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Nowadays, the role of surgery in the treatment of adrenal incidentalomas (AI), considering their biologic behavior, is still debated. Surgery is mandatory in cases of hyperfunctioning adrenal masses, in the presence of suspect radiological malignancy, in cases of discordant computed tomography (CT) and scintigraphy findings and when the maximum diameter is 4 cm or more. On the other hand, studies have suggested relative inaccuracy of conventional CT in evaluating the size. The aim of this paper was to evaluate the safety and effectiveness of laparoscopic adrenalectomy (LA) in the treatment of AI by reviewing our experience. Over the period from 1995 to 2005 we laparoscopically managed 78 AI by anterior transperitoneal approach. Two LA (2.6%) were converted to open surgery. Neither intra- nor post-operative major complications were observed. The mean size of lesions was 5.5 cm (range 3-9). Twenty-one large adrenal lesions (exceeding 6 cm) were removed (27%). Definitive histology resulted as follows: adrenocortical adenoma (63), pheochromocytoma (5), nodular hyperplasia (4), myelolipoma (3), cysts (2), and adrenocortical carcinoma (1, with a size of 3 cm). The patients were followed-up by hormonal and radiological evaluation every 12 months (6 for malignancy); their follow-up (median 60.4 months, range 6-123) was uneventful. Also larger AI were treated safely. Laparoscopy has been safe and effective in the treatment of AI in our experience, according to specific literature.

Chronic cortisol hypersecretion causes central obesity, hypertension, insulin resistance, dyslipidemia, protrombotic state, manifestations which form a metabolic syndrome in all patients with Cushing's syndrome. These associated abnormalities determine an increased cardiovascular risk not only during the active phase of the disease but also long after the "biomedical remission". Clinical management of these patients should be particularly careful in identifying global cardiovascular risk. Considering that remission from hypercortisolism is often difficult to achieve care and control of all cardiovascular risk factors should be one of the primary goals during the follow up of these patients. Extending the indications of the recent consensus on Cushing's syndrome, we suggest to carry out an OGTT to avoid underestimation of diabetes mellitus, an echocardiography and Doppler ultrasonography of the epiaortic vessels in all patients at diagnosis and during follow-up.

Excess production of aldosterone or cortisol has profound effects on cardiovascular function and impacts other major organ systems. The mechanisms leading to the autonomous hypersecretion of aldosterone or cortisol in aldosterone-producing adenoma (APA) or cortisol-producing adenoma (CPA) are unknown.The objective of this study was to compare the expression profiles of several steroid-metabolizing enzymes and transcription factors from normal adrenal (NA), APAs, and CPAs.RNA from NAs, APAs, and CPAs were analyzed by microarray and real-time RT-PCR.This study was performed at academic research laboratories.At least nine normal controls and 12 patients with APA or CPA were studied.There was no intervention procedure.The main outcome measure was the expression of steroidogenic enzymes in adrenocortical disease.A microarray indicated a greater than 3-fold increase in the expression of CYP11B2 (aldosterone synthase) in APA, whereas 11beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) and HSD17B1 had greater than 3-fold increases in expression in CPA compared with NA. Real-time RT-PCR showed that APAs produced higher levels of HSD3B2, CYP21 (21-hydroxylase), and CYP11B2 mRNA, whereas CPAs produced higher levels of CYP11A (cholesterol side-chain cleavage), CYP17 (17alpha-hydroxylase/17-20 lyase), HSD3B2, and CYP11B1 (11beta-hydroxylase) mRNA compared with normal adrenal. Steroidogenic factor-1, DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome gene 1), and GATA-6 were expressed at higher levels in APAs and CPAs, whereas NURR1 was expressed at higher levels in APAs than in CPAs or NAs.Elevated production of aldosterone in APAs and of cortisol in CPAs is associated with increased expression of enzymes needed for corticosteroid production along with alterations in transcription factors that enhance the expression of steroid-metabolizing enzymes.

