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G. Faglia, B. Ambrosi, P. Beck-Peccoz and P. Travaglini

ABSTRACT

Hypothalamic-pituitary-adrenal function was investigated in 43 patients with pituitary tumours (22 acromegalics and 21 chromophobe adenomas) and in 7 patients with craniopharyngiomas. The subjects were divided into two groups, according to the intrasellar or to the suprasellar spread of the tumour. Plasma and urinary 17-OHCS were evaluated in basal conditions and after the following tests: ACTH, metyrapone, dexamethasone, LVP, hypoglycaemia and pyrogen.

Only in 10 subjects were all the tests normal, while there was a complete lack of response to the performed tests in 12 cases.

Under basal conditions a reduced urinary 17-OHCS excretion was observed in 24% of the patients, while plasma 17-OHCS levels appeared to be decreased only in 10 % of patients.

The adrenal reserve was reduced in 4 % of the cases. A greater frequency of negative responses (40 %) was shown by the metyrapone test. Dexamethasone administration failed to suppress plasma 17-OHCS in 29 % of the subjects. The LVP test demonstrated abnormal results in 42 % of the patients examined.

The hypoglycaemia test caused the greatest percentage of impaired responses (58 %) and the pyrogen test gave a higher incidence of normal results.

Our data suggest that the incidence of impaired tests is greater in patients with pituitary tumours with suprasellar spread which particularly tend to cause hypothalamic damage.

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B Ambrosi, L Barbetta, T Re, E Passini and G Faglia

The possibility of assessing hypothalamic-pituitary-adrenal (HPA) function by the standard ACTH test (250 microg) has been widely discussed in the past years and compared with the role of the insulin tolerance test (ITT). Recently, it was shown that low doses of ACTH, such as 1 microg i.v., induce a maximal adrenal response and, by reducing the discrepancies compared with the ITT also allow one to detect mild forms of secondary hypoadrenalism. In the present study the 1 microg ACTH test was performed in patients with hypothalamic-pituitary disease in order to assess adrenal function, and the results have been compared with those obtained after the insulin test. Fifty-seven patients (31 men and 26 women, aged 19-73 years) with hypothalamic-pituitary diseases were studied: 51 patients were affected with pituitary tumor and 6 patients had hypothalamic disorders. All these patients and 18 healthy volunteers (7 men and 11 women, aged 19-46 years) received 1 microg i.v. ACTH injection. In addition, the ITT (0.1-0.15 U/kg body weight) was performed in all patients. In normal subjects mean cortisol levels significantly (P<0.001) increased from a baseline of 393+/-43 nmol/l to a peak of 770+/-41 nmol/l after 1 microg ACTH. In 44 patients with hypothalamic-pituitary disease 1 microg ACTH caused a cortisol rise similar to that of normal subjects (from 332+/-17 to 769+/-24 nmol/l; P<0.001), while an impaired response (from 124+/-23 to 312+/-46 nmol/l) was observed in 13 cases (23%), 7 of them with low morning cortisol levels (10-127 nmol/l) and 6 with basal values at the lower limit of normality. The cortisol response to ITT was compared with that obtained after the 1 microg ACTH test: 10 patients failed both challenges, 4 patients who passed the ACTH test failed the ITT, while 3 patients who failed the ACTH test passed the ITT. The 23 out of 57 patients (40%) who showed a cortisol peak greater than 750 nmol/l after 1 microg ACTH had a normal response to ITT. A positive correlation between cortisol peaks after ACTH and after insulin was also found (r = 0.68, P<0.001). Assuming a 100% accuracy of ITT, the low dose ACTH test yielded a 71% sensitivity and a 93% specificity. In conclusion, the low-dose ACTH test is a useful, safe and inexpensive tool for the initial assessment of HPA function in patients with hypothalamic-pituitary disease. In fact, the ITT is unnecessary when cortisol peaks are greater than 750 nmol/l after 1 microg ACTH and also when very low cortisol basal levels indicate an overt hypoadrenalism. Within these limits the ITT is mandatory and its important role in the recognition of secondary adrenal failure is further confirmed.

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B Ambrosi, C Dall'Asta, L Barbetta and R Libe

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G. Faglia, P. Beck-Peccoz, B. Ambrosi, C. Ferrari and P. Travaglini

