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SummaryObjective Cushing's disease (CD) has an uncertain prognosis because patients achieving remission after transsphenoidal pituitary neurosurgery (TSS) may relapse. We aimed to identify factors predicting relapse, focusing on desmopressin (DDAVP) and corticotropin-releasing hormone (CRH) tests after surgery. Materials and methods Fifty-seven patients with CD (mean age 36 years) after TSS experienced remission (24 cases), late relapse (LR) (15 cases), or persistent disease (18 cases). Results The median time to relapse was 40 months. ACTH levels increased after both DDAVP and CRH stimulation, with a significantly higher response in the late recurrence group, showing this to be an indicator of increased risk of relapse. In the logistic regression model, a rise in ACTH >9 pg/ml after DDAVP and >36·7 pg/ml after CRH showed a sensitivity of 93% and 73%, respectively, a specificity of 82% and 76% in LR group. The area under the curve was 0·91 for DDAVP, 0·80 for CRH and 0·95 for DDAVP+CRH test, i.e. the combined tests performed better than each test alone, but not to a statistically significant degree. A response to both tests resulted in a positive predictive value (PPV) of 100%, while no response to either test in a negative predictive value (NPV) of 100%. Conclusions ACTH hyper-responsiveness to DDAVP stimulation proved a valuable indicator of relapsing patients with high sensitivity and specificity; in selected cases when a clear high increment of ACTH level is not evident, the CRH test might be used as additional tool to confirm the risk of future relapses.

Summary Objective Papillary thyroid cancers (PTCs) with no iodine uptake have an aggressive behaviour and a poor prognosis. The aim of our study was to characterize, at molecular level, a subset of PTC with no 131 iodine (131I) uptake. Design and methods Forty-eight cancer tissues were divided into three groups: Group 1, 28 primary cancers; Group 2, 7 recurrences capable of trapping 131I; and Group 3, 13 recurrences incapable of trapping 131I. mRNA levels of thyroid genes (sodium/iodide symporter NIS, thyroglobulin, thyroperoxidase and pendrin) and glycolytic metabolism genes (GLUT-1, hexokinase I and II) and BRAF mutations were evaluated in the different groups. Results Cancers with no 131I uptake had slightly reduced NIS, significantly reduced thyroglobulin (P

Summary Objective Several splice variants (SVs) of GHRH receptor (GHRH-R) have been identified in various human cancers through which GHRH antagonists may exert their IGF-II-mediated antiproliferative action. Because the overexpression of the IGF-II gene is a frequent feature of adrenal carcinoma, we searched for the presence of GHRH-R SVs in these tumours. Methods and Results The expression of GHRH-R SVs was assessed by nested PCR in 45 human adrenocortical tumours. We have amplified 720-, 566- and 335-bp PCR products only in carcinomas. Their sequence revealed three open reading frames, corresponding to SV1, SV2 and SV4 of GHRH-R. SV2 was detected in five of 24 cancers examined, whereas the incidence of SV1 and SV4 was lower. Their simultaneous expression was observed in one carcinoma. No PCR products for SV3 or wild-type GHRH-R were found in carcinomas; mRNA for wild-type GHRH-R or SVs of GHRH-R were not observed either in adenomas or in normal adrenal or in NCI-H295R cells. Interestingly, all carcinomas which expressed SVs were also positive for the presence of GHRH mRNA. Conclusion This is the first time that the expression of splice variants of GHRH-R has been demonstrated in human adrenal carcinoma. This study raises the possibility that splice variants might play a role in adrenal carcinogenesis and might offer the possibility for new therapeutic strategies at least in a subgroup of adrenal carcinomas.

