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Objective Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and non-reproductive anomalies might be present although information on their frequency are scanty, particularly according to the age of presentation. Design Observational cohort study carried out between January 2008 and June 2016 within a national network of academic or general hospitals. Methods We performed a detailed phenotyping of 503 IHH patients with: (1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; (2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided on IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH (n = 275), KS (n = 184), AO-nIHH (n = 36) and AO-doIHH (AO-IHH with defective olfaction, n = 8). Results 90% of patients were classified as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were also found among the AO-IHH. Mean age at diagnosis was significantly earlier and more frequently associated with congenital hypogonadism stigmata in patients with Kallmann’s syndrome (KS). Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are significantly associated with AO-IHH rather than PPO-IHH. Conclusions Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families.

Fine needle cytology aspirates (FNA) classified as THY4 are a heterogeneous group suspicious for malignancy [papillary thyroid cancer (PTC)], which is confirmed in 50-80% of cases after surgery.To better stratify THY4 FNA specimens for the relative risk of malignancy.We retrospectively analyzed 78 thyroid nodules classified as THY4 because of the presence of atypical cells, hypercellular trabeculae and/or intranuclear inclusions (ICI), in the absence of papillae. Two subgroups were identified: group 1 (38 nodules), showing ICI with (no.=17) or without (no.=21) trabeculae and cellular atypia, and group 2 (40 nodules), showing trabeculae and atypia but without ICI.PTC was detected at histology in 56/78 of the patients (71.8%). Malignancy occurred in 36/38 (94.7%) of the patients in group 1 and in 20/40 (50.0%) of the patients in group 2. Therefore, the positive predictive value (PPV) for PTC was 97.3% in the ICI+ specimens (group 1), with a sensitivity of 64.3% and specificity of 95.2%. When only ICI was present, without atypia and trabeculae, the PPV and specificity were similar (95.0 and 95.2%, respectively), but the sensitivity was decreased (48.7%). In specimens without ICI (group 2), the PPV was only 50.0%; however, combined with young age (40 yr) and male gender, it reached a value similar to that of group1.In ICI+ specimens compared to ICI-, the risk of PTC is nearly doubled, since PPV increases from 50.0% to 97.3%. This observation suggests that surgery should be considered mandatory in all lesions classified THY4 at FNA, although the relevant difference in terms of cancer risk between ICI- vs ICI+ nodules might be an useful information for both the clinician and the patient.

Aims The aim of this case–control study was to compare quality of life (QoL) and treatment satisfaction in adults with Type 1 diabetes (T1DM) treated with either continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI). Methods Consecutive patients aged between 18 and 55 years, and attending diabetes clinics for a routine visit, completed the Diabetes-Specific Quality-of-Life Scale (DSQOLS), the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the SF-36 Health Survey (SF-36). Case (CSII) and control subjects (MDI) were recruited in a 1 : 2 ratio. Results Overall, 1341 individuals were enrolled by 62 diabetes clinics; 481 were cases and 860 control subjects. Cases had a longer diabetes duration and were more likely to have eye and renal complications. Age, school education, occupation and HbA 1c were similar. Of control subjects, 90% followed glargine-based MDI regimens and 10% used NPH-based MDI regimens. On multivariate analysis, after adjusting for socioeconomic and clinical characteristics, scores in the following areas of the DSQOLS were higher in cases than control subjects: diet restrictions ( β = 5.96; P < 0.0001), daily hassles ( β = 3.57; P = 0.01) and fears about hypoglycaemia ( β = 3.88; P = 0.006). Treatment with CSII was also associated with a markedly higher DTSQ score ( β = 4.13; P < 0.0001) compared with MDI. Results were similar when CSII was compared separately with glargine- or NPH-based MDI regimens. Conclusions This large, non-randomized, case–control study suggests quality of life gains deriving from greater lifestyle flexibility, less fear of hypoglycaemia, and higher treatment satisfaction, when CSII is compared with either glargine-based or NPH-based MDI regimens. Diabet. Med. 25, 213–220 (2008)

