Effect of physiological exercise on osteocalcin levels in subjects with adrenal incidentaloma.

AIM: In the present study, we have evaluated whether physical exercise affect low osteocalcin concentrations observed in patients with subclinical hypercortisolism. SUBJECTS AND METHODS: Sixteen patients (10 men and 6 women, age 38-55 yr) with adrenal incidentaloma were studied. Fifteen healthy volunteers matched for age (range 35-47 yr) were used as controls. Subjects were submitted to a 8-week exercise-training program with cycle-ergometer for 1 h/day 3-4 days/week at 60% of their individual VO2 max. Before and after this period, resting venous serum osteocalcin and GH concentrations were measured in the same batch. The blood sampling after 8 weeks of the training program were performed after resting for one day. All patients and controls underwent also the following endocrine evaluation: serum cortisol, plasma ACTH. RESULTS: Our results demonstrate a significant increase of osteocalcin after physical exercise and a positive correlation between osteocalcin and GH. This later might suggest a role of GH in the increased osteocalcin secretion. CONCLUSIONS: The data of the present study suggest a positive effect of physical exercise on bone metabolism in patients with adrenal incidentaloma.

Inhibitory effect of somatostatin on the NPY response to insulin-induced hypoglycemia and the role of endogenous opioids.

The present study was undertaken in order to establish whether somatostatin (SRIH) is able to modify the neuropeptide Y (NPY) response to insulin-induced hypoglycemia during insulin tolerance test (ITT) in man. In addition, the possible involvement of opioid peptides in the mediation of hypoglycemia and/or SRIH action was investigated. Subjects were injected intravenously with 0.15IU/kg insulin alone (control test) or with SRIH (4.1µg/min/90min), naloxone (10mg in an iv bolus) or the combination of the two substances. Plasma NPY concentrations rose significantly during ITT. The NPY response was significantly reduced by the treatment with SRIH. The administration of naloxone did not modify NPY levels whereas when both SRIH and naloxone were given, NPY response to hypoglycemia did not differ from that observed in the control test. These data demonstrate that SRIH inhibits the NPY response to hypoglycemia. Naloxone-sensitive endogenous opiates do not seem to be involved in the control of hypoglycemia-induced NPY release. In contrast, since naloxone reversed the inhibiting effect of SRIH, an involvement of opioid peptides in the SRIH action may be supposed.

Somatostatin reduces neuropeptide Y rise induced by physical exercise.

The effect of an i. v. infusion of somatostatin (SRIH) 4.1 µg/min×90 min on the basal secretion of NPY and on the NPY response to physical exercise was studied in normal men. Basal NPY secretion was not modified by SRIH infusion, whereas the NPY response to physical exercise was significantly lower in the presence of SRIH. These data suggest the involvement of a somatostatinergic mechanism in the regulation of NPY response to physical exercise.

Stimulatory effect of naloxone on plasma cortisol in human: Possible direct stimulatory action at the adrenal cortex.

UNLABELLED: The purpose of the present study was to gain a better insight in the mechanism of naloxone underlying the regulation of adrenal cortisol secretion in humans in vivo; therefore, the stimulatory effect of naloxone on cortisol secretion was assessed in a group of patients with hypothalamo-pituitary disconnection. Patients with hypothalamo-pituitary disconnection because of various pathologies (craniopharingioma, cordoma, suprasellar meningioma, or pituitary macroadenoma) participated in the study. RESULTS: Circulating cortisol, but not adrenocorticotropin (ACTH) levels were significantly higher after naloxone administration than after saline. CONCLUSION: Besides the well-known hypothalamo-pituitary stimulatory action on ACTH release in normal humans, the results of the present study suggest that naloxone exerts direct effects on cortisol secretion at the adrenal gland level; another possibility is that naloxone stimulation of cortisol secretion is mediated by other factor than ACTH.

Systemic oxytocin administration modulates NPY response to insulin-induced hypoglycemia in man.

The present study was undertaken to establish whether oxytocin (OT) is able to modify the NPY response to insulin-induced hypoglycemia in man. At 8:00 AM of 2 different days at least 1 week apart, 10 normal men were tested with insulin (0.15 IU/kg) and with the administration of OT (infused from time -15-60 min, at a constant rate of 2 mIU/ml) or placebo. Plasma NPY concentrations rose significantly during insulin tolerance test (ITT). Oxytocin treatment significantly reduced the NPY response to hypoglycemia. The finding demonstrates for the first time in humans that the systemic administration of OT exerts an inhibitory effect on the NPY rise caused by insulin-induced hypoglycemia.

