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The reduced form of glutathione (GSH) is the most important cell antioxidant and is also an essential cofactor for nitric oxide (NO) synthase that synthesizes NO from l-arginine. Reduced levels of GSH, due both to a hyperglycaemia-induced increase of free radical production and to a decrease of NADPH levels [like in diabetes mellitus (DM)], can hamper the endothelial cell functions. This condition may play an important role in the aetiology of some clinical signs, like erectile dysfunction (ED). The aim of this study was to test the hypothesis that GSH concentration is reduced in patients with ED and type 2 diabetes mellitus. We studied 111 male patients with ED: 64 with diabetes (ED/DM) and 47 without diabetes (ED/wDM); 20 patients with diabetes but without ED (DM) and 26 male normal subjects as a control group (C). The GSH red blood cell concentration was significantly lower in ED than in C (X +/- SD; 1782.12 +/- 518.02 vs. 2269.20 +/- 231.56 mumol/L, p < 0.001). In particular, GSH was significantly reduced in ED/DM vs. ED/wDM (1670.74 +/- 437.68 vs. 1930.63 +/- 581.01 micromol/L, p < 0.01). In DM, GSH was significantly lower than in C and significantly higher than in ED/DM (2084.20 +/- 118.14 vs. 2269.20 +/- 231.56 and vs. 1670.74 +/- 437.68 micromol/L, p < 0.002 and p < 0.001 respectively). GSH showed a negative correlation with fasting glucose concentrations (r = -0.34, p < 0.01) and with the duration of DM (r = -0.25, p < 0.05). A GSH depletion can lead to a reduction of NO synthesis, thus impairing vasodilation in the corpora cavernosa.

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The aim of this study was to verify the effect of goserelin, a GnRH agonist, in women with post-menopausal virilization. Six patients with post-menopausal virilization and increase in 17-hydroxyprogesterone (17-OHP), total (TT) and free testosterone (FT) levels underwent single subcutaneous administration of goserelin, 3.6 mg. Serum 17-OHP, TT, FT, LH, FSH, E2, delta4 and 3alpha-andro-stanediol glucuronide levels were measured before and 4, 8 and 18 days after goserelin administration. Goserelin administration was followed by progressive inhibition of FSH and LH, which fell to premenopausal levels on day 18, and progressive normalization of androgen parameters. The low E2 levels recorded at baseline were further reduced by goserelin administration. Four patients then underwent ovariectomy while in two patients, rejecting surgical treatment, goserelin treatment was protracted up to 6 and 12 months, respectively, with remission of hyperandrogenism. This study shows that in post-menopausal patients with virilization GnRH agonist allows to confirm the diagnosis of gonadotropin-dependent ovarian hyperandrogenism: its administration induces inhibition of gonadotropin levels, normalization of androgen parameters, and remission of virilization when the treatment is protracted in patients waiting for surgery.

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Ionizing irradiation in patients is proposed to cause thrombus formation. An increase in von Willebrand factor secretion in response to irradiation is a major contributing factor to thrombus formation. We have previously reported that the increased VWF secretion in response to irradiation is mediated at the transcriptional level. The VWF core promoter fragment (sequences -90 to +22) was shown to contain the necessary cis-acting element(s) to mediate the irradiation response of the VWF gene. Here we report that a CCAAT element in the VWF promoter is the cis-acting element necessary for irradiation induction and that the NFY transcription factor interacts with this element. These analyses demonstrate that inhibition of NFY's interaction with the CCAAT element abolishes the irradiation induction of the VWF promoter. These results provide a novel role for NFY and add this factor to the small list of irradiation-responsive transcription factors. Coimmunoprecipitation experiments demonstrated that NFY is associated with the histone acetylase P/CAF in vivo and that irradiation resulted in an increased association of NFY with coactivator P/CAF. We propose that irradiation induction of the VWF promoter involves a mechanism resulting in increased recruitment of the coactivator P/CAF to the promoter via the NFY transcription factor.