The insulin receptor (IR) form hybrids with the closely related insulin-like growth factor-I (IGF-I) receptor (IGF-I-R). Because most human breast carcinomas overexpress both the IR and the IGF-I-R, we evaluated whether the insulin/IGF-I hybrid receptor (Hybrid-R) is also overexpressed in these tumors and what role it plays in breast cancer biology. Using specific ELISAs and Western blots, we measured Hybrid-R content and function in 8 human cultured breast cancer cell lines and 39 human breast cancer specimens. Hybrid-R content and function were also compared to the content and function of the IR and the IGF-I-R. Hybrid-R content exceeded the IGF-I-R content in75% of breast cancer specimens and was directly related to the molar ratio of both the IR and IGF-I-R content, suggesting that Hybrid-R formation occurred by random assembly of IR and IGF-I-R half-receptors. Hybrid-Rs became tyrosine autophosphorylated when breast cancer cells were exposed to IGF-I but not when they were exposed to insulin. In cells with an elevated Hybrid-R content, Hybrid-R autophosphorylation in response to IGF-I exceeded IGF-I-R autophosphorylation, suggesting that most of the IGF-I effect occurred via the Hybrid-R. Furthermore, Hybrid-Rs mediated growth in response to IGF-I, as indicated by experiments with blocking antibodies to the IGF-I-R. These data indicated therefore that: (a) Hybrid-Rs are present and play a major role in mediating the IGF-I signal in breast cancer; (b) their expression is directly related to IR overexpression; and (c) potential therapies designed to block IGF-I actions in breast cancer must take into account the role of these Hybrid-Rs.

Twenty years ago we described an area of goiter endemia in North-Eastern Sicily. In this area endemic goiter was associated to a variable degree of iodine deficiency and, in some places, also to an increased thiocyanate urine excretion. Our studies have demonstrated a strict relationship between iodine deficiency and congenital hypothyroidism (both permanent and transient), an increased prevalence of autonomously functioning thyroid nodules and an increased prevalence of thyroid cancer (follicular and anaplastic histotypes). A number of cases of endemic cretinism have also been described. An active iodine prophylaxis program has been carried in the town of Troina in the years 1979-87, by iodinating the municipal water supply. This intervention caused the disappearance of goiter in schoolchildren in only five years. In the last 20 years the prevalence of goiter has decreased in all endemic areas probably because of the "silent prophylaxis", due to improved socio-economic conditions and industrial food consumption. Today the persistence of endemic goiter confirms the inadequacy of the silent iodine prophylaxis and the need to immediately introduce an active iodine prophylaxis in Sicily.

The clinical behavior and outcome was evaluated in 21 nonoccult differentiated thyroid carcinomas occurring in Graves' patients during the period 1982-94 and compared with that of matched tumors occurring in euthyroid controls (n = 70). At surgery, patients with Graves' disease showed distant metastases more frequently than euthyroid patients (3/21 = 14.3% vs. 1/70 = 1.4%, P = 0.0556). Graves' patients also showed a significantly higher cumulative risk of recurrent/progressive distant metastases or total adverse events (odd ratios = 3.14 and 2.07, respectively) as compared with euthyroid patients. At the last follow-up visit, persistence of distant metastases was also more frequent in the Graves' group (P = 0.007), although the cumulative individual dose of radioiodine administered was higher than in the control group (median dose = 805 mCi vs. 350 mCi). Two patients died in the Graves' group vs. none in the control group. Circulating thyroid stimulating antibodies were present in all patients but one and persisted as long as signs of disease were evident. These findings indicate that differentiated thyroid carcinomas in patients with Graves' disease are more aggressive than those occurring in matched euthyroid controls and should, therefore, be managed accordingly.

The insulin receptor (IR), a ligand-activated tyrosine kinase, is present in breast cancers, but its relationship to patient survival is unknown. The IR was measured in 584 tumor specimens from patients with node-negative breast carcinoma by frozen-section immunohistochemistry and light microscopy. The immunostaining signal was quantitated in relation to both the staining intensity and the proportion of positive malignant epithelial cells. Analyses indicated that patients with tumors with undetectable IR content in malignant epithelial cells (260 cases) had a relatively lower predicted 5-year disease-free survival (DFS) (69% +/- 3%) than did patients with tumors with detectable IR content (324 cases; DFS 76% +/- 3%, p = .032). The significance of IR content in these breast malignant epithelial cells was then analyzed along with patient age, tumor size, progesterone and estrogen receptor status, p53 accumulation, and S-phase. Multivariate analysis of these data revealed that after adjustment for these other variables, IR content was the strongest independent predictive factor for DFS (relative risk = 1.73, p = .005). Interestingly, in a small subset of patients with very high IR content (n = 62), DFS was decreased. These data indicate that IR content in node-negative breast cancers is a significant major predictor of reduced DFS. Moreover, they raise the possibility that the measurement of IR content might provide important information concerning breast cancer biology.