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

Selective Alzheimer's disease indicator-1 (seladin-1) is a novel gene with antiapoptotic activity that is down-regulated in vulnerable brain regions in Alzheimer's disease. This gene encodes 3-beta-hydroxysterol Delta-24-reductase (DHCR24), which converts desmosterol into cholesterol. In the adrenal cortex, increased expression of seladin-1/DHCR24, which appears to be modulated by ACTH, has been recently reported in cortisol-secreting adenomas, compared with the adjacent atrophic tissue. In our study, we measured the expression level of seladin-1/DHCR24 in cortisol- (n = 18) and aldosterone-secreting (n = 16) adrenocortical adenomas, in carcinomas (n = 17), and in normal adrenal glands (n = 8) by quantitative real-time RT-PCR. The amount of seladin-1/DHCR24 mRNA was significantly reduced in carcinomas (total RNA, 2.5 +/- 0.8 pg/ micro g) compared with the other groups (P < 0.01). Western blot analysis confirmed the mRNA results. Similarly, in adrenal malignancies, significantly reduced levels of expression of the ACTH receptor gene were found. In the adrenal cancer cell line H295R and in primary cultures from adrenocortical cells, ACTH (1 nM) and forskolin (10 micro M) effectively increased seladin-1/DHCR24 expression, confirming that seladin-1/DHCR24 is modulated by the ACTH/cAMP-driven pathway. In summary, this is the first demonstration that seladin-1/DHCR24 expression is reduced in adrenal cancer, suggesting that it might be viewed as a new potential marker of adrenal malignancies.

Primary adrenal insufficiency (PAI) is clinically evident in one in 8000 individuals. A correct etiological classification is critical for correct disease management. To update the diagnostic criteria for the etiological classification of PAI, a multicentric network was established in Italy, and 222 patients with PAI were studied. Both 21-hydroxylase and adrenal cortex autoantibodies (21OHAb and ACA, respectively) were tested in two independent laboratories on coded samples and found in 65-66% and 58-61% of cases, respectively. Autoimmune polyendocrine syndrome I was diagnosed in 11 of the 222 patients. Of the remaining 211 patients, 38 (18%) had a nonautoimmune form of PAI. In 145 subjects (65%), the presence of adrenal autoantibodies, without signs of other forms of PAI, led to a diagnosis of autoimmune Addison's disease. In six cases (3%), PAI remained idiopathic. Logistic regression analysis showed a 92.2-92.7% probability of correct reclassification for the two 21OHAb assays and 84.5-85.9% for the ACA assays. We conclude that the simultaneous presence of both 21OHAb and ACA permits unambiguous diagnosis of autoimmune Addison's, whereas subjects with low antibody titers should undergo both instrumental and biochemical tests to exclude other causes of PAI. Lastly, we developed a comprehensive flowchart for the classification of PAI for use in routine clinical practice.

A 56-yr-old woman was referred with a diagnosis of Cushing’s disease. Hypertension and severe hypokalemia were present and high urinary free cortisol/cortisone ratio was detected, raising a suspicion of an ectopic ACTH syndrome. Inferior petrosal sinus sampling, thoracic computed tomography, and octreotide scans were negative. Remission and relapse periods lasting 3–4 months were observed during the 3.5 yr of follow-up. Finally a thoracic computed tomography scan showed a basal paracardic nodule in the left lung. After surgery, a well-differentiated neuroendocrine tumor (typical bronchial carcinoid) was diagnosed, staining positively for ACTH. RT-PCR revealed expression of proopiomelanocortin, CRH receptor, and V3 vasopressin receptor. Somatostatin receptor type 1, 2, 3, and 5 mRNA was detected only in tumoral tissue. Interestingly, we observed the simultaneous presence of ghrelin and both GH secretagogue (GHS) receptors (1a and 1b) mRNA in tumoral tissue but not in the normal lung. This finding correlates with the in vivo ACTH hyperresponsiveness to hexarelin (a GHS). This is the first report of a cyclical ectopic ACTH-secreting tumor with an in vivo ACTH response to hexarelin coupled with the tumoral expression of ghrelin and GHS receptors. This finding might imply an autocrine/paracrine modulatory effect of ghrelin in bronchial ACTH-secreting tumors.