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A hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in anorexia nervosa (AN), together with some immunological abnormalities, involving citokine - and particularly Tumor Necrosis-Factor-alpha (TNF-alpha) - production by polymorphonuclear cells. The ability of pro-inflammatory cytokines to activate the HPA axis is well known; however, there are no data demonstrating an interdependence between immunological and endocrine response in AN. To investigate the presence of a correlation between immune response and pituitary-adrenal function, plasma ACTH and serum cortisol concentrations were measured in 13 AN patients and in the same number of controls. TNF-alpha and interleukin (IL)-1beta production by ex-vivo unstimulated and LPS-stimulated peripheral mononuclear cells was also assessed. Circulating cortisol concentrations were higher (p<0.01) in AN (156.7 +/- 45.1 microg/l, mean +/- SD) than in controls (105.9 +/- 25.7 microg/l). Unstimulated IL-1beta release in supernatants of mononuclear cell cultures was slightly but not significantly higher in AN than in controls, while TNF-alpha release was similar in the two groups. A positive correlation was found between IL-1beta concentrations in unstimulated culture supranatants and serum cortisol levels in AN (r=0.782, p=0.002), while in normal subjects there was a trend toward a negative correlation; a slight positive correlation, while not significant, between IL-1beta and plasma ACTH, as well as between TNF-alpha and serum cortisol was also found in AN. These data suggest that the normal relationship between pro-inflammatory cytokines release, particularly IL-1beta, and cortisol secretion is deranged in AN.

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Sex and age are the major determinants of serum levels of dehydroepiandrosterone sulfate (DHEA-S): they are about twice in men than in women and show a progressive reduction from the end of the puberty to aging in both sexes. It has been reported that DHEA-S levels are also negatively influenced by insulin. Moreover, DHEA-S levels reduction has been associated to increased risk for cardiovascular disease, which connotes hyperinsulinemic states, such as obesity. We have evaluated serum levels of DHEA-S and insulin as function of age and body mass index (BMI) in 376 adult women (age 18.1-89.6 yrs, median 42.2; BMI 15.7-57.8 kg/m2, median 32.7) by multiple regression and piecewise regression analysis. Insulin levels positively associated to BMI (p=0.000002) and DHEA-S levels negatively associated with age (p=0.000001). Considering the whole population, DHEA-S levels were related positively with BMI (p=0.0013) independently of age. DHEA-S were also directly related to insulin levels independently of age (p=0.042), but this association disappeared after correction for BMI. Piecewise regression analysis did not reveal a threshold level for the increase of BMI (p=0.0004). Interestingly, DHEA-S levels and BMI were positively associated before but not after menopause. Taking into account only obese population, (no.=143, age 18.7-67.3 yrs, mean 39.0, median 39.4) DHEA-S levels were again related negatively with age and positively with BMI, while were unrelated with waist to hip ratio (p=0.391). Our data show that increasing body mass and insulin secretion is not associated to DHEA-S reduction in women. This evidence suggests that DHEA-S is unlikely implicated in the pathogenesis of cardiovascular disease in obese women.

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Cabergoline (CAB), a new long-acting ergoline derivative, was shown to be very effective in reducing PRL levels in normal volunteers and in hyperprolactinemic patients. We evaluated the hormonal changes after discontinuation of long-term therapy with CAB as well as the safety of drug exposure during pregnancy both for mothers and babies. We therefore studied 48 patients (47 females and one male) with pathological hyperprolactinaemia (mean +/- SE, 117.2 +/- 15.2: median 73.2 micrograms/l), treated for 1-82 months (mean +/- SE, 28.3 +/- 3; median 18). After long-term treatment, CAB was withdrawn in 11 patients and PRL levels were persistently normal for almost 15 days and significantly lower (p < 0.05) than basal at 30, 45, 60, 90, 120 days. Three patients had normal PRL levels still at 45 days after treatment discontinuation. Nine patients became pregnant after 1-37 months (mean 12.4) of therapy. In two patients the pregnancy was interrupted spontaneously in one case and voluntarily in the other. In all but one patients after delivery or three-month breast feeding, PRL levels trended towards reduction. In two cases (one with microadenoma and one with idiopathic hyperprolactinaemia) PRL remained in the normal levels for 1-3 years after delivery. In conclusion CAB is able to inhibit plasma PRL levels for long time (up to 120 days) after withdrawal in patients with pathological hyperprolactinaemia treated with long-term therapy.