We evaluated the occurrence, tissue distribution, and prognostic value of tumor-associated macrophages in 121 papillary thyroid carcinomas using immunohistochemical staining with anti-CD68 antibody in archival paraffin-embedded sections. Lymphocytic infiltration and dendritic cell presence were also evaluated. Three groups were identified according to the presence and characteristics of macrophages: 1) tumors without evidence of infiltrating macrophages: (n = 35); 2) tumors with infiltrating macrophages but no evidence of neoplastic cells phagocytosis (n = 68); and 3) tumors with infiltrating macrophages and in situ evidence of active neoplastic cell phagocytosis (n = 18). Neoplastic cell phagocytosis by macrophages was positively correlated with both lymphocytic infiltration and dendritic cells (P = 0.0000), whereas it was negatively correlated with vascular invasion (P = 0.0032). Distant metastases developed in none of the 18 tumors with neoplastic cell phagocytosis, but occurred in 15 of 103 of the remaining tumors (P = 0.0647) and were significantly and negatively associated with lymphocytic infiltration or dendritic cells. The present study indicates, therefore, that immune reaction, involving neoplastic cell phagocytosis by macrophages and lymphocytic infiltration, plays a role in the development of distant metastases in patients with papillary thyroid cancer.

"Autonomous" thyroid nodule is a localized nodular lesion of the thyroid gland characterized by growth, iodine uptake and function, all independent from TSH control. These nodules represent a heterogeneous anatomic and clinical entity. The clinical diagnosis is based upon a negative suppression of nodule iodine uptake and scan imaging by T3 administration. The nodule function is determined by high serum thyroid hormone levels and/or low TSH (measured by ultrasensitive assay). Etiology and pathogenesis of these nodules is not yet completely clarified. Both genetic and environmental factors determine nodule growth and function: thyroid cells, in fact, are genetically heterogeneous and may have intrinsic (congenital) characteristics that may promote the growth of cellular clones having mitotic and functional activity that is partially independent of TSH. In these particular cell clones, environmental factors like iodine deficiency or other goitrogens may favour the growth of autonomous nodules and also, by activating their function, may induce toxicity. The autonomous thyroid nodules need to be treated only when they become toxic: in this case both surgical excision or radioiodine may be used.

IGF-I receptor (IGFR) content and its prognostic significance were evaluated in human breast cancer specimens using a sensitive and specific radioimmunoassay (V. Pezzino et al., Metabolism, 40: 861, 1991). The prognostic significance of IGFR expression was investigated by two different approaches: (a) detectable IGFR content was measured in 82% of specimens in a consecutive series of 184 human breast cancers and in 32% of 19 normal breast tissues. The average IGFR content in breast cancer was nearly 10-fold higher than the value observed in normal breast tissue (7.6 +/- 0.8 versus 0.8 +/- 0.1 ng/0.1 mg protein, mean +/- SEM; P0.001). IGFR content was positively correlated with estrogen (ER) and insulin receptor content (r = 0.269 and 0.515, respectively, Pearson correlation) but not with progesterone receptors (PR). No significant correlation was observed between IGFR content and a variety of tumor parameters (tumor size, lymph node involvement, grade) and host characteristics (age, body mass index, menopausal status); (b) IGFR content was measured in a noncontinuous series of 265 primary breast cancer specimens subdivided into 136 high-risk and 129 low-risk specimens on the basis of being either negative (ER-/PR-/aneuploid/high S-phase) or positive (ER+/PR+/diploid/low S-phase) for four well-established prognostic factors. IGFR levels were significantly higher in the low-risk group (6.4 +/- 0.4 ng/0.1 mg protein, mean +/- SEM) than in the high-risk group (3.6 +/- 0.5; P0.0001, Wilcoxon sum rank test). In summary, our data indicate that there is an elevated IGFR content in most human breast cancers compared with normal breast tissue and that an elevated IGFR content is a favorable prognostic indicator.

In this study we compared, in 12 NIDDM patients with secondary failure to glyburide, the effect of adding either a single, low-dose bed time NPH insulin injection (0.2 U/Kg) or an oral metformin administration (500 mg x 3) to the previously ineffective sulfonylurea treatment. The addition of both insulin and metformin treatment significantly improved fasting plasma glucose, post-prandial plasma glucose and %HbA1. The effect of both combined therapies was already evident and maximal after 2 weeks of treatment. The addition of bed-time NPH insulin caused a greater decrease of fasting plasma glucose, although the difference with the addition of metformin was not significant. In contrast, the average post-prandial plasma glucose decrease was significantly greater after metformin addition. The addition of bed-time NPH insulin caused a significant increase in average body weight, while after metformin addition, average body weight was unchanged; no change in the average cholesterol and triglyceride level was observed after either combined therapies.

