7.9+/-0.9 pmol/l) and F levels (531+/-73 vs 344+/-58 nmol/l). Two of six cases, followed up for 7 months, showed a mild clinical improvement. Eight patients were nonresponders after 30-60 days of rosiglitazone treatment: their ACTH, F and UFC levels did not differ before and during drug administration. Immunohistochemical analysis of pituitary tumors removed from two responder and two nonresponder patients showed a similar intense immunoreactivity for PPAR-gamma in about 50% of cells. CONCLUSIONS: The administration of rosiglitazone seems able to normalize cortisol secretion in some patients with CD, at least for short periods. Whether the activation of PPAR-gamma by rosiglitazone might be effective as chronic pharmacologic treatment of CD needs a more extensive investigation through a randomized and controlled study.

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F Ermetici, F Donadio, L Iorio, A E Malavazos, A Dolci, E Peverelli, A M Barbieri, L Morricone, I Chiodini, M Arosio, A Lania, P Beck-Peccoz, B Ambrosi and S Corbetta

Background and aim

Hypogonadism frequently occurs in men with type 2 diabetes mellitus (T2DM), while the role of glycemic control and visceral obesity is still unclear. This study aimed to assess the Leydig cell function, including the new sensitive marker insulin-like factor 3 (INSL3), in T2DM patients without overt hypogonadism and the influence of either glycemic control or visceral adiposity.

Subjects and methods

Thirty T2DM patients (age 57.1±6.2 years, body mass index (BMI) 28.0±4.3) without overt hypogonadism and 30 age- and BMI-matched controls were studied. Anthropometric, glycometabolic parameters and testosterone, SHBG, LH, INSL3 levels, bioavailable and free testosterone (BT and cFT) were evaluated. The human chorionic gonadotrophin (hCG) test was also performed.

Results

Patients had lower total testosterone (452.6±130.0 vs 512.6±117.3 ng/dl, P=0.06), BT (189.7±36.4 vs 237.1±94.1 ng/dl, P=0.002), cFT (8.1±1.6 vs 10.1±4.0 ng/dl, P=0.002), and higher LH levels (3.5±1.6 vs 2.6±1.2 mU/ml, P=0.01) versus controls. Serum INSL3 concentrations were also lower in patients (1.1±0.3 vs 1.5±0.7 ng/ml, P=0.01). These hormonal parameters, including INSL3, did not differ between T2DM patients with poor or good glycemic control (HbA1c>9 or <7% respectively). In patients, waist circumferences (97.9±12.4 cm) negatively correlated with INSL3 (P=0.03) and basal, as well as hCG-stimulated testosterone levels (P=0.04 and 0.004 respectively). Basal or stimulated hormonal levels and INSL3 concentrations were not different between patients with (40%) or without erectile dysfunction.

Conclusions

An early impairment of the overall Leydig cell function is present in men with T2DM, mainly related to visceral adiposity rather than to glycemic control.