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Hexarelin (HEX), a synthetic hexapeptide, has a strong and reproducible GH-releasing activity in man after intravenous, subcutaneous, intranasal and oral administration. Its effect undergoes age-related variations, being reduced in elderly subjects. In spite of evidence in animals showing that the activity of GH-releasing peptides (GHRPs) is positively influenced by oestrogens, in young adults no sex-related difference has been found in the GH response to HEX or to other GHRPs. We aimed to clarify the influence of the menopause and oestrogens on the GH-releasing activity of HEX. We studied the GH response to the acute administration of the maximal effective dose of HEX (2 micrograms/kg i.v.) in 24 young women (YW, age: 27.3 +/- 0.5 years: body mass index (BMI): 20.7 +/- 0.3 kg/m2), 14 post-menopausal women (PW, age: 52.9 +/- 1.2 years: BMI: 23.2 +/- 0.9 kg/m2) and 14 aged women (AW, age: 68.9 +/- 1.5 years: BMI: 21.7 +/- 0.7 kg/m2). In 10 post-menopausal women the GH response to HEX was also studied after 3 months of transdermal oestradiol treatment (delivery 50 micrograms/die). Basal oestrogen and GH levels in PW were lower than those in YW (oestrogen: 4.8 +/- 3.6 vs 42.0 +/- 3.4 pg/ml (means +/- S.E.M.). P < 0.001: GH: 1.5 +/- 0.5 vs 2.9 +/- 0.6 micrograms/l, P < 0.02) and similar to those in AW (oestrogen: 1.3 +/- 0.4 pg/ml: GH: 0.9 +/- 0.2 microgram/l). IGF-l levels in PW were not different from those in YW (174.4 +/- 11.9 vs 195.5 +/- 14.9 micrograms/l) and higher than those in AW (109.8 +/- 15.8 micrograms/l, P < 0.01). The GH response to HEX in PW (areas under the curve +/- S.E.M.: 453.6 +/- 56.0 micrograms.min/l) was lower (P < 0.002) than that in YW (1630.4 +/- 259.7 micrograms.min/l) while it did not differ from that in AW (781.8 +/- 189.3 micrograms.min/l). In PW 3-month oestrogen administration increased oestradiol levels (38.3 +/- 5.9 vs 0.8 +/- 0.4 pg/ml, P < 0.001) making them similar to those recorded in YW, while it failed to modify both basal GH and IGF-l levels GH: 1.8 +/- 0.6 vs 1.5 +/- 0.7 micrograms/l: IGF-l: 164.6 +/- 14.3 vs 175.0 +/- 12.3 micrograms/l). Also the GH response to HEX was not modified by oestradiol treatment (518.4 +/- 125.6 vs 425.4 +/- 69.3 micrograms.min/l). In conclusion, present data confirm the strong GH-releasing effect of Hexarelin in humans and demonstrate that its activity is already reduced in post-menopausal women to an extent overlapping that in elderly women. Moreover, oestrogen treatment is not able to restore it. Thus, the lack of oestrogens does not seem to account for the reduced somatotraph responsiveness to GHRPs in the post-menopausal period.

