Italian Society for the Study of Diabetes (SID)/Italian Endocrinological Society (SIE) guidelines on the treatment of hyperglycemia in Cushing's syndrome and acromegaly.

BACKGROUND: Hyperglycemia is a common feature associated with states of increased growth hormone secretion and glucocorticoid levels. AIMS: The purpose of these guidelines is to assist clinicians and other health care providers to take evidence-based therapeutic decisions for the treatment of hyperglycemia in patients with growth hormone and corticosteroid excess. METHODOLOGY: Both the SID and SIE appointed members to represent each society and to collaborate in Guidelines writing. Members were chosen for their specific knowledge in the field. Each member agreed to produce--and regularly update--conflicts of interest. The Authors of these guidelines prepared their contributions following the recommendations for the development of Guidelines, using the standard classes of recommendation shown below. All members of the writing committee provided editing and systematic review of each part of the manuscript, and discussed the grading of evidence. Consensus was guided by a systematic review of all available trials and by interactive discussions.

Italian Society for the Study of Diabetes (SID)/Italian Endocrinological Society (SIE) guidelines on the treatment of hyperglycemia in Cushing's syndrome and acromegaly.

Hyperglycemia is a common feature associated with states of increased growth hormone secretion and glucocorticoid levels. The purpose of these guidelines is to assist clinicians and other health care providers to take evidence-based therapeutic decisions for the treatment of hyperglycemia in patients with growth hormone and corticosteroid excess. Both the SID and SIE appointed members to represent each society and to collaborate in Guidelines writing. Members were chosen for their specific knowledge in the field. Each member agreed to produce-and regularly update-conflicts of interest. The authors of these guidelines prepared their contributions following the recommendations for the development of Guidelines, using the standard classes of recommendation shown below. All members of the writing committee provided editing and systematic review of each part of the manuscript, and discussed the grading of evidence. Consensus was guided by a systematic review of all available trials and by interactive discussions.

The tall cell variant of papillary thyroid carcinoma: clinical and pathological features and outcomes.

BACKGROUND: The tall cell variant (TCV) is a relatively rare variant of papillary thyroid cancer. Since a controversy exists whether or not the TCV has a worse outcome, the aim of our study was to retrospectively compare the clinicopathological features and outcomes in a group of TCV patients and a larger group of patients with classical papillary thyroid carcinoma (cPTC). SUBJECTS AND METHODS: Data from 30 TCV and 293 cPTC patients were analyzed. Among the 293 cPTC, we also selected a "high-risk" cPTC group (no.=103) that was treated with the same protocol used for the TCV patients. All data were managed by Cox analysis. RESULTS: Compared to all cPTC patients, TCV subjects displayed only a significantly higher rate of extrathyroid extension. At multivariate analysis, TCV was not an independent variable for the prediction of a high risk of persistent/recurrent disease. At the last follow-up observation, there was no difference in the disease status between the TCV and all cPTC patients. Moreover, "high-risk" cPTC patients had a significant increase in persistent/recurrent disease. CONCLUSIONS: In our study, although the TCV histotype is associated with a higher prevalence of extrathyroid extension, it is characterized by an outcome that is not significantly different from that of all cPTC patients and is more favorable than that of "high-risk" cPTC patients. Only those TCV patients classified as "high risk" based on specific pathological and clinical features, according to current guidelines, should be treated aggressively, such as with a total thyroidectomy, neck lymph node dissection or ablative radioiodine treatment.

Effects of prophylaxis with iodised salt in an area of endemic goitre in north-eastern Sicily.