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.

Adrenal adenomas and carcinomas are mostly monoclonal, suggesting that a genetic alteration in a progenitor cell may contribute to their development. However, the molecular pathogenesis of these tumors still remains unclear. It has been already excluded that activating mutations of the ACTH receptor or of G protein stimulator alpha sub-units, affecting cAMP pathway, is involved in the tumorigenesis. Therefore, this work has been focused on post-transductional (ACTH) signal alterations and in particular on the mutational analysis of the Steroid Acute Regulatory protein (StAR) gene to verify whether somatic mutations or genomic polymorphisms of this gene may be correlated with adrenal tumorigenesis. Tissue DNA was extracted from 40 functional and non-functional adrenocortical tumors that were removed from patients aged between 17 and 72 years (mean 43 ± 4). Blood DNA was obtained from 24 patients (aged between 26 and 70 years) affected by adrenal tumors and from 100 healthy subjects without radiological and clinical evidence of adrenal masses, aged between 25–35 years (90 Caucasians and 10 Africans). The DNA was used as the template for the amplification of the StAR gene using the polymerase chain reaction. The amplified DNA of each exon of the StAR gene was purified and sequenced in automatic sequenciator. With the exception of exon 5 showing in codon 203 an homozygous missense mutation, the sequence of the other exons of the StAR gene resulted normal in all tumors studied. The same homozygous mutation (Asp203Ala) was observed in the sequence of exon 5 performed on genomic DNA of the 24 affected patients and in the control subjects. The homozigousity of the mutation observed in all patients (either in tissue or blood samples) and in control subjects, independently of their ethnic origin, led us to suggest that the Asp203Ala cannot be considered as mutation or as polymorphism, but that it must be considered as a mistake in the sequence entered in the Genbank, which needs to be modified accordingly. These data, and those up to now reported in the literature, allow us to suggest that mutations of the gene coding for the protein involved in the initial step of the steroidogenesis could not be considered as a possible cause for the development of adrenal tumors. © 2001 Wiley-Liss, Inc.

Levels of coenzyme Q10 (CoQ10) and of its reduced and oxidized forms (ubiquinol, QH2, and ubiquinone, Qox) have been determined in sperm cells and seminal plasma of idiopathic (IDA) and varicocele-associated (VARA) asthenozoospermic patients and of controls. The results have shown significantly lower levels of coenzyme Q10 and of its reduced form, QH2, in semen samples from patients with asthenospermia; furthermore, the coenzyme Q10 content was mainly associated with spermatozoa. Interestingly, sperm cells from IDA patients exhibited significantly lower levels of CoQ10 and QH2 when compared to VARA ones. The QH2/Qox ratio was significantly lower in sperm cells from IDA patients and in seminal plasma from IDA and VARA patients when compared with the control group. The present data suggest that the QH2/Qox ratio may be an index of oxidative stress and its reduction, a risk factor for semen quality. Therefore, the present data could suggest that sperm cells, characterized by low motility and abnormal morphology, have low levels of coenzyme Q10. As a consequence, they could be less capable in dealing with oxidative stress which could lead to a reduced QH2/Qox ratio. Furthermore, the significantly lower levels of CoQ10 and QH2 levels in sperm cells from IDA patients, when compared to VARA ones, enable us to hypothesize a pathogenetic role of antioxidant impairment, at least as a cofactor, in idiopathic forms of asthenozoospermia.