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Galanin enhances both baseline and growth hormone-releasing hormone (GHRH)-induced GH secretion both in animals and in man. Although galanin has a clear influence on the secretion of other anterior pituitary hormones in animals, in man it increases prolactin (PRL) slightly but does not affect spontaneous thyrotropin (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH) or adrenocorticotropin (ACTH) secretion. The aim of our study was to verify the effect of galanin on basal and releasing hormone-stimulated release of gonadotropins, PRL, TSH, ACTH and cortisol secretion. As GH release has been shown to be inhibited by corticotropin-releasing hormone (CRH), we also studied the effect of CRH on galanin-stimulated GH increase. The effect of porcine galanin (15 micrograms/kg iv infused in 60 min) alone and in combination with thyrotropin-releasing hormone (TRH, 200 micrograms iv bolus), CRH (100 micrograms iv bolus) and gonadotropin-releasing hormone (GnRH, 100 micrograms iv bolus) on GH, PRL, TSH, ACTH, cortisol, FSH and LH secretion in seven normal young women (aged 25-30 years) was studied. Galanin infusion caused an increase in serum GH levels (p < 0.02) but failed to modify significantly the spontaneous PRL, LH, FSH, TSH, ACTH and cortisol secretion. The combined administration of TRH, GnRH and CRH caused a significant increase in PRL (p < 0.02), LH (p < 0.02), FSH (p < 0.02), TSH (p < 0.02), ACTH (p < 0.02) and cortisol (p < 0.05), but not in GH levels.(ABSTRACT TRUNCATED AT 250 WORDS)

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Endothelial cells are directly exposed to the metabolic derangements of diabetes mellitus and may be damaged early, if not primitively, in the pathogenesis of diabetic microangiopathy. Cultured human umbilical vein endothelial cells were subjected to equimolar concentrations of glucose or mannitol for the evaluation of 3H-thymidine uptake, cell replication, cell death and repair of standard mechanical lesions. 3H-thymidine uptake was inhibited dose-dependently and to a similar extent by both glucose and mannitol. The former reduced cell replication whereas the latter did not (p less than 0.01 at 27.8 mmol/l, p less than 0.001 at 50.0 mmol/l). Neither caused excess cell death nor interfered with lesion repair. These results suggest that supra-physiological amounts of glucose inhibit DNA synthesis with osmotic mechanisms, delay cell replication through at least partially non osmotic effects, do not cause excess cell death and do not impair local injury repair. The above effects may play a role in the pathogenesis of long-term complications of diabetes.

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Recently, a decrease in bone mineral content (BMC) in hyperprolactinaemic women with long-lasting amenorrhoea has been reported, and attributed either to a direct effect of PRL on bone or secondary to the oestrogen deficiency. To verify if PRL by itself has a direct effect on bone, we have studied BMC at the lumbar level by double-photon absorptiometry in 22 patients with hyperprolactinaemia, selected on the basis of normal or near-normal oestradiol levels. The results were compared with those obtained in 28 healthy closely-matched women, and seven hyperprolactinaemic patients with long-lasting amenorrhoea and oestrogen deficiency. No significant difference in BMC was observed between hyperprolactinaemic patients with normal oestrogen levels (mean +/- SEM = 3.87 +/- 0.10 gHA/cm) and normal subjects (mean +/- SEM = 3.76 +/- 0.10 gHA/cm). Moreover, no significant change was observed during a 6 month follow-up in 13 patients. On the other hand, a significant difference (P less than 0.05) was detected in BMC between the hyperprolactinaemic patients with normal oestradiol levels and those with long-lasting amenorrhoea and oestrogen deficiency (mean +/- SEM = 3.39 +/- 0.18). These results suggest that hyperprolactinaemia by itself is not a risk factor for the development of osteoporosis.

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There is evidence indicating that the cholinergic system positively modulates GH release probably by inhibiting somatostatinergic tone. In the present study, the effects of cholinergic enhancement by pyridostigmine, (PD), a cholinesterases inhibitor, on GH release in normal adults (n = 14) (NA) and in both normal (n = 5) (NC) and short children (n = 19) (SC) with familial short stature (n = 7) or constitutional growth delay (n = 12) were studied. In SC the insulin hypoglycaemia (IH)-induced GH increase was also studied. In both NC and SC 60 mg orally PD induced a significant GH increase with mean peak at 90 min (mean +/- SEM 11.0 +/- 2.2 ng/ml in NC and 11.2 +/- 2.3 ng/ml in SC). The GH areas under response curve (AUC) were 379.3 +/- 76.6 and 327.8 +/- 43.2 ng/ml/h in NC and SC respectively. In NA 120 mg orally PD induced a significant GH increase with mean peak at 120 min (5.1 +/- 1.1 ng/ml) which was significantly lower (P less than 0.05) than that observed in both NC and SC. This statistical difference was strengthened by evaluating AUC (NA:205.6 +/- 33.7 ng/ml/h, P less than 0.05 vs NC and SC). The correlation of drug dosage with body area ruled out that this difference could be related to the different PD dose in adults and children. In SC, IH induced a GH increase significantly lower than that observed after PD (GH peak 7.8 +/- 0.6 vs 16.4 +/- 1.9 ng/ml P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