Effect of serotonergic system on AVP secretion induced by physical exercise.

The present study was undertaken in order to establish the possible involvement of serotonergic receptors in the control of physical exercise-stimulated vasopressin secretion. Twenty-one healthy men (divided in three groups of seven) underwent bicycle-ergometer tests until exhaustion: exercise control test (n=21), exercise plus ondansetron, selective 5-HT3 antagonist (n=7), exercise plus buspirone, selective 5-HT1A receptor agonist (n=7), exercise plus sumatriptan, selective 5-HT1D receptor agonist (n=7). AVP levels, physiological and biochemical variables were measured and compared during tests. Results showed that exercise-induced AVP rise did not change after the administration of buspirone and sumatriptan. In contrast, the administration of ondansetron significantly reduced physical exercise-induced AVP rise. Mean peak levels during physical exercise were 4.9 times higher than basal values in the control test and 2.6 times higher than basal values in the ondansetron plus exercise test. These data demonstrate that 5-HT3 serotonergic receptors at least partially mediate the AVP response to physical exercise. On the other hand, 5-HT1A and 5-HT1D serotonergic receptors do not appear to be involved in the control of AVP secretion during exercise.

Effect of naloxone on somatostatin inhibition of arginine vasopressin response to physical exercise in normal men.

To establish whether somatostatin (SRIH) and/or endogenous opioids play a role in the control of arginine-vasopressin (AVP) response to physical exercise, eight healthy men underwent four bicycle-ergometer tests until exhaustion: exercise control test; exercise plus SRIH, naloxone or SRIH plus naloxone. Serum AVP levels, physiological and biochemical variables were measured during tests. Physiological and biochemical variables were similar in all tests. During control test exercise significantly increased serum AVP levels, with a peak value 4.1 times higher than baseline. The AVP response to exercise was similar in the presence of naloxone, whereas it was significantly reduced by SRIH (AVP peak was only 2.8 times higher than baseline). When SRIH and naloxone were given together, the exercise-induced AVP rise was comparable to that observed in the control test. Results indicate a somatostatinergic involvement in the regulation of the AVP response to physical exercise. Furthermore, naloxone-sensitive endogenous opioids appear to play a role in the mechanism underlying SRIH inhibitory action, but not in mediation of the AVP response to physical exercise.

High-calcium mineral water as a calcium supplementing measure for post-thyroidectomy hypocalcemia.

AIM: The aim of this study was to test the possibility of enhancing blood calcium levels in totally thyroidectomized patients by supplementation with 1 L/d carbonate-bicarbonate-high-calcium mineral water. METHODS: This study enrolled 95 outpatients, totally thyroidectomized four months earlier, and hence treated with oral calcium and vitamin-D. At recruitment, ionized blood calcium was either below (Group A; N. 55) or above (Group B; N. 40, randomly divided in Group B1 [N. 20] and Group B2 [N.20]) the lower limit of the normal range (1.12 mmol/L). For one month, Group A was treated with 1 L/d high-calcium (483 mg/L) mineral water and continued the usual therapy with Ca and vitamin-D. In contrast, Group B1 and Group B2 substituted their Ca and vitamin-D therapy with 1 L/d high-calcium mineral water (Group B1) or 1 L/d of placebo mineral water (Ca:80 mg/L) (Group B2). RESULTS: After one month, a significant 7.5% increase in blood ionized-calcium levels was observed in Group A, no change in Group B1 and a significant drop below normality in Group B2 (Group B2 vs Group B1, P<0.001). Thereafter, 1 L/d of the high-calcium mineral water, given to Group B2 instead of placebo for an additional month, significantly enhanced ionized-calcium levels above the lower limit of normality (Group B2 vs Group B1, NS). CONCLUSION: These experiments show that calcium supplementation as 1 L/d of a high-calcium mineral water may efficaciously enhance blood calcium levels in thyroidectomized patients. This complementary treatment might at least in part contribute to the prevention and/or treatment of hypocalcemia and substitute vitamin-D and calcium therapies after thyroidectomy.

Free fatty acids inhibit adrenocorticotropin and cortisol secretion stimulated by physical exercise in normal men.