The molecular mechanisms leading to adrenocortical tumorigenesis have been only partially elucidated so far. Because the pituitary hormone ACTH, via activation of the cAMP pathway, regulates both cell proliferation/differentiation and steroid synthesis in the adrenal cortex, in this study we focused on the cAMP-dependent transcription factors cAMP responsive element modulator (CREM) and cAMP responsive element binding protein (CREB). We studied CREM and CREB expression by RT-PCR in human normal adrenal cortex (n = 3), adrenocortical adenomas (n = 8), and carcinomas (n = 8). We found transcripts corresponding to the isoforms α, β, γ, and τ2 of the CREM gene in all of the normal adrenal tissues, in the adenomas, and in seven of eight carcinomas. On the other hand, mRNA for the inducible cAMP early repressor isoforms, which derive from an internal promoter of CREM gene, was detected in the normal adrenal and in seven of eight adenomas, but in only three of eight carcinomas. Similarly, CREB transcripts were readily detectable in all normal adrenals and adenomas, whereas they were not found in four of eight adrenal carcinomas. To further characterize the carcinomas, telomerase activity and the expression of the ACTH receptor gene were determined. Telomerase activity in the carcinomas resulted in levels significantly higher than in the adenomas, whereas the levels of ACTH receptor mRNA were lower in the carcinomas. No correlation was found in the carcinomas between the levels of the ACTH receptor transcript and the loss of expression of CREB/inducible cAMP early repressor, suggesting that this alteration is not secondary to an upstream disregulation at the receptor level. In conclusion, our results suggest that an alteration in cAMP signaling may be associated with malignancies of the adrenal cortex.

TGFbeta1, a multifunctional growth modulator, inhibits the proliferation of epithelial cells. TGFbeta1 signaling is dependent on the heterodimerization of the TGFbeta1 receptor II (TGFbeta1RII) with the TGFbeta1 receptor I (TGFbeta1RI). The cytoplasmic proteins Smads are the mediators of the TGFbeta1 signal. TGFbeta1 regulates adult and fetal adrenal growth and function. Previously we have shown by Northern analysis that TGFbeta1mRNA was well expressed in normal adrenal and in adrenocortical adenomas but reduced in carcinomas. To investigate whether TGFbeta1 receptors may act as tumor suppressors of adrenal tumorigenesis, 16 adenomas and 12 carcinomas were studied. We have used SSCP analysis to scan for inactivating mutations in carcinomas. All tumor samples were negative for somatic alterations of both genes. A competitive RT-PCR system was developed to compare the levels of expression of TGFbeta1, TGFbeta1R-I and TGFbeta1R-II, Smad-2 and Smad-4 genes in all tumors. In our study, we confirmed the presence of reduced levels of TGFbeta1 in carcinomas. On the contrary, Smad-4 gene levels were elevated in carcinomas when compared to that of adenomas. No significant differences were observed in gene expression of TGFbeta1RI and Smad-2. Our results suggest that mutations of TGFbeta1 receptors appear not to be involved in adrenal tumorigenesis. Adrenal carcinomas showed a significant reduction of the TGFbeta1 mRNA levels but on the contrary Smad 4 mRNA levels were significantly increased.

We report an unusual case of renovascular hypertension in a 16-year-old boy with primary antiphospholipid syndrome (PAPS), admitted to our clinic for severe drug-resistant hypertension and hypokalemia. Hormonal investigation revealed secondary aldosteronism and positive captopril test for renovascular disease. Aortography confirmed the occlusion of the left renal artery. After nephrectomy, normalization of blood pressure and secondary aldosteronism occurred. Presently the patient remains in good health, receiving warfarin anticoagulant therapy. PAPS is defined by the presence of antiphospholipid antibodies and recurrent thrombosis. Arterial thrombosis (29%) appears to be less prevalent than venous thrombosis. Thrombotic microangiopathy of the kidney is frequently observed but renal artery occlusion, as seen in our patient, is unusual.