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The levels of angiotensin-converting enzyme and Factor VIII-related antigen, 2 endothelial synthesized glycoproteins, were measured in basal conditions and after forearm venous stasis in 12 healthy controls and 12 patients with diabetic microangiopathy. Angiotensin-converting enzyme levels were similar in the controls and in the patients both basally (185 +/- 17 nm/ml/min (SEM) and 192 +/- 15, respectively) and after stasis (238 +/- 17 and 220 +/- 15), whereas Factor VIII-related antigen was lower in the former basally (101 +/- 13% vs 184 +/- 16%, p less than 0.001) and after stasis (140 +/- 21% and 243 +/- 21%, p less than 0.01). It is concluded that Factor VIII-related antigen is a more sensitive indicator of endothelial cell damage in diabetic microangiopathy than angiotensin-converting enzyme.

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The way in which the dopaminergic system controls GH secretion in infancy and adolescence was investigated by studying the effects on GH of a specific dopaminergic agonist apomorphine, and two antagonists, metoclopramide (MC), which can and domperidone (DOM), which cannot cross the blood-brain-barrier, (BBB), in 14 males and 6 females aged 8-17 years. Treatment with both antagonists was followed by a marked increase in Prl, whereas only MC stimulated GH secretion, suggesting that this action must occur inside the BBB if it is linked to antidopaminergic properties. GH secretion was also stimulated by apomorphine, which acts at the central level. The paradox posed by the presence of a central effect on GH secretion derived from both an agonist and an antagonist of the dopaminergic receptors is discussed.

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Plasma von Willebrand factor was studied for quantitative and qualitative assessment in basal conditions and after release from the endothelium, as elicited by venous stasis of the forearm, in 8 healthy subjects and 8 patients with diabetic microangiopathy. von Willebrand factor was measured as factor VIII-related antigen (VIII R:Ag) and ristocetin co-factor (VIII R:Co). Its molecular size distribution was evaluated by bidimensional immunoelectrophoresis. The patients had higher basal levels of VIII R:Ag (171 +/- 45% vs 64 +/- 11% of plasma pooled from 20 healthy donors, p less than 0.05) and VIII R:Co (144 +/- 11% vs 88 +/- 8%, p less than 0.01). After stasis, both moieties increased significantly in the 2 groups, remaining higher in the patients (VIII R:Ag = 292 +/- 74% vs 89 +/- 18%, p = 0.01; VIII R:Co = 216 +/- 25% vs 116 +/- 10%, p less than 0.01). No differences in the molecular size distribution were observed between patients and controls, nor within the 2 groups before and after stasis. It is concluded that, in diabetic microangiopathy, the endothelial cells synthesize and store increased amounts of structurally normal von Willebrand factor.

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To verify if the low estrogen regimen could condition the TSH hyperresponsivity and PRL hyporesponsivity to antidopaminergic drugs seen by us and others in patients bearing prolactinoma, the effect of ethynilestradiol treatment (50 micrograms/day/14 days) on TSH and PRL responses to domperidone in 6 women with tumoral hyperprolactinemia and hypoestrogenemia were studied. Estrogenic treatment was unable to modify the TSH and PRL responsiveness either to domperidone and TRH. These data do not support the hypothesis that hypoestrogenemia could cause the peculiar TSH and PRL pattern in response to antidopaminergic drugs, in patients bearing prolactinoma. Also the TRH releasable pool of TSH and PRL in these patients seems to be unaffected by estrogenic treatment.

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