Gf Argenio

Influence of endogenous androgens on carotid wall in postmenopausal women.

ObjectiveThere is increasing evidence of a direct association between normal androgen levels and reduced cardiovascular morbidity and mortality in women. After menopause the influence of estrogens declines, whereas that of androgens increases. Therefore, we investigated the effects of androgens on atherosclerosis in postmenopausal women, by using carotid artery intimal-medial thickness as a marker of vascular damage. DesignBlood pressure, body mass index, waist-to-hip ratio, serum dehydroepiandrosterone sulfate, androstenedione, total and free testosterone, estrone, insulin, lipid profile, and glucose were evaluated in 44 women in stable physiological menopause. All subjects underwent carotid ultrasound (Biosound 2000 II s.a. high-resolution unit). ResultsSpearman correlation coefficients indicated that serum androstenedione and free testosterone were negatively associated with several carotid intimal-medial thickness measures with correlation coefficients (r) ranging from 0.477 to 0.397 (p < 0.01–0.04). Moreover, age-adjusted androstenedione and free testosterone highest tertiles showed intimal-medial thickness values significantly (p < 0.03–0.05) lower than the other tertiles. There was a favorable association between hormones and the most important cardiovascular risk factors. This association, however, did not reach statistical significance. Stepwise multiple regression analysis showed that the inverse relationships between the hormones (androstenedione and free testosterone) and several intimal-medial thickness measures were maintained (F: 4.15–6.07, p < 0.05–0.02) after adjustment for major cardiovascular risk factors. ConclusionsOur data demonstrate that in postmenopausal women endogenous steroid precursors and androgens are inversely related to carotid intimal-medial thickness, an established marker of atherosclerosis. In addition, these hormones show favorable associations with cardiovascular risk factors. Therefore, our study suggests that, after menopause, normal androgen levels may benefit the carotid artery wall.

Comparison between the suppressive effects of dexamethasone and loperamide on cortisol and ACTH secretion in some pathological conditions

Since in patients with Cushing’s disease, unlike in normal subjects, tonic inhibitory opioid control of ACTH secretion does not operate, use of the opiate agonist loperamide (LOP) has recently been proposed in the diagnosis of hypercortisolemic states. We compared the sensitivity, specificity and diagnostic accuracy of the LOP test (16 mg orally) with corresponding results of the dexamethasone test (DXM, 1 mg orally overnight) in 23 normal subjects and in a total of 42 patients, affected by Cushing’s disease (n=8), incidentally discovered adrenal masses with impaired function of the hypothalamic-pituitary-adrenal (HPA) axis (n=6), obesity (n=21) and depression (n=7). While in controls both DXM and LOP strongly suppressed plasma cortisol and ACTH, in Cushing’s disease and in incidentalomas no patient showed a decrease in cortisol levels below 50 ng/ml or a reduction in plasma cortisol greater than 50% of basal values in response to LOP and DXM. In obese subjects both drugs significantly reduced plasma cortisol and ACTH without giving false positive results. In the depressed group only 3/7 patients showed a decrement in cortisol levels below 50 ng/ml after LOP in contrast to 6/7 after DXM. Thus, in patients with impairment of the HPA-axis, i.e. in Cushing’s disease and in patients with adrenal incidentalomas and hormonal abnormalities, LOP and DXM test sensitivity was 100%. In controls and in obese patients specificity was 100% both with LOP and DXM, while in depressed patients it was 43% and 86% with LOP and DXM, respectively. In conclusion, since the diagnostic accuracy of the LOP test (94.9%) is slightly lower as compared to DXM (98.5%), use of loperamide gives no additional advantages in diagnosis of hypercortisolemic states. However, in account of its good specificity, the LOP test may be considered a complementary diagnostic procedure to DXM in pathological conditions such as obesity in which the DXM test may give false positive results.

IMPAIRED GROWTH HORMONE RESPONSE TO INSULIN‐INDUCED HYPOGLYCAEMIA IN OBESE PATIENTS: RESTORATION BLOCKED BY RITANSERIN AFTER FENFLURAMINE ADMINISTRATION

