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This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.

Carney complex is a rare familial multiple syndrome characterised by myxomas, endocrine overactivity, schwannomas, and spotty pigmented lesions on the skin. …

High vascular morbidity and mortality is associated with acromegaly. The aim of the present study was to assess the effects of octreotide therapy on several known cardiovascular risk factors and to correlate them with octreotide-induced hormonal changes. Lipid levels, LDL particle size distribution as evaluated by single vertical spin density gradient ultracentrifugation, apolipoproteins AI and B, lipoprotein (a) [Lp(a)] concentrations and apo(a) phenotypes were evaluated in 20 non-diabetic acromegalic patients (6 M, 14 F), with normal thyroid, adrenal and gonadal function, aged 29-66 years. Normal subjects (20), matched for age, sex and BMI served as control for lipid variables. Acromegalic patients were characterized by lower HDL cholesterol (and apoA-I) and by higher Lp(a) concentrations in comparison to controls. Treatment with octreotide (100 microg t.i.d. for 3 months) led to: an increase in HDL cholesterol (median: + 22%), a decrease in LDL cholesterol (-14%) and a decrease of the Lp(a) levels (all phenotypes) (-28%). The expected decreases of IGF-I levels (median: -48%) and 7-h AUC of GH (-50%), insulin (-40%) and glucagon (-20%) were observed. Only Lp(a) modifications showed a correlation with GH modifications. The study of LDL physical properties showed that acromegalic patients had smaller and/or more dense LDL particles, in comparison with normal controls (relative flotation rate, Rf: 0.40 +/- 0.03 versus 0.42 +/- 0.02 P0q05), an alteration that might contribute to the high vascular risk of acromegalic patients. However, the LDL subfraction distribution remained unmodified during octreotide therapy (Rf 0.39 +/- 0.03). In conclusion, this study shows that in acromegalic patients octreotide treatment is indeed associated with an amelioration of some lipoprotein parameters, i.e. LDL, HDL, and Lp(a) concentrations. However, this treatment has no effect on the small and/or dense LDL particles present in these patients.

As there are few data on the evaluation of the adequacy of levothyroxine (L-T4) therapy in patients with central hypothyroidism (CH), a prospective study was performed to assess the accuracy of various parameters in the follow-up of 37 CH patients. Total and free thyroid hormones, TSH, and a series of clinical and biochemical indexes of peripheral thyroid hormone action have been evaluated off and on L-T4 therapy. Samples were taken before the daily administration of L-T4. In all patients off therapy, clinical hypothyroidism and low levels of free T4 (FT4) were observed, whereas values of FT3, total T4, and total T3 were below the normal range in 73%, 57%, and 19% of cases, respectively. Most of the indexes of thyroid hormone action were significantly modified after L-T4 withdrawal and exhibited significant correlation with free thyroid hormone levels. During L-T4 replacement therapy, 32 patients had circulating levels of FT4 and FT3 and indexes within the normal range with a mean L-T4 daily dose of 1.5 +/- 0.3 microg/kg BW. Despite normal serum FT4, 3 patients had borderline high values of FT3 and a clear elevation of serum-soluble interleukin-2 receptor concentrations, suggesting overtreatment. Low or borderline low FT4/FT3 levels indicated undertreatment in 2 patients. The clinical parameters lack the required specificity for the diagnosis or follow-up of CH patients. The L-T4 daily dose should be established, taking into account the weight, the age, and the presence of other hormone deficiencies or pharmacological treatment of CH patients. In conclusion, our results indicate that the diagnosis of CH is reached at best by measuring TSH and FT4 concentrations. In the evaluation of the adequacy of L-T4 replacement therapy, both FT4 and FT3 serum levels together with some biochemical indexes of thyroid hormone action are all necessary to a more accurate disclosure of over- or undertreated patients.

The p16 gene, which encodes a physiological inhibitor of the cyclin D-CDK4 complex, is now considered as an important tumour-suppressor gene in a variety of tumours. A marked reduction of its expression has been reported to occur without significant genetic alterations in human pituitary adenomas, although rare point mutations of uncertain functional significance have been described. On the other hand, p16 gene silencing due to hypermethylation has been reported in several human primary tumours. The aim of this study was to further investigate the pathogenetic events leading to p16 gene inactivation in pituitary tumours.To screen a european series of human pituitary tumours for p16 gene alterations and possible gene hypermethylation.A representative series of 31 human pituitary tumours-30 macroadenomas, including a MEN-1 non-secreting pituitary adenoma and a non-MEN-1 familial giant GH-secreting adenoma, and one FSH-secreting pituitary carcinoma-was studied.Polymerase chain reaction/single strand conformation polymorphism (PCR-SSCP) analysis was used to screen for p16 gene alterations in all cases. Direct sequencing of PCR-products was obtained by the di-deoxynucleotide method where suspected abnormalities of the PCR-SSCP analysis were observed. In 24 samples, a methylation-specific PCR assay (MSP-PCR) was used to determine p16 gene methylation status.Two sporadic cases of pituitary adenomas had a similar single A to G base substitution leading to an heterozygous Ala140Thr p16 polymorphism, which has not previously been described in such tumours, but is known to be functionally silent. No other p16 abnormality could be suspected from PCR-SSCP analysis in this series. In contrast, the presence of methylated-specific PCR products was observed in 20/24 cases (83.3%).This study confirms that p16 gene mutations are not involved in the pathogenesis of human pituitary tumours, although polymorphisms can be demonstrated, depending on the population considered. In contrast, the high incidence of hypermethylation of the p16 gene suggests that such an alteration occurs early in pituitary tumours, and may play a role in pituitary tumorigenesis.

The acute GH lowering effects of a single dose of either octreotide (OCT) or cabergoline (CAB), given alone and in combination, were studied in a series of 21 patients with acromegaly.Plasma GH was measured for 8 hours after a single subcutaneous injection of OCT (100 micrograms) and for 48 hours after a single oral dose of CAB (0.5 mg) in all patients. Fourteen patients, who did not suppress GH levels below 5 micrograms/L after either OCT or CAB given alone, also received a combination of both drugs (OCT 100 micrograms s.c. + CAB 0.5 mg p.o. 24 h before OCT).GH levels were acutely suppressed by more than 50% in 15/21 cases after OCT alone and in 5/21 after CAB alone, respectively (P0.01). In the 14 patients who received the combined test, the magnitude of GH suppression was significantly higher than after OCT alone 4, 6 and 8 hours after OCT administration (P0.02). In patients with mixed GH/PRL-secreting tumors, the additive effect of OCT and CAB was observed at each time point.These results suggest that combined therapy with OCT and CAB may be more effective in suppressing GH secretion than either compound given alone, especially in patients with GH/PRL-secreting adenomas.