We previously reported that ACTH receptor (ACTH-R) mRNA is expressed in cortisol-secreting adrenal tumors, with significant differences between adenomas and carcinomas. In order to complete the study we have now evaluated 11 aldosteronomas (APA), 14 non-hypersecreting adenomas, 2 androgen-secreting adenomas and 8 normal adrenal glands. The level of ACTH-R mRNA was evaluated by competitive RT-PCR using a non-homologous competitor. ACTH-R gene was expressed in all tissues. All APA showed highest ACTH-R mRNA levels. Despite signs of individual heterogeneity, the level of ACTH-R transcripts was reduced in carcinomas. Furthermore, no significant differences were observed among cortisol-secreting adenomas, non hypersecreting adenomas and controls. The results show that ACTH-R mRNA is expressed in all adrenocortical tumors. The overexpression of ACTH-R in APA supports the role of ACTH on aldosterone secretion in these tumors, as also suggested by the presence of a diurnal rhythm, the lack of response to Angiotensin II, upright posture and captopril administration. The low abundance of ACTH-R in carcinomas might be a useful molecular marker of malignancy even if some overlap between carcinomas and adenomas does exist.

OBJECTIVE: To investigate the feasibility, safety and results of laparoscopic transperitoneal adrenalectomies performed with the patient supine, in patients affected by secreting and silent adrenal lesions. METHODS: Exclusion criteria were suspected adrenal primary malignancies. Fifty patients (33 women and 17 men; mean age 49.6 years, range 19-75 years) underwent 51 laparoscopic adrenalectomies (one bilateral). After complete endocrinological evaluation, computed tomography or magnetic resonance imaging, or a combination thereof, 14 non-secreting adenomas, 13 aldosterone-producing adenomas, 13 cortisol-producing adenomas, eight phaeochromocytomas (one bilateral), one androgen-secreting adenoma, and two metastases were considered eligible for adrenalectomy. In five patients, associated procedures were performed during surgery. RESULTS: The lesions ranged in size from 1.5 to 10 cm. There were no intraoperative complications and no blood transfusions were required. The postoperative course was uneventful and painless in all patients. Mean postoperative hospital stay was 2.5 days. In all hypertensive patients, significant improvement or cure of hypertension was observed at follow-up (mean 18 months). In patients with secreting adenomas, normalization of hormone concentrations was obtained after removal of the tumour. In six patients with incidentaloma, the exaggerated 17-hydroxyprogesterone response to ACTH disappeared after surgery. CONCLUSIONS: Secreting and non-secreting adrenal lesions were treated safely by laparoscopy. Relatively small incidentalomas and subclinical hormonally active tumours can be removed by laparoscopy. Early diagnosis enhances prevention and treatment.

Morosini PP, Taccaliti A, Arnaldi G, Simonella G, Petrelli MD, Mancini V, Montironi R, Scarpelli M. Diamanti L, Mantero F. Enhanced expression of transforming growth factor β1 in rat thyroid hyperplasia is thyrotropin induced and time dependent. Eur J Endocrinol 1996:134:373–8. ISSN 0804–4643 Forty-three 8-week-old male Wistar rats were studied to evaluate temporal changes of transforming growth factor β1 TGF-β1) mRNA levels in thyroid tissue during pharmacologically induced goiter. Four rats were treated with purified bovine thyrotropin (TSH; Ambinon, 2 mU/day sc) for 7 days before being sacrificed. Thirty-one were treated with propylthiouracil (PTU), added to their drinking water at a concentration of 0.2 g%, and subsequently were sacrificed as follows: five after 1 week PTU-1): five after 2 weeks PTU-2): five after 4 weeks PTU-4): five after 8 weeks PTU-8): five after 12 weeks (PTU-12). In six rats, after 12 weeks of treatment, PTU was withdrawn for 2 months and subsequently started again in three rats which were sacrificed after 2 weeks (PTU-R); the remaining three rats were sacrificed without any further treatment (PTU-R control). Eight rats (control rats) were never treated and served as controls. After sacrifice, blood was drawn for determination of total thyroxine and the thyroid was excised and subdivided into two lobes. Northern analysis for TGF-β1 was performed in one lobe, while histological and immunohistochemical studies were performed in the other lobe. Gene expression of TGF-β1 was induced in TSH- and PTU-treated rats. In TSH-treated rats TGF-β1 gene expression was less detectable than in PTU-treated rats, where it became evident after 2 weeks and remained through weeks 4–8. Gene expression of TGF-β1 was also seen in PTU-R rats, but not in the control and in the PTU-R control. Immunohistochemical analysis showed a different presence and location for the TGF-β1 protein, which appears to be dependent on the time of exposure to mitogenic stimulus. In conclusion, TGF-β1 is produced in response to both a direct (TSH by itself) and indirect (TSH induced by PTU-induced hypothyroidism) cellular proliferative stimulus and is not linked to an adaptative phenomenon secondary to hypothyroidism. The immunohistochemical location of TGF-β1 within the thyrocytes is influenced by mitogen exposure time. A TGF-β1 immunohistochemical evaluation may be important to define exposure time and activity of goitrogenic stimuli. Pierpaolo Morosini, Clinica di Endocrinologia, c/o Ospedale Regionale, Via Conca, 60100 Torrette Ancona, Italy