Summary objective Despite the very recent discovery that about 25% of apparently sporadic forms of pheochromocytoma are actually due to germline mutations of RET, VHL, SDHB or SDHD genes, the genetic bases of the tumourigenesis of this type of cancer are still incompletely understood. Recent studies provided evidence that a new tumour suppressor gene, mapping on the short arm of chromosome 1, could be involved in early tumourigenesis of pheochromocytoma. design We have performed a fine analysis of loss of heterozygosity (LOH) of this region. In particular, we have analysed 31 highly polymorphic microsatellites distributed at 3·8 Mege base (Mb) mean intervals along the short arm of the chromosome 1 in paired samples of DNA extracted from peripheral blood lymphocytes and tumour tissues. patients The study was carried out on 38 patients with pheochromocytoma that had been grouped, by careful clinical and molecular investigation, in the following classes: 21 sporadic, five multiple endocrine neoplasia type 2 (MEN2), two type 1 neurofibromatosis (NF1), five von Hippel–Lindau (VHL), one somatic VHL mutated and four nonsyndromic familial cases. results In 12/21 sporadic cases (57·1%), in 4/5 MEN2 (80%), 2/4 non-syndromic familial cases (50%), and in 2/2 NF1 (100%), the entire short arm was deleted, while in 6/21 sporadic (28·6%) and 1/5 MEN2 (20%) cases a partial deletion was detected. On the other hand, none of the five cases due to VHL mutation (either germline or somatic) had LOH at chromosome 1. In total, complete or partial deletion of 1p was detected in 27/38 (71%) of the cases. The most frequently deleted marker was D1S2890, which maps at 1p32.1. This region, which spans from 50 to 62 Mb from telomere, was therefore further investigated with markers located at a mean interval of 1·3 Mb in the subset of cases that showed a partial deletion of 1p. This analysis showed that a small region between 55·1 and 59·0 Mb was most frequently missing, which could therefore contain a novel pheochromocytoma locus. conclusions The results presented here confirm that the short arm of chromosome 1 harbours one or more genes responsible for the development of pheochromocytoma and suggest that one of them could map in a 3·9-Mb fragment between 1p32.3 and 1p32.1.

Summary objective Clinical acromegaly is characterized by elevated GH secretion in the presence of high circulating IGF-I levels. We hypothesized that the physiological IGF-I/GH negative feedback loop may be reset in somatotroph adenomas, specifically in terms of the level of expression of these receptors or mutations of the GH receptor (GH-R) in such tumours. methods We therefore investigated the full coding sequence of the GH-R in a series of somatotroph and other pituitary adenomas. We also investigated the mRNA expression of these putative feedback receptors in a series of pituitary adenomas and normal pituitary tissue, and their protein expression by immunostaining. Real-time RT–PCR assay was used for the quantification of the type 1 IGF receptor (IGF-R) and GH receptor (GH-R) mRNA, and sequence analysis was performed on the coding region of the GH-R gene. results No somatic mutations of the GH-R mRNA were detected in 18 GH-secreting tumours or two nonfunctioning pituitary adenomas (NFPAs). However, the levels of GH-R mRNA were significantly lower in both somatotroph tumours and NFPAs compared to the normal pituitary (P

Summary objective The aim of this study was to compare bone turnover and mass in women with either Cushing's syndrome (CS) or adrenal incidentaloma (AI), which is a possible model for minimal hypersecretion of cortisol. design and patients We studied 15 patients with CS (seven premenopausal and eight postmenopausal women); 23 patients with AI (five premenopausal and 18 postmenopausal women) and 20 matched controls (seven premenopausal and 13 postmenopausal women). Alkaline phosphatase (ALP), bone alkaline phosphatase (bALP), osteocalcin (BGP), 24-h urinary pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) and serum and 24-h urinary calcium and phosphorus were determined in all subjects. Bone mineral density (BMD) at lumbar spine and proximal femur was measured by dual energy X-ray absorptiometry (DEXA). results We found a significant reduction of BGP and serum phosphorus in CS and AI (P