BACKGROUND: The basal circulating levels of ACTH and cortisol, but not the ACTH/cortisol response to hCRH, are significantly reduced by free fatty acid (FFA) infusion. OBJECTIVE: To verify whether FFA infusion modifies the ACTH/cortisol response to physical exercise, a well-known activator of the HPA axis at suprapituitary level. DESIGN: Exercise tests on a bicycle ergometer during infusion of a lipid-heparin emulsion (LHE) (experimental test) or normal saline (NaCl 0.9%) (control test). SETTING: Department of Cardiology at the University-Hospital. SUBJECTS: Seven healthy male subjects aged 25-33 years. INTERVENTIONS: On two mornings, at weekly intervals, LHE or saline were infused for 60 min; infusion started 10 min before exercise test on a bicycle ergometer, which lasted about 15 min. MAIN OUTCOME MEASURES: Circulating ACTH/cortisol levels and physiological variables during physical exercise. RESULTS: FFA levels (0.4 +/- 0.1 mEq/l) remained constant during control test, whereas they progressively rose (peak at 60 min, 2.7 +/- 1.0 mEq/l) during LHE infusion. Neither basal nor exercise-induced changes in physiological variables were modified by LHE infusion. Both ACTH and cortisol increased during exercise, with peak levels at 20 min and 30 min (control test: 103% and 42%, P < 0.001; experimental test: 28.5% and 18.6%, P < 0.05 higher than baseline, respectively). Both ACTH and cortisol responses were significantly lower in the experimental than in the control test (at 20 min P < 0.002 and at 30 min P < 0.05 for ACTH; at 20 min P < 0.05 and at 30 min, 40 min and 50 min P < 0.001 for cortisol). CONCLUSIONS: These data represent the first demonstration of an inhibitory action of increased circulating FFA levels on the HPA axis under stimulatory conditions (i.e. physical exercise, a challenge acting at suprapituitary level). In contrast, previous studies did not show FFA effects on the CRH-induced ACTH/cortisol response. Therefore, our data suggest negative effects of FFAs on the HPA axis at hypothalamic or higher centres in the central nervous system.

Extraprostatic complications of testosterone replacement therapy.

Testosterone therapy has been reported to be useful in the treatment of hypogonadism and partial androgen deficiency of the aging male (PADAM) syndrome. Testosterone administration is needed in order to maintain secondary sexual characteristics, muscle mass, bone mineral density, cognitive function and sexual drive. Newer testosterone-containing compounds, particularly gel preparations, are known to produce more stable circulating testosterone levels than im-administered drugs, with scarce side-effects and good patient compliance. All patients treated with testosterone must undergo a careful follow-up to prevent the development of the major side effects, such as sleep-apnea, erythrocytosis, cardiovascular diseases and the alterations of hepatic function and plasma lipid concentrations.

Difference between diabetic and nondiabetic smokers in the pituitary response to physical exercise.

The growth hormone (GH), cortisol, and arginine vasopressin (AVP) responses to bicycle ergometry (with increasing workload until exhaustion) were measured in 20 patients affected by insulin-dependent diabetes mellitus (IDDM) (10 habitual smokers and 10 nonsmokers) and 20 nondiabetic subjects (normal controls) (10 habitual smokers and 10 nonsmokers). Cardiorespiratory parameters such as heart rate, blood pressure, ventilation, frequency of breathing, tidal volume, oxygen consumption (Vo(2)), carbondioxide production (Vco(2)), and respiratory exchange ratio (R) were monitored before and during exercise tests. No significant differences between groups were observed; furthermore, there were no differences in circulating somatomedin-C (SM-C) and free fatty acids (FFA) levels between groups. Blood glucose levels were similar before exercise and followed a similar pattern during tests in diabetic smokers and nonsmokers. Basal GH, cortisol, and AVP levels were similar in diabetic smokers, diabetic nonsmokers, normal smokers, and normal nonsmokers. In all groups, exercise induced a significant increase in the serum concentrations of all examined hormones. Increments were significantly higher in diabetic than in nondiabetic groups. No significant differences were observed between diabetic smokers and nonsmokers for all examined hormones. AVP responses during tests were similar in normal smokers and nonsmokers. In contrast, exercise-induced GH and cortisol increments were significantly lower in normal smokers than in normal nonsmokers. These data support the hypothesis that in normal subjects habitual nicotine consumption may attenuate both GH and cortisol responses to a releasing stimulation, such as physical exercise. This phenomenon may represent an expression of adaptation of nicotinic neurotransmission to chronic stimulation. Furthermore, the data show that the effect induced by habitual smoking is absent in diabetics, probably because of diabetes-induced neuroendocrine alterations in the central nervous system.