The aim of the present study was to test whether the serotoninergic system may be involved in the well known reduced growth hormone (GH) response to insulin‐induced hypoglycaemia (IIH) in obese patients. Ten obese women and 10 normal‐weight control women underwent three IIH tests, at 14‐day intervals: the first in basal conditions, the other two after randomized administration of a serotoninergic drug, fenfluramine (FF, 120 mg/day for 7 days) and FF plus ritanserin (RIT, 30 mg/day for the first 2 days and 20 mg/day on the following days). Ritanserin is a new selective 5‐HT2 blocker receptor agent. Both controls and obese patients showed similar normal basal GH levels before each test and insulin administration always effectively reduced glucose levels to values lower than 2‐2 mmol/1. In the controls, the expected GH increase to IIH (peak value 56±13.4 mU/1, AUC 234.4±55 mU/min/m1) was unaffected by FF administration (peak value 43±11.4;AUC 216.8±34.8). In response to the first IIH, the obese patients showed a significantly lower GH increase than in the case of the controls (peak value 21.4±4.6 mU/1, P<0.02; AUC 93.2±18.6, P<0.02). However, in comparison with the basal test, FF administration significantly (P < 0.001) enhanced GH response to insulin hypoglycaemia (peak value 33.4±4; AUC 150±14.6), reaching values not significantly different from those of the controls. This effect was completely antagonized by RIT administration (peak value 18±5; AUC 85.6±21). In conclusion, the reduced GH response to insulin hypoglycaemia in obese women has been confirmed in the present study. However, the restoration of the hormonal response obtained after FF administration in obese patients only, which is effectively antagonized by RIT, strongly suggests the involvement of the serotoninergic system in this impaired secretary pattern and provides indirect evidence of the failure of this system in human obesity.

Effects of long-term simvastatin treatment on testicular and adrenal steroidogenesis in hypercholesterolemic patients

Simvastatin is an inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, the key enzyme in the synthesis of cholesterol, recently introduced in the therapy of hypercholesterolemic patients. Cholesterol is the precursor of the biosynthesis of steroid hormones; thus, a reduction of the availability of cholesterol in the adrenal and testicular cells may reduce the synthesis of corticosteroids and androgens. To establish whether chronic therapy with simvastatin interferes with the integrity of the hypothalamic-pituitary-adrenal axis and with the adrenal and testicular reserve, we administered simvastatin orally in a single-day 10 mg dose for 6 months in 8 mildly hypercholesterolemic male patients. At weeks 0, 6 and 24 of treatment we evaluated the lipids, the activity of the hypothalamic-pituitary-adrenal axis by means of the Corticotropin-Releasing Hormone (CRH) test, the adrenal reserve by means of the Corticotropin rapid test and, finally, the testicular reserve by means of the Human Chorionic Gonadotropin (HCG) test. Total cholesterol and LDL-cholesterol were significantly reduced by Simvastatin, while the HDL-cholesterol and triglycerides did not change significantly. The hormonal responses to CRH, ACTH and HCG tests at weeks 6 and 24 of treatment were comparable to those obtained in basal conditions. We conclude that Simvastatin, while effective in reducing total and LDL-cholesterol in hypercholesterolemic male patients, did not interfere with hypothalamic-pituitary-adrenal axis activity or with basal and stimulated adrenal and testicular steroidogenesis.

Serotoninergic receptor activation by dextrofenfluramine enhances the blunted pituitary-adrenal responsiveness to corticotropin-releasing hormone in obese subjects

To explore the interrelationships between the serotoninergic system and the hypothalamic-pituitary-adrenal (HPA) axis in human obesity, we evaluated cortisol and adrenocorticotropic hormone (ACTH) response to synthetic human corticotropin-releasing hormone (hCRH, 1 microgram/kg intravenously [IV]) before and after stimulation of the serotoninergic system by dextrofenfluramine (d-FF, 30 mg/d for 3 months) in nine obese women. These responses were compared with a CRH test (1 microgram/kg) carried out in nine age-matched normal-weight women. Plasma cortisol of obese subjects did not significantly increase after CRH (peak value 127.1 +/- 11.2 ng/mL v 104.1 +/- 9.5 ng/mL). This response was lower (P less than .005) than in the controls, in whom the basal cortisol value of 120.6 +/- 11.8 ng/mL reached a peak value of 221.2 +/- 13.4 ng/mL. However, after administration of d-FF, CRH significantly increased (P less than .0001) plasma cortisol (peak value 170.6 +/- 18.0 ng/mL v 111.5 +/- 10.8 ng/mL) and the response was enhanced (P less than .05) as compared with that obtained before d-FF. The ACTH levels of our patients showed a small increment after CRH injection (peak value 13.5 +/- 1.7 pg/mL v 9.6 +/- 1.1 pg/mL), but the hormonal response was lower (P less than .005) than in controls (peak value 38.1 +/- 5.5 pg/mL v 13.8 +/- 0.8 pg/mL). However, after d-FF, CRH induced a significant increment (P less than .05) in plasma ACTH at 30 minutes (20.4 +/- 3.7 pg/mL v 10.9 +/- 0.9 pg/mL) and 45 minutes (18.0 +/- 2.6 pg/mL), even though this response was not significantly different from that observed before d-FF administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Blunted growth hormone (GH) responsiveness to GH-releasing hormone in obese patients: Influence of prolonged administration of the serotoninergic drug fenfluramine

