Vincenzo Toscano

AME Position Statement on Adrenal Incidentaloma.

OBJECTIVE To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice. DESIGN A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus. RADIOLOGICAL ASSESSMENT Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of ≤10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma). HORMONAL ASSESSMENT: Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushings syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l. MANAGEMENT Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism.

Prostate growth and inflammation.

INTRODUCTION There is emerging evidence that prostatic inflammation may contribute to prostate growth either in terms of hyperplastic (BPH) or neoplastic (PC) changes. Inflammation is thought to incite carcinogenesis by causing cell and genome damage, promoting cellular turnover. METHODS We reviewed our personal experience and the international recent literature on the clinical data supporting a role of inflammation on BPH and PC growth and progression. RESULTS BPH: Among those patients with self-reported prostatitis, 57% had a history of BPH. MTOPS study showed that men with inflammation had a significantly higher risk of BPH progression and acute urinary retention. We showed that the use of a COX-2 inhibitor in combination with a 5 alpha reductase inhibitor could increase the apoptotic index in BPH tissue. Prostate cancer: A PCR-based analysis of bacterial colonization in PC specimens and normal prostate tissue showed highly suggestive correlation of bacterial colonization and chronic inflammation with a diagnosis of PC. Evidence from genetic studies support the hypothesis that prostate inflammation may be a cause of prostate cancer. De Marzo proposed that proliferative inflammatory atrophy (PIA) is a precursor to PIN and cancer. CONCLUSION The concept that inflammation can promote prostate growth either in terms of BPH and PC risk remains highly suggestive.

Ultrasound Sensitivity for Thyroid Malignancy Is Increased by Real-Time Elastography: A Prospective Multicenter Study

CONTEXT Thyroid nodules are selected for biopsy on the basis of clinical and ultrasound (US) findings. Ultrasonography detects nodules at risk of malignancy, but its diagnostic accuracy does not rule out with certainty the possibility of cancer in lesions without suspicious findings. OBJECTIVE The objective of the study was to evaluate the diagnostic accuracy of real-time elastography (RTE) in thyroid nodules and to assess the improvement provided by combination of RTE, B-mode US, and color flow Doppler (CFD). DESIGN This was a prospective multicenter study. PATIENTS A consecutive series of 498 thyroid nodules was blindly evaluated by US, CFD, and RTE before biopsy or surgery. Nodules were classified at RTE by four-class color scale. Patients with benign cytology underwent follow-up over 12 months, whereas patients with indeterminate, suspicious, or malignant cytology were surgically treated. RESULTS At follow-up, 126 nodules were malignant and 372 benign. RTE classes III-IV showed 81% sensitivity and 62% specificity. The presence of at least one US risk factor (hypoechogenicity, microcalcifications, irregular margins, intranodular vascularization, and taller than wide shape) had 85% sensitivity and 91% negative predictive value. When RTE was combined with US, the presence of at least one of the six parameters had 97% sensitivity and 97% negative predictive value, with an odds ratio of 15.8 (95% confidence interval 5.7-43.8). CONCLUSIONS RTE is a valuable tool for detecting malignant thyroid lesions with a sensitivity similar to traditional US and CFD features. By adding RTE evaluation, the sensitivity for malignancy of US findings is markedly increased and the selection of nodules that do not need cytology is made more reliable.

Importance of gluten in the induction of endocrine autoantibodies and organ dysfunction in adolescent celiac patients