Gitelman's syndrome (GS) is characterized by hyperreninaemic hyperaldosteronism, hypokalaemia, metabolic alkalosis, hypomagnesaemia and hypocalciuria and is due to a defect of the Na-Cl cotransporter at the distal tubule, which may appear in a sporadic or in a familial form. It is an autosomal recessive disorder associated with normal or reduced blood pressure. We report a case of severe hypomagnesaemia-induced hypocalcaemia in a 39-year-old Caucasian woman with GS. The patient had impaired parathormone (PTH) responsiveness to peripheral stimuli, as proved by the marked PTH increase and normalization of plasma calcium levels after acute and chronic administration of magnesium salts. Secondary normotensive hyperreninaemic hyperaldosteronism with hypokalaemia and metabolic alkalosis was also present. Normal plasma renin activity (PRA) and aldosterone levels were restored by administration of an inhibitor of prostaglandin synthesis. The electrolyte imbalance was successfully corrected with chronic treatment with magnesium and potassium salts. Genetic analysis identified a compound heterozygous mutation in the Na-Cl cotransporter gene (NCCT), confirming the diagnosis of GS. The striking feature of this case of GS was impaired PTH responsiveness to peripheral stimuli determined by hypomagnesaemia and the resulting severe hypocalcaemia, which had not previously been described in this syndrome.

Objective Cushing's disease (CD) presents a remarkable preponderance in female gender, with a female-to-male ratio of 3–8:1. The aim of this study was to evaluate gender-related differences in the presentation of CD, as regards: biochemical indices of hypercortisolism; sensitivity of diagnostic tests; clinical features and complications of disease. Methods We retrospectively studied 84 adult patients with CD, 67 women and 17 men, evaluated at diagnosis. We compared the features of the disease between the sexes and analysed the effect of gender on CD complications, adjusted for potential confounders (age, gonadal status, BMI, urinary free cortisol values). Results We observed no differences between males and females as regards age at diagnosis, disease duration and BMI. Men, compared with women, presented higher urinary free cortisol values (P

OBJECTIVE Two isoforms of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyse the interconversion of cortisol to hormonally inactive cortisone; defects in the 11 beta-HSD2 isoform result in hypertension. The kidney, expressing high levels of 11 beta-HSD2, is the principal source of cortisone in man. We have validated the measurement of urinary free cortisone (UFE) excretion in normals and in patients with disorders of the pitultary-adrenal axis in an attempt to more accurately measure the activity of 11 beta-HSD2 in vivo. SUBJECTS Forty-one normal adults, 12 normal children < 12 years of age, 15 patients with Cushing's syndrome, 12 with hypopitultarism on replacement hydrocortisone, 12 with the syndrome of apparent mineralocorticoid excess (AME) and 7 volunteers consuming liquorice. MEASUREMENTS A complete 24-hour urine collection was analysed by gas chromatography/mass spectrometry for "A-ring' reduced cortisol and cortisone metabolites, i.e. tetrahydrocortisols (THF and allo-THF) and tetrahydrocortisone (THE). In addition, urinary free cortisol (UFF) and urinary free cortisone were quantified using deuterium-labelled internal standards. RESULTS In normal adults and children, UFE excretion exceeded that of UFF (UFF 30.4 +/- 2.4 micrograms/24h (mean +/- SE), UFE 54.6 +/- 4.1 micrograms/24h, adults) (for conversion to nmol/24h multiply E by 2.78 and F by 2.76 respectively). Thus the normal UFF/UFE ratio was 0.54 +/- 0.05 in contrast to the (THF + allo-THF)/THE ratio of 1.21 +/- 0.06. UFE excretion was normal in hypopituitary patients on replacement hydrocortisone. Although UFE was elevated in all forms of Cushing's syndrome, the UFF/UFE ratio was grossly elevated in patients with the ectopic ACTH syndrome (14.0 +/- 6.7, n = 6). UFE was below the lower limit of the assay (< 1 microgram/24h) in most patients with the so-called type 1 variant of AME and significantly reduced in 4 patients described as having the type 2 variant of AME (10.5 +/- 3.5 micrograms/h, P < 0.05) and in 7 volunteers consuming liquorice (26.8 +/- 10.0 micrograms/24h, P < 0.01). In ectopic ACTH syndrome, AME, and liquorice ingestion the UFF/UFE ratio was more deranged than the (THF + allo-THF)/THE ratio. CONCLUSION In normals the discrepant THF + allo-THF/ THE and UFF/UFE ratio suggests that much more of the UFE is derived from the kidney. Reduction in UFE excretion is seen following liquorice ingestion and in both variants of AME, though it is more profound in AME1. The high UFF/UFE ratio in the mineralocorticoid excess state seen in the ectopic ACTH syndrome is compatible with substrate-saturation of renal 11 beta-HSD2. The measurement of UFE and the UFF/UFE ratio is a significant advance in the analysis of human 11 beta-HSD activity in vivo; in particular, the UFF/UFE ratio appears to be a more sensitive index than the (THF + allo-THF)/THE ratio of renal 11 beta-HSD2 activity.