In developed countries, the use of iodised salt represents the best prophylaxis of endemic goitre in areas exposed to iodine deficiency. In the present study we re-evaluated goitre prevalence and iodine intake 10 years after the introduction of iodised salt in an area of goitre endemia in north-eastern Sicily (Italy), and we compared these results with those obtained in previous surveys. Three centres with known moderate goitre endemia (Bronte, Nicosia, and Gagliano) and three other smaller ones with severe goitre endemia (Sperlinga, Villadoro, and Maniace) were studied. We surveyed 697 schoolchildren. Goitre prevalence was assessed by thyroid palpation and by a thyroid ultrasound scan. Iodine urinary excretion was also measured. Iodised salt consumption was 44% of total salt consumption. Goitre prevalence assessed by thyroid palpation was significantly decreased in all towns studied compared to previous surveys. However, the persistence of a mild goitre endemia was observed in some small rural centres (5.8% in Sperlinga/Villadoro, and 11.4% in Maniace). Goitre prevalence evaluated by thyroid ultrasound scan was greater than 5% in all centres of the endemic area and was always greater than that assessed by thyroid palpation. Iodine urinary excretion was above 100 microg/l in all localities studied. In conclusion, our studies indicate a progressive reduction in goitre prevalence over a period of about 30 years in schoolchildren in a well-characterised endemic area in northeastern Sicily. The decrease in goitre prevalence was associated with a significant increase in urinary iodine excretion. However, it may be speculated that iodine deficiency is the pre-eminent, but not the exclusive cause of goitre endemia in this area.

Radiometabolic treatment of hyperthyroidism with a calculated dose of 131-iodine: results of one-year follow-up.

Oral administration of radioactive iodine (131I) is a well-known and effective procedure for the treatment of hyperthyroidism. However, the optimal dose is still a matter of debate, as is the frequency of recurrence and hypothyroidism. The aim of our study was to evaluate the 1-yr outcome of a calculated dose of 131I activity in the treatment of hyperthyroidism, following the guidelines published jointly by the Italian Society of Endocrinology and the Italian Society of Nuclear Medicine.We studied 84 patients affected with hyperthyroidism (55 with Graves' disease and 29 with toxic adenoma), who were treated with a dose of 131I activity obtained by using the formula from the guidelines. In all patients serum free T4, free T3, and TSH were measured before, and 2, 6, and 12 months after radiometabolic therapy. A thyroid scan and thyroid uptake with 131I were also performed before treatment, and a thyroid ultrasound scan was obtained before and 1 yr after treatment. One year after treatment, 22 out of 55 patients with Graves' diseases (40.0%) had persistence/ recurrence of hyperthyroidism, whereas only 1 patient of the 29 with toxic adenoma (3.4%) was still in a hyperthyroid state. The frequency of hypothyroidism in patients responsive to therapy was higher in subjects with Graves' disease (45.5%), than in those with toxic adenoma (17.3%, p=0.02). Overall size reduction of the target lesion was 56.2+/-23.1%. In conclusion, the dose calculation suggested by the guidelines represents an effective method for treating thyroid toxic adenoma. In subjects with Graves' disease, we propose using a pre-determined 131I activity, which is higher than that derived from the guidelines. Such an approach would reduce the incidence of recurrent/persistent hyperthyroidism. On the other hand, an increase in post-131I hypothyroidism should not be regarded as a negative effect in these patients, since hypothyroidism is easily corrected, and the risk of worsening ophthalmopathy is reduced.

Therapeutic options for elderly diabetic subjects: open label, randomized clinical trial of insulin glargine added to oral antidiabetic drugs versus increased dosage of oral antidiabetic drugs.