OBJECTIVE:It is well known that a high number of celiac patients may develop autoantibodies against endocrine glands, but it has not yet been clarified if this increased autoimmune response and the impaired organ function that can develop may be related to the presence or absence of gluten in the diet. The aim of the present study was to evaluate the effect of gluten on the autoimmunity and function of the endocrine glands in adolescent celiac patients.METHODS:To clarify this aspect we investigated 44 patients (28 females), aged 11–20 yr (15.21 ± 2.7 yr): 25 (mean age, 15.1 ± 2.2 yr) on a gluten-free diet (treated patients) and 19 (mean age 15.4 ± 2.9 yr) with a diet containing gluten (untreated patients). Forty adolescent subjects, aged 14–19 yr (mean age, 14.9 ± 2.7 yr), of whom 20 were females, were studied as controls. Antibodies against the thyroid, adrenal, and pancreas were evaluated. Thyroid-stimulating hormone FT3, FT4, T3, T4, dehydroepiandrosterone sulphate, 17-OH progesterone, and cortisol, analyzed basally and 60 min after intravenous ACTH stimulation, were assayed to evaluate thyroid and adrenal function. The fasting glycemia level was used to evaluate the endocrine pancreas function. An ultrasonogram of the thyroid gland was performed on all patients. HLA class II typing for DR3 and DQB1 was performed in 32 of 44 patients.RESULTS:Seven of 44 (15.9%) patients were positive for antibodies against peroxidase. Six of 44 (13.6%) were positive for antibodies against thyreoglobulin and four of them also showed positive antibodies against peroxidase. Therefore, in nine of 44 at least one antibody directed against thyroid tissue was positive. Seven of 44 (15.9%) were positive for antibodies against islet cell, one of 44 (2.3%) positive for antibodies against glutamic acid decarboxilase, one of 44 (2.3%) positive for antibodies against insulin, and none for antibodies against islet cell- 512bdc. In 15 of 44 (34%) at least one antibody against an endocrine tissue was positive. The genotype DR3 was found in 21 of 32 (65.6%) celiac patients (10 in the untreated and 11 in the treated group, respectively) and the genotype DQB1*02 (DQ2) was found in 30 of 32 (93.8%) patients (16 in the treated and 14 in the untreated group, respectively). DHA-S values were significantly lower in the untreated (30.5 ± 28.5 μg/dl) than in the treated group (61.3 ± 59.4 μg/dl, p < 0.05), and both showing significantly (p < 0.01) lower levels with respect to the controls (161 ± 52 μg/dl). One patient showed diabetes, another one clinical hypothyroidism (thyroid-stimulating hormone > 6), and two patients showed preclinical hypothyroidism. Interestingly, at least one antibody was positive in 10 of 19 untreated patients (52.6%) but only in five of 25 treated patients (20%), with a significantly different distribution (p < 0.001) between the two groups and without differences in the HLA genotype. The ultrasonographic evaluation of the thyroid resulted in a pathological score in six patients of the 44 examined (13.6%), suggesting the presence of thyropathy.CONCLUSIONS:The main results of this study are the high incidence of thyroid and pancreatic antibodies, and the possible role of gluten in the induction of the antibodies as well as, in few cases, the consequent organ dysfunction.

Effects of long‐term treatment with Serenoa repens (Permixon®) on the concentrations and regional distribution of androgens and epidermal growth factor in benign prostatic hyperplasia

The n‐hexane lipido‐sterol extract of Serenoa repens (LSESr, Permixon®, Pierre Fabre Médicament, Castres, France), a phytotherapeutic agent used in the treatment of benign prostatic hyperplasia (BPH), has a multisite mechanism of action including inhibition of types 1 and 2 5α‐reductase and competitive binding to androgen receptors in prostatic cells. Here, the response of testosterone (T), dihydrotestosterone (DHT), and epidermal growth factor (EGF) in BPH tissue of patients treated with LSESr (320 mg/day for 3 months) is analyzed.

3,5,3′-triiodothyronine (T3) is a survival factor for pancreatic β-cells undergoing apoptosis

3,5,3′‐triiodothyronine (T3) is essential for the growth and the regulation of metabolic functions, moreover, the growth‐stimulatory effect of T3 has largely been demonstrated and the pathways via which T3 promotes cell growth have been recently investigated. Type 1 diabetes (T1D) is due to the destruction of β‐cells, which occurs even through apoptosis. Aim of our study was to analyze whether T3 could have an antiapoptotic effect on cultured β‐cells undergoing apoptosis. We have demonstrated that T3 promotes cell proliferation in islet β‐cell lines (rRINm5F and hCM) provoking an increment in cell number (up to 55%: rRINm5F and 45%: hCM), cell viability, and BrdU incorporation, and regulating the cell cycle‐related molecules (cyc A, D1, E, and p27kip1). T3 inhibited the apoptotic process induced by streptozocin, S‐Nitroso‐N‐Acetylpenicylamine (SNAP), and H2O2 via regulation of the pro‐ and anti‐apoptotic factors Bcl‐2, Bcl‐XL, Bad, Bax, and Caspase 3. The T3 protective effect was PI‐3 K‐, but not MAPK‐ or PKA‐mediated, involving pAktThr308. Thus, T3 could be considered a survival factor protecting islet β‐cells from apoptosis. J. Cell. Physiol. 206: 309–321, 2006.