SummaryObjective Diagnosing thyroid nodules preoperatively using traditional diagnostic tools – ultrasonography (US) and cytology – still carries a considerable degree of uncertainty, and surgery is recommended for a far from negligible number of patients simply for diagnostic purposes. Thyroid elastosonography (USE) and BRAF analysis have recently proved useful in detecting thyroid malignancies. The aim of this study is to establish whether combining USE and BRAF testing ameliorates preoperative diagnosis of thyroid nodule candidates for intervention by conventional approaches, thereby avoiding the need for diagnostic surgical procedures. Design and Patients We retrospectively analysed the files of 155 consecutive patients with 164 nodules, all assessed by ultrasonography, cytology, USE and BRAF testing, who underwent thyroid surgery. Results Of the 164 nodules, 74 (45%) were benign and 90 (55%) were malignant at final histology. Combining ultrasonography and cytology identified 21 (13%) as benign, 93 (57%) as malignant or probably malignant and 50 (30%) as ‘suspended’ (when the combined test was not able to classify the node as benign or malignant) with a 99% sensitivity, 28% specificity, 63% PPV, 95% NPV and 67% accuracy. Combining USE and BRAF testing indicated that 59 (36%) were benign, 74 (45%) were malignant and 31 (19%) were in a ‘suspended’ category, with a 95% sensitivity, 74% specificity, 82% PPV, 93% NPV and 86% accuracy. Conclusions In assessing thyroid nodules suspected of malignancy, the combined analysis of USE and BRAF is equally sensitive and more specific than conventional procedures, achieving more accurate preoperative diagnoses than US and cytology combined. USE and BRAF analysis for thyroid nodule evaluation might reduce the number of unnecessary surgical procedures.

Objective Our study aimed to investigate whether physiological doses of selenium (Se) influence the natural course of autoimmune thyroiditis (AIT). Design and patients A total of 76 consecutive patients (65 F, 11 M, median 43, range 15-75 years) with AIT, normal or slightly elevated TSH and fT4 within the normal range were divided into two groups: Group 0 (30 cases) was given no treatment while Group 1 (46 cases) was treated with sodium selenite 80 μg/day as a single oral dose for 12 months. Thyroperoxidase and thyroglobulin autoantibodies (TPO-Ab; Tg-Ab), TSH, fT4 and urine iodine concentrations (UIC) were measured at baseline and after 6 and 12 months of follow-up. Thyroid ultrasonography (US) was performed at each follow-up point. Echogenicity was measured by histographic analysis of gray-scale pixels (gsp) ranging from 0 = black to 255 = white. Results Thyroid echogenicity decreased significantly in both groups after 6 months, but after 12 months, it had changed no more in Group 1, whereas it had dropped further in Group 0. No significant variation in TPO-Ab or Tg-Ab levels was observed between the two groups after 6 months, but both values decreased significantly after 12 months in Group 1, and five patients in this group became negative for TPO-Ab. TSH and FT4 showed no significant variations in either group. Conclusions Dietary supplementation with physiological doses of Se seems to be effective in preventing a reduction in thyroid echogenicity after 6 months of treatment and in reducing TPO-Ab and Tg-Ab after 12 months, but does not modify TSH or FT4.