Glycemic control in elderly persons with type 2 diabetes mellitus (T2DM) is challenging because they are more likely to have other age-associated medical conditions and to experience hypoglycemia during intensive therapy. A best therapeutic strategy for these patients has not yet been defined. We investigated the efficacy and safety of adding once-daily insulin glargine to patients' current oral antidiabetic drugs (OAD) regimen, compared to increasing the OAD doses. The study enrolled patients aged 65 years or more, with poor glycemic control. Patients were randomized to two groups and entered a 3-week titration period in which their actual therapy was adjusted to meet the study's glycemic goals, by either adding insulin glargine to current therapy (group A, 27 patients) or increasing current OAD dosages (group B, 28 patients). Thereafter, therapies were continued unchanged for a 24-week observation period. The mean therapeutic dosage of insulin glargine in group A was 14.9 IU/day (SD = 5.0 IU/day). During the observation period, mean levels of glycosylated hemoglobin (HbA1c) reduced by 1.5% in group A and 0.6% in group B (P = 0.381). An HbA1c level <7.0% was achieved by five patients in each group. Mean fasting blood glucose levels reduced by 29 and 15% in groups A and B, respectively (P = 0.029). Group A had fewer total hypoglycemic events (23 vs. 79, P = 0.030) and fewer patients experiencing any such event (9 vs. 17, P = 0.045). Neither a serious hypoglycemic event nor other adverse event occurred. These results suggest that, compared to increasing OAD dosage, the addition of insulin glargine to current OAD therapy is as effective but safer in terms of the risk for hypoglycemia in elderly patients with T2DM.

Acute changes in clinical parameters and thyroid function peripheral markers following L-T4 withdrawal in patients totally thyroidectomized for thyroid cancer.

After total thyroidectomy, differentiated thyroid cancer (DTC) patients have to undergo L-T4 withdrawal for measuring serum thyroglobulin and 131I whole-body scan (131I WBS) to evaluate residual/recurrent malignant disease. The aim of the present work was to study in these patients the effects of acute thyroid hormone deficiency on various target organs and tissues. Clinical parameters and thyroid function peripheral markers were evaluated in 20 DTC patients, both before and after L-T4 withdrawal. A 24-h urine collection, a fasting blood sample for laboratory examinations, a clinical score for hypothyroidism and cardiovascular, neurological and neuropsychological evaluations were carried out. After L-T4 withdrawal, the clinical score significantly increased, as well as total cholesterol, triglycerides, creatine kinase, lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase, whereas SHBG, osteocalcin and urine hydroxyproline levels significantly decreased. The acute thyroid hormone deficiency caused a systolic dysfunction of the left ventricle associated with an increase in systemic vascular resistance without cardiac contractility alterations. A significant increase in the left ventricular mass and thickness was also observed. Carpal tunnel syndrome appeared in 30% of patients and a significant reduction in the immediate auditive memorization and in attentive performance was also detected. These observations indicate that acute hypothyroidism causes significant clinical alterations of peripheral tissue function. In the follow-up of DTC patients, therefore, L-T4 withdrawal procedure should be restricted to cases where the cost/benefit ratio is favorable. Alternative procedures, such as the use of recombinant human TSH, should be used whenever possible.

Usefulness of recombinant human thyrotropin in the radiometabolic treatment of selected patients with thyroid cancer.

Treatment of persistent/recurrent differentiated thyroid cancer is based on surgery, when feasible, and malignant tissue ablation by 131I administration. This procedure requires levothyroxine withdrawal to obtain high levels of endogenous thyrotropin (TSH) to stimulate radioactive iodine uptake by the malignant tissue. Levothyroxine withdrawal may cause severe adverse effects and complications in patients with concomitant illness or advanced metastatic disease. The recent availability of recombinant human thyrotropin (rhTSH) allows diagnostic whole-body scan (WBS) and thyroglobulin testing without levothyroxine withdrawal. We describe six patients with metastatic differentiated thyroid cancer (DTC) and concomitant illness in whom the use of rhTSH was effective in preventing the complications that patients had previously experienced during hypothyroidism consequent to levothyroxine withdrawal. Our results indicate that rhTSH can be particularly advantageous to avoid signs and symptoms of hypothyroidism and complications because of associated diseases in view of 131I treatment of DTC metastases in selected cases in which levothyroxine withdrawal may be dangerous. Its efficacy to treat advanced metastatic disease should be further investigated.

Measurement of IGF-1 Receptor Content in Tissues and Cell Lines by Radioimmunoassay (RIA) and ELISA Techniques.