ABSTRACT

The effects of thyrotrophin releasing hormone (TRH) on plasma thyrotrophin (HTSH), thyroxine iodine (T4-I), growth hormone (HGH) and cortisol were studied in healthy and endocrinopathic subjects. In normal subjects rapid iv injection of 100, 200, 400, 600, 800 μg of TRH caused definite increases in plasma HTSH with a dose-response correlation between 100 and 200 μg; the peak occurred at 20–30 min at any dose level; iv infusion of 1000 μg over 30 min was followed by highly variable rises in plasma HTSH; the oral administration of 20 mg caused a definite and prolonged increase. In endocrinopathic subjects a standard dose of 600 μg of TRH was rapidly iv injected: 5 euthyroid patients with high 131I thyroidal uptake showed a normal increase in HTSH; 10 cases of Graves' disease, 5 of hyperactive adenomas as well as 4 normal subjects pre-treated with triiodothyronine showed no response; out of 5 cases of Graves' disease re-investigated after remission 3 showed no response, while 2 had an exaggerated response; 5 cases of primary myxoedema showed a very marked and prolonged response; out of 2 patients with idiopathic secondary hypothyroidism 1 did not respond at all and 1 showed a large and prolonged increase with a late peak; out of 4 cases of secondary hypothyroidism due to pituitary tumours, 2 gave normal responses, 1 showed a very marked and prolonged rise and 1 had a poor response; the same subject, after selective adenomectomy, however, had an exaggerated response; 12 euthyroid patients with pituitary tumours were examined: 3 did not respond at all, 4 had a normal increase in plasma HTSH and 5 gave a prolonged and exaggerated response. The serum T4-I showed an upward trend after TRH iv; however, the increase was not present in all instances. After oral administration of TRH a more definite increase was reached. It was demonstrated that TRH does not promote the release of HGH and ACTH.

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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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Cyrille B Confavreux, Florence Canoui-Poitrine, Anne-Marie Schott, Véronique Ambrosi, Valérie Tainturier and Roland D Chapurlat

Objective

Treatments against osteoporosis have demonstrated fracture risk reduction but persistence to therapy remains a major issue. Intermittent regimens have been developed to improve persistence. The aim of this 1-year prospective study was to compare, in the general population, the persistence of various oral regimens of antiosteoporotic treatment.

Methods

We conducted this prospective study in the French comprehensive public health insurance database of the Rhône-Alpes region. Women aged 45 years or older who had a first reimbursement of an oral antiosteoporotic treatment during February 2007 composed the study cohort. Persistence was defined by the proportion of patients refilling a prescription in the pharmacist delivery register (ERASME). Using statistical analyses like Kaplan–Meier survival curves and log-rank tests, we compared the treatment persistence of strontium ranelate, raloxifene, and daily-, weekly-, and monthly bisphosphonates.

Results

Two thousand four hundred and nineteen patients were included over a period of 1 month and followed up for 12 months. Two hundred and eighty-nine (11.9%) patients were treated with monthly bisphosphonates, 1298 (53.7%) with weekly bisphosphonates, and 832 (34.4%) with daily treatments (526 strontium ranelate (21.7%), 296 raloxifene (12.2%), and 10 bisphosphonates (0.4%)). At 1 year, overall persistence was 34%. Fifty percent of patients on monthly bisphosphonates were still persistent while only 37% of patients on weekly bisphosphonates, 34% on raloxifene, and 16% on strontium ranelate were persistent. Therapy monitoring with biochemical markers or bone mineral density was associated with improved persistence.

Conclusion

Overall persistence at 1 year was low, but intermittent regimens were associated with higher persistence rates, along with women who had therapy monitoring.

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P Colombo, C Dall'Asta, L Barbetta, T Re, E Passini, G Faglia and B Ambrosi

OBJECTIVE: To evaluate the plasma ACTH and serum cortisol responses to desmopressin in patients with Cushing's disease either before or after pituitary adenomectomy during long-term follow-up, and to compare the results with those obtained after corticotrophin-releasing hormone (CRH) testing. DESIGN: Plasma ACTH and serum cortisol concentrations were evaluated after the administration of desmopressin (10 microg i.v.) or CRH (1 microg/kg i. v.) in 34 patients with Cushing's disease. Twenty-four patients with active Cushing's disease were evaluated both before and after transsphenoidal pituitary surgery (TSS); these patients were followed up for 1-36 months. Ten patients were studied only after a long-term period (1-19 years, median 4 years) after TSS (six patients), TSS plus external pituitary irradiation (three patients) and TSS plus radiosurgery (one patient). RESULTS: In 24 patients with active Cushing's disease a significant ACTH/cortisol response (P<0.001) was induced by either desmopressin (ACTH from a baseline of 15.3+/-2.7 pmol/l to a peak of 40.9+/-7.3 pmol/l; cortisol from 673+/-59 nmol/l to 1171+/-90 nmol/l) or CRH (ACTH from a basal of 14. 2+/-2.5 pmol/l to a peak of 47.2+/-7.7 pmol/l; cortisol from 672+/-50 nmol/l to 1192+/- 80 nmol/l). In all patients a positive cortisol response to desmopressin was found. After pituitary adenomectomy the 14 'cured' patients were followed up for 1-36 months; desmopressin administration never induced ACTH or cortisol responsiveness in any patient. In contrast, a progressive recovery of ACTH and cortisol responses after CRH was observed at different intervals of time in all patients but one. Five patients, in whom the cortisol concentration only normalized after surgery, showed a persistent responsiveness to desmopressin, and two of them relapsed 12 and 24 months later. In five patients who were not cured, the hormonal responsiveness to either CRH or desmopressin was similar before and after operation. Of 10 patients studied only after long-term follow-up, six were cured and a normal response to CRH was present, whereas no changes in ACTH/cortisol concentrations were induced by desmopressin. The other four unsuccessfully operated patients underwent pituitary irradiation and showed different and equivocal hormonal responses to desmopressin and to CRH. CONCLUSIONS: During the postoperative follow-up of patients with Cushing's disease, the maintenance or the disappearance of the hormonal response may be related to the persistence or the complete removal of adenomatous corticotrophs, respectively. It is suggested that desmopressin test should be performed in the preoperative evaluation and follow-up of patients with ACTH-dependent Cushing's syndrome.