The aim of the present study was to ascertain if reduced central serotoninergic activity might contribute to the well-known blunted growth hormone (GH) response to GH-releasing hormone (GHRH) in obese patients. Thus, we studied the effect of prolonged stimulation of the serotoninergic system by fenfluramine (FF; 60 mg twice daily for 7 days) on GHRH-induced GH release in nine obese and seven normal subjects. In controls, GHRH (100 micrograms intravenously [IV]) injection increased GH levels from 2.3 +/- 1.8 (+/- SE) to 18.5 +/- 2.8 mU/L, P less than .002. FF administration enhanced both basal and GHRH-stimulated GH levels (peak, 38.4 +/- 8.3 v 6.9 +/- 2.6 mU/L, P less than .002). This response was significantly higher (P less than .02) than in pretreatment. In obese patients, GH responsiveness to GHRH was slight (peak, 7.1 +/- 2.0 v 0.6 +/- 0.18 mU/L, P less than .01) and lower (P less than .01) than in controls. FF administration did not affect this response. In controls, the enhanced FF-induced GH release after a maximal dose of GHRH indicates that serotoninergic activation influences GH secretion and that the mechanism involved is independent of endogenous GHRH. In obese patients, we found a blunted GH responsiveness to GHRH that was not affected by FF, thus supporting the hypothesis that the serotoninergic control on GH release is impaired.

Effect of fenfluramine on prolactin and thyroid-stimulating-hormone response to thyrotropin-releasing-hormone in obese and normal women

SummaryIn order to demonstrate the suggested failure of the serotoninergic system in human obesity and to evaluate the role of central serotoninergic activity in prolactin (PRL) and thyroid stimulating hormone (TSH) release in this condition, 13 euthyroid obese and 9 healthy women of normal weight were studied. A TRH test (200 µg i. v.) was performed before and after administration of fenfluramine (FF) 60 mg b. d. for 14 days. In the controls, FF did not modify the expected significant increase in PRL induced by TRH. In obese patients, however, the PRL levels was significantly increased after TRH, but the increase was less than in the controls. After FK the PRL response to TRH was larger than in the pretreatment phase, with values similar to those observed in normal subjects. In neither group FF did change the TSH-stimulating effect of TRH, but the hormonal response in obese patients was greater than in the controls.The restoration of the responsiveness of PRL to TRH after central serotoninergic stimulation confirms the hypothesis that a failure of the serotoninergic system may occur in human obesity. Since FF does not interfere with the secretory pattern of basal and stimulated TSH in normal or obese subjects, the serotoninergic system does not seem to play a major role in the control of TSH secretion.

Naloxone does not modify fenfluramine-induced prolactin increase in obese patients.

objective To evaluate whether the supposed physiological interaction between serotoninergic and opioidergic pathways in the modulation of PRL release is preserved in human obesity, a pathological condition in which these two systems are greatly impaired

Amplification of LH response to LHRH by dopamine infusion in eugonadal women

Although the role of biogenic amines in the regulation of gonadotropin release has been studied extensively, the precise role of dopamine (DA) in stimulating LHRH and/or LH release is still controversial. In the present study 6 eugonadal women, aged 20–30, were given an LHRH infusion on day 6 of the menstrual cycle and the pattern and magnitude of LH and FSH responses were estimated. On day 6 of the next cycle, the experiment was repeated and DA was also infused beginning 60 min after the start of the LHRH infusion. Following LHRH infusion plasma LH showed a marked and significant rise with a mean peak increment at 4 h, and with a cumulative response (CR) of 9136 ± 955 mlU/ml/6h. The pattern of FSH response tended to parallel that of LH; however, mean peak increment at 4 h and a CR of 2640±169 mlU/ml/6h were markedly lower. Plasma prolactin levels remained unchanged. Addition of DA to LHRH at 60 min evoked a significantly greater mean peakLH increment at 4 h and a CR of 15514±1836 mlU/ml/6h (p < 0.001). There were no significant changes in either mean FSH peak at 4h or in the CR (3257 ± 309 mlU/ml/6h). As expected, a highly significant (p < 0.001) decrease in circulating PRL from 12.1 ± 3.1 to 3.0 ± 1.5 ng/ml was seen during DA infusion. In conclusion, DA given by iv infusion enhances LH response to LHRH in eugonadal women under the conditions of the present investigation, supporting a role for a dopaminergic component in the control of LH release in women.