Release In Men Research Articles

Thyrotropin-releasing hormone enhances event-related brain potentials and growth hormone release in man

Changes in contingent negative variation (CNV), a brain-evoked potential related in arousal, as well as in serum triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), prolactin (PRL), cortisol and growth hormone (GH) levels were recorded in 12 male volunteers receiving either thyrotropin-releasing hormone (TRH) or saline infusion. Only during TRH administration an increase in CNV ( P < 0.02) and, 30 min later, in GH ( P < 0.05) occurred; thyroid hormones and PRL increased as well, in the absence of any correlation with CNV areas. Cortisol was not affected by TRH. As dopamine (DA) agonistic drugs notoriously increase both CNV areas and GH levels and experimental evidence for prodopaminergic properties of TRH has accumulated in animal models, a possible explanation of the results here presented might be the activation of DA pathways by TRH also in the human.

Water immersion increases the concentration of the immunoreactive N-terminal fragment of proatrial natriuretic factor in human plasma

Atrial natriuretic factor (ANF) N-terminal (ANF 1-98) and C-terminal (ANF 99-126) fragments were determined by radioimmunoassay in human plasma. Mean basal plasma ANF N-terminal concentrations in 9 healthy subjects were 461 +/- 58 fmol/ml, significantly (p less than 0.0001) higher than ANF C-terminal concentrations (4.8 +/- 0.5 fmol/ml). Central volume stimulation by one hour head-out water immersion (WI) induced a significant (p less than 0.01) increase of the C-terminal peptide levels to 11.6 +/- 2.3 fmol/ml, paralleled by a significant (p less than 0.001) increase of the N-terminal fragment levels to 749 +/- 96 fmol/ml. Increases of plasma concentrations of both fragments upon WI correlated significantly (r = 0.71; p less than 0.05). These data suggest cosecretion of the N-terminal fragment with the C-terminal fragment of pro ANF 1-126 following a physiological stimulus of ANF release in man.

Tolbutamide inhibits gastrin release in man.

Tolbutamide significantly decreased fasting plasma gastrin after 5 min of intravenous infusion in patients with atrophic gastritis, duodenal ulcer, or insulin-dependent diabetes mellitus (IDDM) as well as in healthy volunteers. Increased plasma insulin and decreased blood glucose were observed in patients with atrophic gastritis, duodenal ulcer and healthy volunteers, but not in patients with IDDM. Suppression of plasma gastrin in healthy volunteers was also observed following oral administration of tolbutamide. Despite the observed decrease in plasma gastrin, neither basal nor tetragastrin-stimulated acid output was changed for 30 min following tolbutamide infusion in healthy volunteers. Thus, our data suggest that tolbutamide inhibits gastrin release in man via mechanisms independent of changes in plasma insulin, blood glucose or acid secretion.

Different effects of bombesin on glucose- and tolbutamide-induced insulin release in man.

1. The effect of bombesin, a neurogastrointestinal peptide, on basal and stimulated insulin release was studied in man. 2. Two different stimuli were used, hyperglycaemic (20 g glucose) and hypoglycaemic (1 g tolbutamide). They were injected intravenously to two groups of male healthy volunteers during saline or bombesin (5 ng kg-1 min-1 for 60 min) infusion. 3. The peptide had no significant effect on basal levels of glucose and insulin. However, the insulin response to intravenous glucose was strongly potentiated by bombesin, the integrated insulin response being 2.23 +/- 0.59 mu ml-1 . 90 min and 0.98 +/- 0.19 mu ml-1 . 90 min during infusion of bombesin and saline, respectively (P less than 0.05). The behaviour of plasma glucose was not significantly modified by the peptide. Indeed, the glucose disappearance rate (K of Conard, mg min 10(-2)) changed from 2.5 +/- 0.3 during saline to 2.4 +/- 0.4 during bombesin infusion. 4. When the hypoglycaemic stimulus (i.e. tolbutamide) was used, no effect of the peptide on insulin release could be detected. Here again, the drop in plasma glucose (expressed as Marigo's coefficient) was not affected by the peptide, with a value of 92.8 +/- 12.6 and 84.0 +/- 10.9 during bombesin and saline administration. 5. These data therefore show that, at normal or low blood glucose levels, the dose of bombesin used is unable to modify insulin release and suggest that this peptide might be regarded as a glucose-dependent insulinotropic peptide.