Serum total prostate-specific antigen assay in women with Cushing's disease or alcohol-dependent pseudo-Cushing's State.

BACKGROUND: The distinction between Cushing's disease (Cushing's syndrome dependent on adrenocorticotropic hormone (ACTH)-secreting tumors of pituitary origin) and pseudo-Cushing's states (Cushingoid features and hypercortisolism sometimes present in alcoholic, depressed or obese subjects) can present a diagnostic challenge in clinical endocrinology. Recently, the availability of a highly sensitive immunofluorometric assay for the measurement of total prostate-specific antigen (PSA) provided the possibility to measure serum PSA levels in women. Interestingly, PSA gene expression and protein production has been found to be upregulated by steroid hormones, such as androgens, glucocorticoids, mineral corticoids and progestins. In fact, serum total PSA concentrations appear to be higher in female patients with Cushing's disease than in normal women. We wondered whether a similar phenomenon also occurs in pseudo-Cushing's state. METHODS: In order to answer this question, we compared the serum total PSA levels measured in 10 female subjects with alcohol-dependent pseudo-Cushing's state with those observed in 8 female patients with Cushing's disease and in 15 age-matched healthy women. Serum testosterone, ACTH and cortisol, and 24-hour urinary cortisol levels were measured; cortisol suppression after dexamethasone was also tested in all subjects. RESULTS: The basal serum levels of ACTH and cortisol were significantly lower in normal subjects than in patients with Cushing's disease or pseudo-Cushing's state; these latter groups showed similar basal hormonal values. Dexamethasone administration was unable to suppress serum cortisol levels in 5 subjects with Cushing's disease and 6 subjects with pseudo-Cushing's state. Serum testosterone values in the group with Cushing's disease were higher than in the other groups. No differences were observed between pseudo-Cushing's and normal subjects. Serum total PSA levels were significantly higher in women with Cushing's disease than in subjects with pseudo-Cushing's state and normal controls; these latter groups showed similar PSA values. When serum total PSA and testosterone levels were considered together, a significant positive correlation was observed in the group with Cushing's disease, but not in the other groups. CONCLUSIONS: These data indicate that the steroid milieu responsible for the elevation in serum PSA in women with Cushing's disease is not present in subjects with alcohol-dependent pseudo-Cushing's state, suggesting the possible use of PSA as a marker of differentiation between these pathological conditions in women.

Effect of oxytocin on nitric oxide activity controlling gonadotropin secretion in humans.

BACKGROUND: Previously described inhibitory effects of the nitric oxide synthase (NOS) inhibitor L-NAME on luteinizing hormone-releasing hormone (LH-RH)-induced LH and follicle stimulating hormone (FSH) secretion in humans suggested modulation by nitric oxide (NO) of the gonadotropin-releasing action of LH-RH. DESIGN: In order to establish whether oxytocin (OT) participates in this regulatory mechanism, 10 normal men were treated with LH-RH (100 micro g as an i.v. bolus) given alone or in the presence of L-NAME (40 micro g kg-1 injected plus 50 micro g kg-1 infused i.v. for 60 min), OT (2 IU injected plus 4 IU infused i.v. for 60 min) or a combination of both drugs. RESULTS: The administration of OT was unable to change the gonadotropin responses to LH-RH. In contrast, L-NAME significantly reduced both FSH and LH increments induced by LH-RH. When L-NAME was given in the presence of OT, the LH and FSH responses to LH-RH were similar to those observed after the administration of LH-RH alone. CONCLUSION: These data suggest antagonistic actions of OT and L-NAME in the control of NOS activity in regulation of gonadotropin secretion induced by LH-RH.

Effect of dexamethasone on TSH secretion induced by TRH in human obesity.