Objective Ketoconazole treatment of Cushing's syndrome has been reported in single cases and a few small groups of 5-8 patients. We report our experience in 34 patients. Design Clinical study, with pretreatment and post-treatment evaluations. Patients Out of 67 patients with Cushing's syndrome admitted during the last 6 years, 34 (28 females/six males; age range 14-67 years) received ketoconazole as a palliative treatment due to severe clinical conditions or management of the disease while awaiting results of definitive therapy. Measurements Urinary cortisol, plasma cortisol and ACTH, and routine chemistry were measured every week for 4 weeks, and then once a month. Results Comparing the last values (mean +/- SEM) during treatment with baseline, urinary cortisol decreased from 1296 +/- 176 to 270 +/- 69 nmol/d (n = 34; P less than 0.001); plasma cortisol decreased from 672 +/- 31 to 549 +/- 35 nmol/l (n = 34; P less than 0.001). For patients with pituitary-dependent Cushing's syndrome, urinary cortisol decreased from 1073 +/- 126 to 200 +/- 21 nmol/d (n = 28; P less than 0.001) while plasma ACTH changed from 12.5 +/- 1.3 to 11.3 +/- 0.8 pmol/l (n = 26; not significant). Twelve patients were treated for more than 6 months, and those with pituitary-dependent disease all received pituitary radiation therapy, except the two who eventually escaped pharmacological control. One additional patient with adrenal carcinoma and one with ectopic ACTH syndrome showed lack of control of urinary cortisol levels. Ketoconazole was withdrawn within the first week in two patients for allergic reaction and acute liver toxicity. Other side-effects included: asymptomatic liver function abnormalities in three patients; gastrointestinal symptoms in four; worsening of gynaecomastia in one. Rapid clinical improvement was observed together with the normalization of urinary cortisol levels, with regression of symptoms such as diabetes mellitus, hypertension, hypokalaemia, and restoration of well being. Conclusions These data confirm that ketoconazole is valuable in the management of hypercortisolism, provided that patients are closely watched to exclude those who may develop liver toxicity and to prevent the occurrence of adrenal insufficiency.

OBJECTIVES A study was conducted on iodine status during pregnancy and its dependence on dietary habits, racial and geographical origin, and time since arrival in Italy. DESIGN AND METHODS We enrolled 322 consecutive pregnant women: 217 Italians, 62 Eastern Europeans and 43 from Northern and Central Africa. All women completed a food frequency questionnaire on their dietary habits. The urinary iodide concentration (UIC) was determined in spot morning urine samples. RESULTS In the group as a whole, the median UIC was 83 microg/l; the UIC was < 50 in 33% and of 150 microg/l or more in 27%; it was significantly lower in Africans and Eastern Europeans than in Italians (medians 45 and 46 vs. 100 microg/l, respectively, P = 0.005). For the foreign women, there was a significant correlation between UIC and time since arrival in Italy (r = 0.22, P = 0.02). A significant link emerged between UIC and cow's milk intake (P = 0.0001). Iodine supplements were used by 40% of the women, and UIC were higher in those who did so than in those who did not (median 103 vs. 75 microg/l, P = 0.03), particularly if the latter did not drink milk (median 98 vs. 42 microg/l, P = 0.01). Multivariate analysis showed that milk was the only variable influencing UIC (OR 1.29, P = 0.0005). CONCLUSIONS (i) Iodine levels are too low among pregnant women in our region, and particularly in foreign women. (ii) Cow's milk intake is their main source of iodine. (iii) Iodine supplementation is mandatory during pregnancy, particularly for women do not drink milk.