Retinal laser photocoagulation in diabetic patients causes prolactin, growth hormone and cortisol release.

Stress of many kinds (psychological, physical, metabolic) is able to induce endocrine modifications in humans, such as growth hormone (GH), prolactin (PRL), luteinizing hormone (LH), glucagon and cortisol release. Argon laser photocoagulation of the retina (RP), the treatment of choice for diabetic retinopathy, is a painful and stressful maneuvre and represents a direct injury onto a nervous tissue. Therefore it was decided to evaluate the possible endocrine modifications induced by RP in diabetic patients affected by retinopathy. In 19 insulin-dependent diabetic patients (12 men and 7 women), RP induced cortisol release in all cases, GH and PRL release in men, but not in women, and no modification of LH and glucagon plasma levels; in 12 similar patients receiving saline infusions without RP, no endocrine modifications were observed. It is concluded that RP elicits GH, PRL and cortisol release in diabetic patients.

The localization of the site(s) of neurotensin release in man and dog

AbstractThe major source of neurotensin in the gut is the ‘N’ cell and this is found in the highest density in the ileum. The ingestion of food, particularly fat, causes the biphasic release of neurotensin‐like immunoreactivity (NTLI) into the circulation. The early peak occurs sooner than expected if it is due to the presence of chyme in the ileum, suggesting that the early release of neurotensin is due to a more proximal concentration of N cells or that neurotensin is released from the ileum by a more proximal stimulus. This paper investigates the site(s) of neurotensin release by studying: three groups of patients with various resections of the small intestine and the fashioning of duodenostomies, jejunostomies and ileostomies; and the dog with chronic gastric, duodenal and ileal fistulae, and following ileal resection. The results indicate that the jejunum and ileum are critical in the release of neurotensin following fat stimulation and that the stomach and duodenum have no direct role. The stimulation of the jejunum by fat causes the early rise of plasma NTLI by releasing neurotensin from the ileum. If chyme is prevented from passing to the distal jejunum the magnitude of the early peak is diminished and the second, later, peak is abolished. The second peak of plasma NTLI is due to the direct luminal stimulation of the distal jejunum and ileum by the products of fat digestion. Ileal resection completely abolishes any release of plasma NTLI in response to fat. It was concluded that the source of neurotensin released by the ingestion of food is the ileum. The release of neurotensin from the distal gut is dependent upon a signal from the proximal to the distal gut. The identity of the signal is unknown, but it is either neural or humoral and previous studies suggest a cholinergic‐dependent reflex.

The renal vasodilating effect of dopamine is mediated by calcium flux and prostacyclin release in man.

A low dose of dopamine (DA; 1 microgram/kg.min for 3 h) was infused into 10 normal subjects to determine whether vasodilator prostaglandins might be involved in the vascular action of this vasoactive hormone. Although this DA dose did not alter blood pressure, pulse, or cardiac index, it significantly increased renal blood flow (RBF), as estimated by para-amino-hippurate clearance [1.40 +/- 0.10 (+/- SE) to 1.93 +/- 0.18 L/min.1.73 m2; P less than 0.02]. This increase was due to DA receptor action since it was blocked by metoclopramide, a DA antagonist, and was not altered by prazosin, an alpha-adrenergic antagonist. DA simultaneously increased the urinary excretion rate of 6-keto-PGF1 alpha, a stable metabolite of prostacyclin [PGI2; 79 +/- 16 to 154 +/- 32 ng/g creatinine (2 +/- 0.40 to 3.88 +/- 0.78 pmol/mumol creatinine); P less than 0.02], but there was no change in PGE2 excretion. This dose of DA increased urinary Na+ and K+ excretion and slightly increased creatinine clearance from 0.12 +/- 0.01 to 0.16 +/- 0.02 L/min.1.73 m2 (P less than 0.05). Metoclopramide also blocked the increase in PGI2 excretion, indicating that this increase was due to DA. The relationship between RBF and PGI2 was supported by studies in which either indomethacin or ibuprofen, both cyclooxygenase inhibitors, blocked the increase in both RBF and PGI2 excretion rate. Since some DA actions may be mediated through calcium flux, we also administered nifedipine, a calcium channel-blocking drug, and found that the DA effect on RBF and PGI2 was significantly reduced. These studies suggest that the DA effect on RBF is mediated by calcium flux, which probably activates renal vascular phospholipase, leading to release of arachidonic acid and synthesis of PGI2, a potent vasodilator.