The IGF-1 receptor (IGF-1-R) belongs to the tyrosine kinase growth factor receptor family. It is structurally similar to, but distinct from, the insulin receptor, with which it shares a 70% homology. As expected, it crossreacts with insulin and, vice versa, insulin receptor crossreacts with IGF-1. Numerous studies suggest that IGF-1-R is very important for mitogenesis and is essential for phenotype transformation, at least in rodents (1). In particular, the IGF-1-R has been described in human breast cancer (2-4) and ovarian cancer (5) tissues and in cultured human breast cancer cell lines (6,7).

[Differentiated carcinoma of the thyroid in the young. Clinical and histopathologic aspects]. / Carcinoma differenziato della tiroide in età giovanile. Aspetti clinici ed istopatologici.

BACKGROUND: The surgical approach to Differentiated Thyroid Carcinoma (DTC) is controversial. Aim of this study is to evaluate the opportunity of total thyroidectomy as treatment of choice for DTC in children. METHODS: We examined the tumor features at diagnosis, the complications of surgery and the clinical outcome in a consecutive series of 33 young patients, (age range 7-19 yrs), who underwent total thyroidectomy for DTC as compared to a consecutive series of 181 adult patients operated for DTC (age range 20-64 yrs). RESULTS: Histopathological examination has shown that bilateral foci of the tumor and extrathyroidal extension, were present with similar frequency in both groups of patients (15 vs 18% and 39 vs 48% respectively); node metastases and distant metastases were more frequent in young patients than in adult patients. Complications of total thyroidectomy were not frequent with 6% of permanent hypoparathyroidism. No case of laryngeal nerve damage was observed. In 7/8 patients with lung metastases the radioiodine treatment was effective: in four patients we observed a complete remission of disease, and in three patients a partial response with a decrease of Tg levels and a reduction of the radioiodine uptake areas. CONCLUSIONS: Thyroid carcinoma is not less aggressive in children than in adults. Total thyroidectomy plus lymph node dissections appears to be the treatment of choice as routine surgical treatment of DTC in children. Radioiodine therapy gives good results for the treatment of lung metastases.

Appearance of anti TSH-receptor antibodies and clinical Graves' disease after radioiodine therapy for hyperfunctioning thyroid adenoma.

Radioiodine treatment use is frequent in patients with benign hyperfunctioning thyroid diseases and the side-effects are rare. In this paper we described the appearance of TSH-receptor antibodies and the concomitant development of persistent hyperthyroidism in a patient with hyperfunctioning thyroid adenoma after 131I treatment. A 70-year-old man presented a hyperfunctioning thyroid adenoma with suppressed uptake in the adjacent normal gland. Antibodies against the thyroglobulin (TgAb), thyroid peroxidase (TPOAb) and TSH-receptor (TRAb) were absent. One year after remission by radioiodine therapy the patient developed severe and persistent hyperthyroidism associated with diffuse 131I uptake in the gland. TgAb and TPOAb remained absent, but TRAb were present. Although spontaneous development of Graves' disease cannot be excluded, the time sequence and the negative familial and personal history for autoimmune diseases suggest a possible connection between the two phenomena. The release of TSH-receptor antigen from follicular cells damaged by 131I may have triggered the autoimmune response turning a toxic nodular goiter patient into a Graves' disease patient.

Functional insulin receptors are overexpressed in thyroid tumors: is this an early event in thyroid tumorigenesis?