objective In patients with Cushing's syndrome (CS) cardiovascular complications determine a mortality rate four times higher than in an age- and gender-matched population. Therefore, we calculated the global cardiovascular risk in patients with CS. design and patients We applied the World Health Organization − International Society of Hypertension (WHO/ISH) 1999 guidelines for the estimation of cardiovascular risk in 38 females and 11 males with CS; 27 pituitary adenomas, 15 adrenal adenomas, four adrenal carcinomas and three ectopic ACTH-secreting tumours. The risk of major cardiovascular events was estimated considering the combined effect of several risk factors (hypertension, diabetes, etc.), organ damage (left ventricular hypertrophy (LVH), proteinuria, etc.) and associated pathologies. Four categories of absolute cardiovascular disease risk were defined (low, medium, high, very high). results Eighty per cent of patients presented a ‘high’ or ‘very high’ cardiovascular risk; 85·1% of the patients were hypertensive with a mild-moderate hypertension (68%). Forty-seven per cent of patients were diabetics and 41·3% were obese. Hyperlipidaemia was less frequent (37·5%). Fasting glycaemia was the only cardiovascular risk factor that correlated with a degree of hypercortisolism. Duration of disease correlated with the presence of obesity (P

Despite the very recent discovery that about 25% of apparently sporadic forms of pheochromocytoma are actually due to germline mutations of RET, VHL, SDHB or SDHD genes, the genetic bases of the tumourigenesis of this type of cancer are still incompletely understood. Recent studies provided evidence that a new tumour suppressor gene, mapping on the short arm of chromosome 1, could be involved in early tumourigenesis of pheochromocytoma.We have performed a fine analysis of loss of heterozygosity (LOH) of this region. In particular, we have analysed 31 highly polymorphic microsatellites distributed at 3.8 Mege base (Mb) mean intervals along the short arm of the chromosome 1 in paired samples of DNA extracted from peripheral blood lymphocytes and tumour tissues.The study was carried out on 38 patients with pheochromocytoma that had been grouped, by careful clinical and molecular investigation, in the following classes: 21 sporadic, five multiple endocrine neoplasia type 2 (MEN2), two type 1 neurofibromatosis (NF1), five von Hippel-Lindau (VHL), one somatic VHL mutated and four nonsyndromic familial cases.In 12/21 sporadic cases (57.1%), in 4/5 MEN2 (80%), 2/4 non-syndromic familial cases (50%), and in 2/2 NF1 (100%), the entire short arm was deleted, while in 6/21 sporadic (28.6%) and 1/5 MEN2 (20%) cases a partial deletion was detected. On the other hand, none of the five cases due to VHL mutation (either germline or somatic) had LOH at chromosome 1. In total, complete or partial deletion of 1p was detected in 27/38 (71%) of the cases. The most frequently deleted marker was D1S2890, which maps at 1p32.1. This region, which spans from 50 to 62 Mb from telomere, was therefore further investigated with markers located at a mean interval of 1.3 Mb in the subset of cases that showed a partial deletion of 1p. This analysis showed that a small region between 55.1 and 59.0 Mb was most frequently missing, which could therefore contain a novel pheochromocytoma locus.The results presented here confirm that the short arm of chromosome 1 harbours one or more genes responsible for the development of pheochromocytoma and suggest that one of them could map in a 3.9-Mb fragment between 1p32.3 and 1p32.1.

OBJECTIVE: Clinical acromegaly is characterized by elevated GH secretion in the presence of high circulating IGF-I levels. We hypothesized that the physiological IGF-I/GH negative feedback loop may be reset in somatotroph adenomas, specifically in terms of the level of expression of these receptors or mutations of the GH receptor (GH-R) in such tumours. METHODS: We therefore investigated the full coding sequence of the GH-R in a series of somatotroph and other pituitary adenomas. We also investigated the mRNA expression of these putative feedback receptors in a series of pituitary adenomas and normal pituitary tissue, and their protein expression by immunostaining. Real-time RT-PCR assay was used for the quantification of the type 1 IGF receptor (IGF-R) and GH receptor (GH-R) mRNA, and sequence analysis was performed on the coding region of the GH-R gene. RESULTS: No somatic mutations of the GH-R mRNA were detected in 18 GH-secreting tumours or two nonfunctioning pituitary adenomas (NFPAs). However, the levels of GH-R mRNA were significantly lower in both somatotroph tumours and NFPAs compared to the normal pituitary (P < 0.05 for both). Immunostaining for GH-R also showed significantly less GH-R expression in somatotroph adenomas compared to normal pituitary tissue (P < 0.0001). IGF-R mRNA levels were significantly lower in somatotroph tumours compared to normal pituitary (P = 0.005), and trended lower in corticotroph tumours (P = 0.07), while the other tumour types showed no significant difference from normal pituitary. Immunostaining for IGF-R also showed less IGF-R protein in the somatotroph adenomas compared to the normal pituitary tissue (P < 0.01). CONCLUSIONS: Our findings suggest that decreased feedback inhibition of GH because of somatic mutations of the coding region of the GH-R are unlikely to be a common factor in the pathogenesis of these tumours. Nevertheless, decreased expression of the GH-R and of IGF-R in somatotroph tumours (both at the mRNA and protein level) may, at least in part, help explain the continuous secretion of GH from the tumour despite the high circulating levels of IGF-I and GH.