It is well known that TSH is the main factor responsible for thyrocyte proliferation and growth. Recent studies have shown that other growth factors, including transforming growth factor-beta 1 (TGF-beta 1), have an important role in the control of thyrocyte proliferation and differentiation. The aim of the study was to evaluate the expression of the TGF-beta 1 gene in thyroid follicular adenoma (FA) by Northern analysis, and its protein localization by immunohistochemistry. Surgically removed thyroid tissue from 56 patients with thyroid FA was screened for the study. Normal thyroid tissue from 4 patients with papillary carcinoma was used as a control. Sixteen FA (8 with a "cold" and 8 with a "hot" scintiscan pattern) having homogeneous histological characteristics were subsequently selected. FA showed greater TGF-beta 1 gene expression than control tissue. There was not a statistically significant difference between "cold" and "hot" FA. Immunohistochemistry analysis showed that TGF-beta 1 was located in various histological structures of the adenomas (thyrocytes, endothelium, perinervium and connective tissue); on the other hand, perinodular and control tissue did not show appreciable TGF-beta 1 protein. Our data suggest that TGF-beta 1 may be involved in the pathogenesis of FA. The different TGF-beta 1 distribution in thyrocytes, endothelium, perinervium and connective tissue in FA suggests that TGF-beta 1 may be variably expressed during the natural history of FA. Since no significant difference in TGF-beta 1 gene expression between "hot" and "cold" adenomas was found, it appears that other factors are involved in their functional differentiation.

The syndrome of apparent mineralocorticoid excess (AME) is currently understood to reflect impaired peripheral metabolism of cortisol, which is then able to activate the non-selective mineralocorticoid (MC) receptor. The failure of glucocorticoid inactivation at the MC target tissue level in AME involves abnormal activity of 11β-hydroxysteroid dehydrogenase, with impaired conversion of cortisol to cortisone, and also of 5β-reductase. We have discovered a new form of AME (Type II) in four patietns with the same clinical picture of hypertension, hypokalemia, and suppressed renin-angiotensin-aldosterone system, but in whom this conversion seems either to be normal (since cortisol to cortisone metabolite ratio is normal) or to be impaired in both directions, leaving the ratio unchanged. Both types are characterized by a profound decrease in cortisol turnover quotient and Ring A reduction constant. Short-term dexamethasone treatment is effective in correcting the MC-derived abnormalities, while in the long term the addition of other antihypertensive drugs may be required to control the severity of hypertension.