BACKGROUND: Insulin receptor (IR), a member of the receptor tyrosine kinase family, is expressed in normal thyroid cells and affects thyroid cell proliferation and differentiation. METHODS: The authors measured IR content in benign and malignant thyroid tumors by three independent methods: a specific radioimmunoassay, 125I-insulin binding studies, and immunohistochemistry. The results obtained were compared with the IR content in paired, adjacent, normal thyroid tissue. To assess IR function in thyroid carcinoma cells, glucose uptake responsiveness to insulin was also studied in a human transformed thyroid cell line (B-CPAP) and in follicular carcinoma cells in primary culture. RESULTS: In 9 toxic adenomas, the average IR content was similar to that observed in the 9 paired normal thyroid tissue specimens from the same patients (2.2+/-0.3 vs. 2.1+/-0.3). In 13 benign nonfunctioning, or "cold," adenomas, the average IR content was significantly higher (P < 0.001) than in paired normal tissue specimens (4.3+/-0.5 vs. 1.8+/-0.1). In 12 papillary and 10 follicular carcinomas, IR content was significantly higher (P < 0.001) than in the adjacent normal thyroid tissue (4.0+/-0.4 vs. 1.6+/-0.2 and 5.6+/-1.0 vs. 1.8+/-0.2, respectively). The finding of a higher IR content in benign "cold" adenomas and in thyroid carcinomas was confirmed by both binding and immunostaining studies. CONCLUSIONS: The current studies indicate that 1) IR content is elevated in most follicular and papillary differentiated thyroid carcinomas, and 2) IR content is also elevated in most benign follicular adenomas ("cold" nodules) but not in highly differentiated, hyperfunctioning follicular adenomas ("hot" nodules), which very rarely become malignant. This observation suggests that increased IR expression is not restricted to the thyroid malignant phenotype but is already present in the premalignant "cold" adenomas. It may contribute, therefore, to thyroid tumorigenesis and/or represent an early event that gives a selective growth advantage to transformed thyroid cells.

Insulin-stimulated cell growth in insulin receptor substrate-1-deficient ZR-75-1 cells is mediated by a phosphatidylinositol-3-kinase-independent pathway.

In many human breast cancers and cultured cell lines, insulin receptor expression is elevated, and insulin, via its own insulin receptor, can stimulate cell growth. It has recently been demonstrated that the enzyme phosphatidylinositol-3-kinase (PI3-K) mediates various aspects of insulin receptor signaling including cell growth. In order to understand the mechanisms for insulin-stimulated cell growth in human breast cancer, we measured insulin-stimulable PI3-K activity in a non-transformed breast epithelial cell line, MCF-10A, and in two malignantly transformed cell lines, ZR-75-1 and MDA-MB157. All three cell lines express comparable amounts of insulin receptors whose tyrosine autophosphorylation is increased by insulin, and in these cell lines insulin stimulates growth. In MDA-MB157 and MCF-10A cells, insulin stimulated PI3-K activity three- to fourfold. In ZR-75-1 cells, however, insulin did not stimulate PI3-K activity. In ZR-75-1 cells PI3-K protein was present, and its activity was stimulated by epidermal growth factor, suggesting that there might be a defect in insulin receptor signaling upstream of PI3-K and downstream of the insulin receptor. Next, we studied insulin receptor substrate-1 (IRS-1), a major endogenous substrate for the insulin receptor which, when tyrosine is phosphorylated by the insulin receptor, interacts with and activates PI3-K. In ZR-75-1 cells, there were reduced levels of protein for IRS-1. In these cells, both Shc tyrosine phosphorylation and mitogen-activated protein kinase (MAP-K) activity were increased by the insulin receptor (indicating that the p21ras pathway may account for insulin-stimulated cell growth in ZR-75-1 cells). The PI3-K inhibitor LY294002 (50 microM) reduced insulin-stimulated growth in MCF-10A and MDA-MB157 cell lines, whereas it did not modify insulin effect on ZR-75-1 cell growth. The MAP-K/Erk (MEK) inhibitor PD98059 (50 microM) consistently reduced insulin-dependent growth in all three cell lines. Taken together, these data suggest that in breast cancer cells insulin may stimulate cell growth via PI3-K-dependent or-independent pathways.

Insulin receptor content in tissues of normal and diabetic rats measured by radioimmunoassay.