Clinical acromegaly is characterized by elevated GH secretion in the presence of high circulating IGF-I levels. We hypothesized that the physiological IGF-I/GH negative feedback loop may be reset in somatotroph adenomas, specifically in terms of the level of expression of these receptors or mutations of the GH receptor (GH-R) in such tumours.We therefore investigated the full coding sequence of the GH-R in a series of somatotroph and other pituitary adenomas. We also investigated the mRNA expression of these putative feedback receptors in a series of pituitary adenomas and normal pituitary tissue, and their protein expression by immunostaining. Real-time RT-PCR assay was used for the quantification of the type 1 IGF receptor (IGF-R) and GH receptor (GH-R) mRNA, and sequence analysis was performed on the coding region of the GH-R gene.No somatic mutations of the GH-R mRNA were detected in 18 GH-secreting tumours or two nonfunctioning pituitary adenomas (NFPAs). However, the levels of GH-R mRNA were significantly lower in both somatotroph tumours and NFPAs compared to the normal pituitary (P0.05 for both). Immunostaining for GH-R also showed significantly less GH-R expression in somatotroph adenomas compared to normal pituitary tissue (P0.0001). IGF-R mRNA levels were significantly lower in somatotroph tumours compared to normal pituitary (P = 0.005), and trended lower in corticotroph tumours (P = 0.07), while the other tumour types showed no significant difference from normal pituitary. Immunostaining for IGF-R also showed less IGF-R protein in the somatotroph adenomas compared to the normal pituitary tissue (P0.01).Our findings suggest that decreased feedback inhibition of GH because of somatic mutations of the coding region of the GH-R are unlikely to be a common factor in the pathogenesis of these tumours. Nevertheless, decreased expression of the GH-R and of IGF-R in somatotroph tumours (both at the mRNA and protein level) may, at least in part, help explain the continuous secretion of GH from the tumour despite the high circulating levels of IGF-I and GH.

The aim of this study was to compare bone turnover and mass in women with either Cushing's syndrome (CS) or adrenal incidentaloma (AI), which is a possible model for minimal hypersecretion of cortisol.We studied 15 patients with CS (seven premenopausal and eight postmenopausal women); 23 patients with AI (five premenopausal and 18 postmenopausal women) and 20 matched controls (seven premenopausal and 13 postmenopausal women). Alkaline phosphatase (ALP), bone alkaline phosphatase (bALP), osteocalcin (BGP), 24-h urinary pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) and serum and 24-h urinary calcium and phosphorus were determined in all subjects. Bone mineral density (BMD) at lumbar spine and proximal femur was measured by dual energy X-ray absorptiometry (DEXA).We found a significant reduction of BGP and serum phosphorus in CS and AI (P0.05) vs. controls and significantly lower levels of Pyr only in CS (P0.05) vs. AI and controls. Spinal and femoral BMD z-values were significantly lower (P0.05) in patients with CS (z-score: lumbar spine -1.44 +/- 1.5 and femoral neck -1.07 +/- 1; mean +/- SD) compared to AI and controls.Our data show that hypercortisolism reduces osteoblastic function and bone resorption and that osteocalcin can contribute to the precocious diagnosis of silent glucocorticoid excess. Patients with active CS were found to have lower BMD, particularly at vertebral level.