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A Sartorio, A Conti, S Ferrero, S Giambona, T Re, E Passini and B Ambrosi

Although steroid-induced negative effects on bone and collagen have been well described in corticosteroid-treated patients, few studies have extensively evaluated bone and collagen turnover in patients with endogenous Cushing's syndrome. In this work serum bone-Gla protein (BGP), C-terminal cross-linked telopeptide of type I collagen (ICTP) and N-terminal propeptide of type III procollagen (PIIINP) levels were determined in patients with active (n = 12) and preclinical (n = 6) Cushing's syndrome, adrenal incidentalomas (n = 35) and in healthy controls (n = 28). In patients with overt Cushing's syndrome, serum BGP (0.9+/-0.2 ng/ml), ICTP (2.7+/-0.2 ng/ml) and PIIINP (1.9+/-0.2 ng/ml) levels were significantly lower (P < 0.0001) than in controls (5.5+/-0.2, 3.9+/-0.2 and 3.2+/-0.2 ng/ml respectively). In preclinical Cushing's syndrome, serum BGP (2.5+/-0.8 ng/ml), ICTP (2.2+/-0.1 ng/ml) and PIIINP (2.2+/-0.2 ng/ml) levels were significantly lower than in normal subjects (P < 0.0001, P < 0.0001 and P < 0.02 respectively), being similar to those recorded in overt Cushing's syndrome. In patients with adrenal incidentaloma, serum BGP (4.2+/-0.5 ng/ml) and ICTP (2.9+/-0.2 ng/ml) levels were significantly lower than those found in controls (P < 0.05 and P < 0.001 respectively), while serum PIIINP levels (3.6+/-0.2 ng/ml) did not differ from those of normals. In particular, 9/35 patients with adrenal incidentaloma had markedly depressed BGP levels (<2.0 ng/ml; mean 0.8+/-0.1 ng/ml): all patients of this subgroup showed an exaggerated 17-hydroxyprogesterone increase after ACTH administration. In the same patients, serum ICTP (3.0+/-0.4 ng/ml) and PIIINP (3.6+/-0.2 ng/ml) levels did not differ from those found in the incidentaloma group. In conclusion, our study indicates that bone and collagen turnover are markedly affected in patients with overt and preclinical Cushing's syndrome. Although patients with adrenal incidentaloma do not show any signs or symptoms of overt hypercortisolism, the presence of reduced BGP and ICTP levels might be considered a further index of an 'abnormal' pattern of steroid secretion in some of them. As a consequence, the presence of early alterations in markers of bone turnover might be useful for selecting those patients who need more accurate follow-up of the adrenal mass.

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R Libe, C Dall'Asta, L Barbetta, A Baccarelli, P Beck-Peccoz and B Ambrosi

BACKGROUND: The incidence of adrenal incidentalomas has sharply increased in recent decades and concurrent subtle endocrine abnormalities, or even subclinical conditions, have been identified. Nonetheless, data concerning possible changes in adrenal size and/or hormonal pattern during follow-up are still inadequate. OBJECTIVE: To evaluate long-term morphological and functional evolution of adrenal incidentalomas after initial diagnosis and to identify possible risk factors for hormonal hyperactivity and mass enlargement. PATIENTS: Sixty-four patients (34-79 years) were followed-up for 12-120 months (median 25.5 months). Initial computerized tomography scan showed a unilateral mass in 51 patients and bilateral lesions in 13 patients. Average mass diameter at diagnosis was 2.5+/-0.1 cm (range 1.0-4.0). Twelve patients had subclinical Cushing's syndrome, 41 had mild hormonal alterations, and 11 had normal adrenal function at baseline. All patients were investigated by morphological and functional evaluation 6 and 12 months after diagnosis, and then at 1-year intervals. RESULTS: During follow-up, a mass size increase >/=1 cm was observed in 13 patients, and 18 developed further subtle endocrine alterations. Cumulative risk of developing endocrine abnormalities was 17% at 1 year, 29% at 2 years, and 47% at 5 years. The risk was higher in the first 2 years of follow-up if the initial tumor diameter was >or=3 cm. Overall, cumulative risk of mass enlargement was 6% at 1 year, 14% at 2 years, and 29% at 5 years, and it was greater in patients with normal adrenal function than in those with subtle hormonal abnormalities (P<0.05). One female subject showed a mass enlargement after 6 months of follow-up and was eventually diagnosed with non-Hodgkin's lymphoma. CONCLUSIONS: Patients with an adrenal incidentaloma are at risk for tumor growth and development of hormonal alterations. The risk of adrenal malignancy, although not elevated, also indicates the need for long-term follow-up.

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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.