BACKGROUND: The presence of an abnormally high thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) makes it difficult to distinguish some euthyroid obese subjects from subelinically hypothyroid obese patients. Here, we examine whether such distinction may be achieved after treatment with glucocorticoids, which inhibit TSH secretion at the hypothalamic-pituitary level. METHODS: TRH tests (200 microg as an intravenous bolus injection) were performed in 30 age- and weight-matched, obese, but otherwise healthy, men. All subjects were tested again with TRH after treatment with dexamethasone (dex) (2 mg/d in four divided doses orally for 3 days). RESULTS: In all subjects, total thyroxine and triiodothyronine concentrations were in the normal range. According to basal and TRH-stimulated serum thyrotropin (TSH) levels, subjects were divided into the following three groups: group I (n=10), euthyroid subjects; group II (n=10), euthyroid subjects with normal basal but abnormally elevated TSH responses to TRH; group III (n=10), subjects with elevated basal and TRH-induced TSH levels (subclinical hypothyroidism). Basal TSH levels were 1.8+/-0.4 mU/L in group I, 1.7+/-0.3 in group II, and 6.0+/-0.7 in group III. In both groups II and III, TRH-induced TSH increments were above the normal range (maximal increment> 15 mU/L) and were significantly higher than in group I. After the second treatment with TRH, pretreatment with dex significantly decreased both basal TSH levels and peak TSH responses to TRH in all groups. However, a striking percentage decrease (>50%) in TRH-induced peak TSH responses was observed in euthyroid obese subjects of groups I and II, whereas hypothyroid subjects of group III showed only a slight decrement (<25%). CONCLUSIONS: The sensitivity of the TSH secretory system to glucocorticoid inhibitory action is preserved in obese subjects with abnormally elevated TSH response to TRH, but not in subclinically hypothyroid obese patients. The TRH plus dex test might be useful in future studies to understand the mechanisms underlying alterations in TSH secretion in obesity.

Different control of GH secretion by gamma-amino- and gamma-hydroxy-butyric acid in 4-year abstinent alcoholics.

The present study attempted to establish whether long term abstinence from alcohol restores the stimulatory effects on GH secretion of gamma-aminobutyric acid (GABA) and gamma-hydroxybutyric acid (GHB) that are absent during the first month of alcohol withdrawal. Six 4-year abstinent alcoholic subjects--already tested with GHB 4 years earlier, and seven age- and weight-matched normal controls, were tested p.o. with 800 mg sodium valproate (a drug that enhances endogenous GABA activity), 10 mg baclofen (a GABA(B) receptor agonist), 25 mg/kg body-weight GHB, or a placebo. The blood samples for growth hormone (GH) assay were taken every 30 min for the next 150 min. Placebo administration did not modify GH secretion in any subject. All drugs induced a significant increase in serum GH levels in normal controls. GH secretion in abstinent alcoholics did not change after baclofen or sodium valproate administration, whereas the GH response to GHB was similar to that observed in normal controls. The data confirm previous observations which suggest that different neuroendocrine mechanisms underlie GABA and GHB control of GH secretion. The data also indicates that the GHB--but not the GABA--stimulated pathway returns to normal in alcoholics after 4 years abstinence.

Effect of systemic oxytocin administration on dexamethasone-induced leptin secretion in normal and obese men.

To establish whether the regulatory mechanism of leptin secretion is sensitive to oxytocin (OT), seven healthy nonobese men were tested with dexamethasone (dex; 4 mg, iv, at 0730 h) in feeding (2000 Cal given at 3 meals over 7 h) conditions either in the absence (iv normal saline infusion) or in the presence of a constant iv infusion of OT (1, 2, or 4 mIU/min from 0730 h for 10 h). In six additional subjects under similar experimental conditions, normal saline or OT (1, 2, or 4 mIU/min from 0730 h for 10 h) were infused iv without the previous treatment with dexamethasone. Serum leptin concentrations were measured in samples taken at 60-min intervals during infusion. Leptin levels remained constant during the infusion of normal saline or OT (1, 2, or 4 mIU/min) alone. In contrast, serum leptin concentrations rose significantly from the baseline after dex administration. The leptin response to dex was not modified by the concomitant infusion of 1 mIU/min OT, whereas it was completely abolished by the administration of 2 or 4 mIU/min OT. These findings led us to evaluate the secretory pattern of leptin in 12 obese patients in similar experimental conditions. In all patients basal leptin levels were significantly higher than those in normal weight subjects. In 6 obese subjects, the infusion of OT alone (1, 2, or 4 mIU/min) was unable to change serum leptin levels. In the remaining 6 obese subjects, dex administration significantly increased serum leptin levels; however, the leptin response to dex was not modified by the concomitant infusion of 1, 2, or 4 mIU/min OT. These data show inhibition by elevated circulating OT levels of glucocorticoid-induced, but not basal, leptin secretion in normal weight subjects, suggesting a possible role for OT in the regulatory control of leptin. Furthermore, the results obtained in obese subjects indicate that this regulation is disrupted in obesity.