Depending on the time of administration, dexamethasone potentiates or blocks growth hormone-releasing hormone-induced growth hormone release in man.

In humans, corticoids suppress growth hormone (GH) secretion elicited by a variety of stimuli, while in vitro they potentiate GH release. To further study this problem, the effect of two doses of dexamethasone on GH secretion elicited by GH-releasing hormone (GHRH) in 6 normal volunteers was studied. Each subject underwent three tests, on 3 separate days with GHRH 1-29 (1 microgram/kg i.v. at 12.00 h). On the control day, only GHRH was given, on the second day dexamethasone 4 mg i.v. was administered at 09.00 h (3 h before GHRH) and on the third day dexamethasone 8 mg p.o. was given 12 h before GHRH (at 00.00 h). The GHRH-induced GH peak was 9.9 +/- 2.0 ng/ml, while 4 mg dexamethasone significantly (p less than 0.05) potentiated GH secretion elicited by GHRH (29.2 +/- 5.7 ng/ml). When dexamethasone 8 mg was given 12 h before, GHRH-induced GH secretion was completely blocked (3.0 +/- 1.1 ng/ml) (p less than 0.05). These results indicate that corticoids have two different actions: an acute potentiating activity on GHRH, and a delayed blocking action on GHRH-induced GH secretion.

The effects of intravenous L-dopa on plasma renin activity, renal function, and blood pressure in man.

L-dopa 7 micrograms.kg-1.min-1 was given intravenously over 2 h to six healthy subjects, controlled by an infusion of saline on a separate occasion, with measurement of plasma renin activity (PRA), urinary sodium and potassium excretion, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), blood pressure, and pulse rate. Mean PRA fell by 50% following L-dopa, which was significantly different from the slight rise which occurred after saline infusion. There was a significant increase in urinary sodium excretion and effective renal plasma flow on infusion of L-dopa. Mean diastolic blood pressure fell during L-dopa infusion, in contrast to the slight increase which occurred during the control study. These observations confirm the anticipated renal dopaminergic effects of L-dopa and also suggest a dopaminergic influence on renin release in man.

Temporal responses of cutaneous blood flow and plasma catecholamine concentrations to histamine H1- or H2-receptor stimulation in man

We have studied the effect of histamine and H1- or H2-receptor antagonists on cutaneous blood flow and catecholamine release in man. Histamine was infused alone or in combination with mepyramine, an H1-antagonist or cimetidine, an H2-antagonist for 2 h. Cutaneous blood flow was measured continuously with a laser Doppler flowmeter, and noradrenaline and adrenaline concentrations were determined in blood samples drawn every 15 min. The infusion of histamine caused an immediate and sustained vasodilatation. The Concomitant infusion of mepyramine prevented the immediate vasodilatation, but had no effect on the sustained response. The Concomitant infusion of cimetidine was without effect on the immediate vasodilatation, but abolished the sustained response. Infusion of the antagonists alone had no effect on cutaneous blood flow. Histamine caused a rapid and sustained increase in plasma noradrenaline, while the increase during concomitant H1-receptor blockade was delayed but achieved the level observed during the histamine infusion. The response to histamine during H2-receptor blockade was small and transient. The rise in plasma adrenaline was not significant. These findings suggest that histamine causes an immediate cutaneous vasodilatation through H1-receptors and a more sustained response through H2-receptors. The vasodilatation is accompanied by an increase in plasma catecholamine concentrations. Despite the continuous infusion of histamine, blood flow decreased during the last hour of histamine infusion, while the plasma noradrenaline concentration was still elevated.

Atrial natriuretic factor inhibits ACTH stimulated aldosterone, but not cortisol, secretion in man.

The effects of human ANF 99-126 on the aldosterone and cortisol responses to ACTH infusion were studied in 8 normal volunteers. ACTH infusion caused a significant rise in aldosterone and cortisol on each study day. On the day that ANF was concomitantly infused the aldosterone, but not the cortisol, response to ACTH was significantly attenuated. These results show that a pharmacological dose of ANF selectively inhibits ACTH mediated mineralocorticoid as opposed to glucocorticoid release in man. These results support in vitro and in vivo findings from animal experiments. These findings also compliment previous studies showing that ANF inhibits ANG II stimulated aldosterone release in normal subjects.