Previous investigations have demonstrated certain similarities in the cellular changes occurring in the arterial wall in response to hypertension and aging. We undertook the current studies to examine the expression of platelet-derived growth factor (PDGF) receptors and ligands and transforming growth factor-beta 1 (TGF-beta 1) in aorta and heart of spontaneously hypertensive rats (SHRs), Wistar-Kyoto (WKY) controls, and Wistar rats studied at ages ranging from 5 to 40 weeks. A progressive increase with age in aortic steady-state messenger RNA (mRNA) levels of the receptor for the B chain of PDGF (PDGF-r beta) was present in all three strains but was greatest in the SHR. The aortic expression of PDGF A or B ligands as well as of the PDGF-r alpha-receptor was not significantly influenced by age or blood pressure. In contrast, in the heart of the SHR and WKY rat, there was an age-related decrease in expression of both PDGF receptors and of the PDGF B chain. Hypertension and aging were associated with increases in steady-state mRNA for TGF-beta 1 in aorta, but in the heart, reductions again were observed. These studies indicate that both hypertension and aging increase the in vivo expression of PDGF-r beta and TGF-beta 1 in aortic tissue. Such changes might be functionally significant and provide autocrine or paracrine mechanisms for regulation of cellular growth in the arterial wall in response to these conditions. The findings also provide further support for the concept that hypertension accelerates the arterial changes associated with aging.

Background: In 2007, we published an opinion document to review the role of pegvisomant (PEG) in the treatment of acromegaly. Since then, new evidence emerged on the biochemical and clinical effects of PEG and on its long-term efficacy and safety. Aim: We here reviewed the emerging aspects of the use of PEG in clinical practice in the light of the most recent literature. Results: The clinical use of PEG is still suboptimal, considering that it remains the most powerful tool to control IGF-I in acromegaly allowing to obtain, with a pharmacological treatment, the most important clinical effects in terms of signs and symptoms, quality of life and comorbidities. The number of patients with acromegaly exposed to PEG worldwide has become quite elevated and the prolonged follow-up allows now to deal quite satisfactorily with many clinical issues including major safety issues, such as the concerns about possible tumour (re)growth under PEG. The positive or neutral impact of PEG on glucose metabolism has been highlighted, and the clinical experience, although limited, with sleep apnoea and pregnancy has been reviewed. Finally, the current concept of somatostatin receptor ligands (SRL) resistance has been addressed, in order to better define the acromegaly patients to whom the PEG option may be offered. Conclusions: PEG increasingly appears to be an effective and safe medical option for many patients not controlled by SRL but its use still needs to be optimized.

BackgroundGermline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene and the p27KIP1 encoding gene CDKN1B have been associated with two well-defined hereditary conditions, familial isolated pituitary adenoma (FIPA) and multiple endocrine neoplasia type 4 (MEN4). Somatotropinomas are present in most AIP mutated FIPA kindreds, as well as in two-thirds of MEN4 patients who carry pituitary tumors.MethodsGermline DNA samples of 131 Italian sporadic acromegalic patients including 38 individuals with multiple tumors, and of six FIPA families (four homogeneous for prolactinomas and two heterogeneous with prolactin/nonfunctioning pituitary adenomas) were collected in a multicentric collaborative study. The prevalence of AIP and CDKN1B gene point mutations and copy number variations were evaluated.ResultsTwo novel (IVS3+1G>A and c.871G>A) and one previously described (c.911G>A) AIP mutations were detected in four apparently sporadic cases (3.1%) with relatively high age at diagnosis (49±18, range 30–67). No mutations/rearrangements were detected in FIPA families. The highly conserved c.871G>A substitution was detected in a patient who also carried a MEN1 mutation suggesting that she is a double heterozygote. The possible pathogenic effect on AIP splicing of the silent substitution c.144G>A found in another patient was ruled out using a minigene-based approach. CDKN1B mutations/rearrangements were neither identified in patients with multiple neoplasia nor in FIPA families.ConclusionAIP is mutated in about 3% of apparently sporadic acromegalic patients. The relatively high age at diagnosis, as well as its sporadic presentation, suggests that these patients are carriers of mutations with reduced pathogenicity. p27KIP1 is unlikely to represent the common unifying nonendocrine etiology for acromegaly and cancer.