Lack of linear relationship between hyperinsulinaemia and hyperandrogenism

objective Because of continued debate about the role of Insulin in the development of hirsutism and in the induction of the polycystic ovary syndrome, we have evaluated the hormonal pattern in a group of hirsute patients

Rosiglitazone induces autophagy in H295R and cell cycle deregulation in SW13 adrenocortical cancer cells

Thiazolidinediones, specific peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands, used in type-2 diabetes therapy, show favourable effects in several cancer cells. In this study we demonstrate that the growth of H295R and SW13 adrenocortical cancer cells is inhibited by rosiglitazone, a thiazolidinediones member, even though the mechanisms underlying this effect appeared to be cell-specific. Treatment with GW9662, a selective PPAR-γ-inhibitor, showed that rosiglitazone acts through both PPAR-γ-dependent and -independent mechanisms in H295R, while in SW13 cells the effect seems to be independent of PPAR-γ. H295R cells treated with rosiglitazone undergo an autophagic process, leading to morphological changes detectable by electron microscopy and an increased expression of specific proteins such as AMPKα and beclin-1. The autophagy seems to be independent of PPAR-γ activation and could be related to an increase in oxidative stress mediated by reactive oxygen species production with the disruption of the mitochondrial membrane potential, triggered by rosiglitazone. In SW13 cells, flow cytometry analysis showed an arrest in the G0/G1 phase of the cell cycle with a decrease of cyclin E and cdk2 activity, following the administration of rosiglitazone. Our data show the potential role of rosiglitazone in the therapeutic approach to adrenocortical carcinoma and indicate the molecular mechanisms at the base of its antiproliferative effects, which appear to be manifold and cell-specific in adrenocortical cancer lines.

3,5,3′‐Triiodo‐L‐thyronine enhances the differentiation of a human pancreatic duct cell line (hPANC‐1) towards a β‐cell‐Like phenotype

The thyroid hormone, 3,5,3′‐Triiodo‐L‐thyronine (T3), is essential for growth, differentiation, and regulation of metabolic functions in multicellular organisms, although the specific mechanisms of this control are still unknown. In this study, treatment of a human pancreatic duct cell line (hPANC‐1) with T3 blocks cell growth by an increase of cells in G0/G1 cell cycle phase and enhances morphological and functional changes as indicated by the marked increase in the synthesis of insulin and the parallel decrease of the ductal differentiation marker cytokeratin19. Expression analysis of some of the genes regulating pancreatic β‐cell differentiation revealed a time‐dependent increase in insulin and glut2 mRNA levels in response to T3. As last step of the acquisition of a β‐cell‐like phenotype, we present evidence that thyroid hormones are able to increase the release of insulin into the culture medium. In conclusion, our results suggest, for the first time, that thyroid hormones induce cell cycle perturbations and play an important role in the process of transdifferentiation of a human pancreatic duct line (hPANC‐1) into pancreatic‐β‐cell‐like cells. These findings have important implications in cell‐therapy based treatment of diabetes and may provide important insights in the designing of novel therapeutic agents to restore normal glycemia in subjects with diabetes.

Two different pathogenetic mechanisms may play a role in acne and in hirsutism

OBJECTIVE Acne is one of the most common skin disorders. Androgens are known to play an important and possibly central role. Androgens secreted from ovaries and adrenal glands (androstenedione, dehydroepiandro‐sterone and its sulphate, testosterone) and target tissue‐produced androgens (testosterone and its 5α‐reduced metabolite, dihydrotestosterone) have been implicated. Although the sebaceous gland and the hair follicle form a single morphological entity, the pilosebaceous unit, acne and hirsutism do not always appear concomitantly, thus leading to the supposition that these two structures may have different degrees of sensitivity to similar androgenic stimulation.