The effects of progesterone on the growth of breast carcinoma cells are undefined. In the present study we investigated the effect of progestins on insulin receptor gene expression and insulin action in human breast cancer cells. Treatment of T47D cells with the synthetic progestin R5020 induced a time- and dose-dependent increase in insulin receptor content as measured by both ligand-binding studies and radioimmunoassay. Binding was half-maximally stimulated at 300 pM R5020 and maximal levels were reached after 4 days of treatment. Progesterone was 10-fold less potent than R5020. Cortisol had no effect on insulin receptor levels, while 17 beta-estradiol and dihydrotestosterone had minimal effects. Progestin treatment both increased insulin receptor mRNA levels and altered the relative distribution of the multiple insulin receptor mRNA transcripts. In order to study the functional significance of the increased insulin receptor levels, we incubated T47D cells with progesterone and then treated them with insulin. Insulin alone had a small effect on cell growth; however, the effect of insulin was markedly potentiated by progesterone treatment. These studies in breast cancer cells demonstrate, therefore, that insulin receptor gene expression is under the regulation of progestins and raise the possibility that progestin-insulin interactions may regulate breast cancer cell growth in vivo.

Several reports have shown that average plasma GH concentrations in insulin-treated and in juvenile diabetics are elevated in respect to normal values: these findings have been alternatively attributed to an increased pituitary GH secretion or to a lower GH catabolism induced by the disease. To reinvestigate the problem we studied GH kinetics in twentyfour diabetics using 125I-GH. The patients were all normal in body weight and their fasting blood sugar did not exceed 190 mg. per 100 ml.; fourteen normal subjects were included as a control group. After single injection of the tracer, the plasma disappearance curve of labeled hormone was obtained. Starting from this curve, metabolic clearance rate (MCR), fractional catabolic rate (FCR), initial distribution volume (IDV), and total distribution volume (TDV) were computed; MCR and plasma concentration of endogenous GH in plasma samples were used to estimate the amount of hormone irreversibly lost during the experiment (IHL240). The major points that result from the comparison of the values obtained in diabetic patients with those in the normal group are: MCR values in diabetics do not differ from those found in normals (63.6 ± 19.6 and 64.6 ± 24.3 ml./min./m.2 respectively*). The higher plasma concentrations of endogenous GH in diabetics together with a normal MCR, yield hormone loss values (IHL240) significantly larger than normal (46.4 ± 29.5 μg/240 min. as compared to 23.7 ± 24.5) thus indicating that an increased GH secretion is present in diabetics. TDV, fairly constant in normals, (5.8 ± 0.9 L./m.2) tends to decrease in diabetic patients as the disease progresses; in fact the values of TDV are significantly reduced (P10 yrs. of disease) while TDV of short-term diabetics (

The binding of both insulin and glucagon to receptors in plasma membranes from five hepatomas of varying growth rates was diminished when compared to plasma membranes from normal liver. Scatchard analyses of the binding data suggested that the decrease in glucagon binding was due to a decrease in binding capacity, whereas the decrease in insulin binding was due either to a decrease in binding affinity or to site-site interactions. The decreased binding of insulin, but not of glucagon, showed a significant correlation with increasing growth rate of the tumors. These data suggest, therefore, that decreased binding of insulin to receptors could be a feature of increasing growth rate in hepatomas.

Insulin is a major anabolic hormone for most mammalian species. The hormonal potency of insulin results, to a large extent, from its ability to regulate target cells at a variety of cellular sites. The effects of insulin on membrane transport, enzyme activity, and protein synthesis have been studied extensively. Most likely many of these effects result from the direct interaction of insulin with its plasma membrane receptor. Insulin also regulates nuclear functions such as DNA and RNA synthesis, but how insulin influences these processes is unknown. The presence of specific binding sites for insulin on nuclei and nuclear envelopes has been documented and characterized. These binding sites have biochemical characteristics that are different from insulin binding sites on the plasma membrane. Moreover, direct in vitro effects of insulin on messenger RNA (mRNA) metabolism have now been reported. These effects include: (1) stimula- tion of mRNA efflux from intact nuclei; (2) stimulation of nuclear envelope nucleoside triphosphatase (NTPase), the enzyme that regulates mRNA efflux; and (3) inhibition of 32P incorporation into nuclear envelopes. Thus, significant insight is now being gained concerning the actions of insulin on nuclear function.