Insulin receptor (IR) content in different tissues has been quantitatively evaluated by means of steady state binding studies with radiolabeled insulin. The information provided by this approach, however, does not give a direct measurement of the receptor protein. Rather, it depends on the binding function of the IR, evaluated on the basis of curvilinear plots derived by Scatchard analysis of the experimental data. In the present report we employed a sensitive and specific radioimmunoassay (RIA) that allows a direct measurement of IR in solubilized cells or tissues. By this method we studied: a) IR distribution in several tissues of the rat, the animal model most frequently used in studies of insulin action; b) IR regulation in streptozotocin-treated, diabetic insulin deficient rats. Tissues from male Wistar rats (11 controls and 6 streptozotocin-treated diabetic animals) were homogenized, solubilized with Triton X-100 in the presence of protease inhibitors and stored at -80 C. IR content in the solubilized material was then measured by RIA. IR were detectable in all 11 tissues tested. Liver, kidney and brain neocortex had the highest IR content. (24.7 +/- 1.0, 20.5 +/- 1.1, 25.9 +/- 1.6 ng/mg protein, m +/- SE, respectively). As expected, circulating insulin levels were lower in diabetic rats than in control rats. In diabetic, insulin deficient rats, liver, kidney and skeletal muscle contained more IR than in control rats (p = 0.001; p = 0.018; p = 0.003, respectively), whereas IR content in neocortex was similar in the two groups. The IR RIA may represent a useful tool for the study of IR regulation and patho-physiology. Our data provide a comparative direct measurement of IR distribution in a variety of rat tissues. IR content in diabetic rats is increased in typical target organs for insulin action, as a consequence of up-regulation due to the reduced insulin levels. This is not the case for metabolically insulin-dependent tissues, like brain.

Clinical features and hormonal characteristics in a case of ovarian arrhenoblastoma.

We report a case of a 34-year-old woman affected with ovarian arrhenoblastoma characterized by very high testosterone (T) levels (34.0-60.0 ng/ml; n.v.0.2-0.9) and suppressed gonadotropin levels. The physical examination revealed: severe hirsutism, acne, amenorrhea and other virilization signs. Basal hormonal evaluation also showed a markedly elevated 17-hydroxyprogesterone (17-OHP) and a mild delta 4 Androstenedione (A) and dehydroepiandrosterone sulfate (DHEAs) increase. ACTH test induced only slight changes in androgen secretion. By contrast, dexamethasone test greatly decreased A and DHEAs whereas T levels were only partially suppressed. Moreover, hCG test was clearly stimulatory for T and A. Suppressed gonadotropin levels did not respond to LHRH stimulation. The removal of the neoplasia was followed by normalization of T levels and increase of serum gonadotropins with subsequent restoration of a normal responsiveness to LHRH and resumption of an ovulatory menstrual cycle. This observation suggests that the high T levels played a primary role in the pathogenesis of the gonadotropin suppression and anovulation. Recovery of acne was complete whereas hirsutism score was reduced but still elevated after one year. This may be due to postoperative A and DHEAs levels slightly above the normal range, indicating the presence of adrenal hyperandrogenism.

Pubarche induction with testosterone treatment in women with panhypopituitarism.

OBJECTIVE: To evaluate the efficacy and safety of T therapy in the induction of pubic hair growth in women with congenital panhypopituitarism. DESIGN: Prospective clinical study. SETTING: Patients followed at the University Endocrinology Clinic. PATIENTS: Four women with congenital panhypopituitarism, showing no pubic hair development, currently treated with substitutive therapy with L-thyroxine, cortisone acetate, and estrogen-progestin combination. INTERVENTIONS: A long-acting T preparation (25 to 50 mg) was given IM each month; serum T levels were determined before and after 12 and 24 months of therapy. MAIN OUTCOME MEASURE: Evaluation of pubarche stages (according to Tanner classification of stages). RESULTS: Patients developed pubarche (Tanner stage 3 to 5) after 3 to 18 months of T therapy. Testosterone levels were within the normal range during treatment. No hirsutism or other side effects were recorded. CONCLUSION: A cautious T treatment represents an effective and safe approach to the problem of pubarche induction in women with congenital panhypopituitarism.