The effects of the two groups of oral agents on insulin receptors were studied in several types of cells in tissue culture: MCF-7 human breast cancer cells, IM-9 human lymphocytes, human fibroblasts, and H-35 rat hepatoma cells. In none of these cells did the four sulfonylureas tested, tolbutamide, glibenclamide (glyburide), gliclazide, and glisolamide, have any significant effects on insulin binding to its receptor. In contrast the two biguanides tested, phenformin and metformin, increased insulin binding in all cell types by 44 to 101%. These studies raise the possibility, therefore, that biguanides may have a direct effect on insulin receptors and this effect may account for the known effects of biguanides to lower elevated blood sugar levels in diabetic patients.

We evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific 125I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific 125I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin (850 mg orally, b.i.d., for 4 days). Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitro to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects (+ 31%, P less than 0.05) and diabetic patients (+ 63%, P less than 0.01). Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded. By this mechanism, therefore, metformin may contribute to restoring insulin effectiveness in subjects with impaired insulin responsiveness.

The Authors have evaluated the relationship between the presence of estrogen (ER) and progesterone (PgR) receptors and the ovarian function in 321 consecutive and unselected women who have undergone surgery for breast cancer. A significant relationship was found between the presence and the concentration of steroid receptors (ER and PgR) in the neoplastic tissue and the ovarian function. The Authors confirm the importance of considering the menopausal status in the evaluation of the results of steroid receptor assay.

Insulin is a major anabolic hormone for most mammalian species. The hormonal potency of insulin is largely the result of its ability to regulate target cells at a variety of cellular sites. The effects of insulin on membrane transport, enzyme activity, and protein synthesis have been studied extensively. Most likely, many of these effects result from the direct interaction of insulin with its plasma membrane receptor. Insulin also regulates nuclear functions such as DNA and RNA synthesis, but just how insulin influences these processes is unknown. The presence of specific binding sites for insulin on nuclei and nuclear envelopes has been documented and characterized. These binding sites have biochemical characteristics that are different from insulin binding sites on the plasma membrane. Moreover, direct in vitro effects of insulin on messenger RNA (mRNA) metabolism have now been reported. These effects include (1) stimulation of mRNA efflux from intact nuclei; (2) stimulation of nuclear envelope nucleoside triphosphatase (NTPase), the enzyme that regulates mRNA efflux; and (3) inhibition of 32P incorporation into nuclear envelopes. Thus, significant insight is now being gained concerning the actions of insulin on nuclear functions.

The significance of the radioimmunological dosage of the thyrotropic hormone (TSH) is examined as regards accordance between the experimental measure and the real behaviour of the hormone; as a matter of fact, in some particular conditions the problem of the specificity of dosage must be taken into account because of the possible interference of other hormones. From the clinical point of view the TSH radioimmuno assay is advisable for its accuracy, sensibility and specificity. On the other other hand, it is a lengthy and complex determination; instability of the labelled hormone is to be pointed out as the worst shortcoming. The procedures for clinical study of TSH are also examined with reference to an indirect evaluation of the thyroid function. tthe clinical application of TSH dosage in endrocrinology diagnostics, concerning both thyroid and hypophysis pathology, are discussed.

The endocytosis, recycling, and degradation of the insulin receptor were studied in IM-9 cells and U-937 cells by employing two monoclonal antibodies directed at the alpha subunit of the human insulin receptor, antibodies MA-5 and MA-10. Antibody MA-5 is an insulin agonist and MA-10 is an insulin antagonist (Forsayeth, J., Caro, J.F., Sinha, M.K., Maddux, B.A., and Goldfine, I.D. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 3448-3451). Both monoclonal antibodies, like insulin, induced the endocytosis of the insulin receptor within 15 min. Upon removal of extracellular ligand the internalized receptor recycled to the cell surface. At this time there was no degradation of the receptor as measured by a sensitive insulin receptor radioimmunoassay. After 20 h of incubation, insulin and MA-5, but not MA-10, induced significant receptor degradation as measured by both insulin receptor radioimmunoassay and metabolic labeling studies. These studies demonstrated, therefore, that: 1) internalization and recycling of the receptor can be induced by antireceptor monoclonal antibodies that are either insulin agonists or insulin antagonists; 2) enhanced receptor degradation can be induced by monoclonal antibodies that are insulin agonists; and 3) the process of receptor internalization does not necessarily lead to enhanced receptor degradation. Since prior studies have indicated that neither MA-5 nor MA-10 enhance insulin receptor kinase activity, the present studies also suggest that insulin receptor endocytosis and degradation induced by ligands different than insulin can occur without activation of this process.