The effect of angiotensin II on endogenous noradrenaline release in man.

1. Considerable data from animal studies suggest that angiotensin II exerts a facilitatory effect on noradrenaline release. We sought evidence for such an effect in man by examining how a subpressor dose of angiotensin II (1.5 ng kg-1 min-1) influences the haemodynamic and plasma noradrenaline responses to physiological stimulation of the sympathetic nervous system. 2. The physiological stimuli investigated were a cold pressor test, the response to standing from lying, bicycle exercise and forearm isometric exercise. 3. The presence of the angiotensin II infusion had no effect on the systolic blood pressure, diastolic blood pressure, heart rate or plasma noradrenaline responses to stimulation of the sympathetic nervous system. 4. We have therefore found no evidence to support the enhancement of noradrenaline release by this low dose of angiotensin II in man.

Neuroendocrine regulation of thyrotropin release in cultured human pituitary cells.

The regulation of TSH release in man was investigated using cell cultures derived from human pituitaries obtained within 24 h of accidental death. TRH stimulated TSH release in a dose-dependent manner. The ED50 was 2.9 +/- 0.6 (+/- SEM) nmol/L, similar to that reported for rat pituitary cell cultures. The release of TSH was calcium dependent, since the calcium channel antagonist verapamil inhibited TRH-stimulated TSH release, and the calcium ionophore A23187 stimulated TSH release. 12-O-Tetradecanoyl-phorbol-13-acetate stimulated TSH secretion, while dibuytryl cAMP had no effect. Epinephrine and serotonin stimulated TSH release, and dopamine and somatostatin inhibited TRH-stimulated TSH release. These findings have directly demonstrated that the regulation of TSH secretion by hypothalamic neuropeptides and biogenic amines in the human pituitary is similar to that in the rat. The development of a tissue culture system to study thyrotrophs from postmortem human pituitaries provides the means for detailed studies of the regulation of TSH secretion in man.

Raw soya-bean flour increases cholecystokinin release in man.

1. The aim of the present study was to determine whether oral ingestion of raw soya-bean flour, which contains trypsin inhibitors, alters the release of cholecystokinin (CCK) in man. 2. Eleven healthy volunteers ate two mixed meals: one with raw soya-bean flour and the other with soya-bean flour that had been heat-treated. The two flours inhibited 34 and 3 mg trypsin/g flour respectively. 3. CCK was measured in plasma using a bioassay based on the release of amylase (EC 3.2.1.1) from dispersed rat pancreatic acini. 4. The peak CCK response was 16.8 (SE 8.1) pmol/l with raw soya-bean flour but 4.9 (SE 2.8) pmol/l with heat-treated flour (P less than 0.05). 5. We conclude that ingestion of raw soya-bean flour increases CCK release in man and that heat treatment which reduces the trypsin inhibitor content of the flour also diminishes its CCK-releasing effect.

Comparison of the effects of pulsatile and continuous TRH infusion on TSH release in men

Pulsatile secretion of hypothalamic releasing factors modulates the release of pituitary hormones. To compare the effects of pulsatile and continuous administration of TRH on TSH secretion, we studied six healthy euthyroid 20- to 38-year-old men by obtaining blood samples every 20 minutes for 12 hours (8 am to 8 pm) during five days of study. TRH was administered according to the following schedule: day 1 (no TRH, control); day 2 and subsequent day 3 (20 μg IV bolus of TRH every 96 minutes); 6 to 17 days rest; then consecutive days 4 and 5 (continuous infusion of 20 μg TRH 96 minutes) for 12 hours on and 12 hours off. The highest mean serum TSH levels occurred on the first day of pulsatile TRH. Serum TSH on pulsatile days 1 and 2 and continuous day 1 was significantly greater than on the control day. Similarly, the mean TSH on each day of pulsatile TRH was greater than the mean TSH on the corresponding days of continuous TRH administration. The highest serum T 4 and T 3 levels were observed on pulsatile day 2, suggesting that the decrease in serum TSH on this day was due to thyroid hormone negative feedback at the pituitary. The mean T 4 and T 3 values on continuous days 1 and 2 did not differ significantly, suggesting that other factors, including “down-regulation” of the pituitary TRH receptors by the continuous TRH infusion may be involved in the further decline of TSH levels on continuous day 2. We conclude that pulsatile TRH infusion releases more TSH, T 3, and T 4 than the corresponding amount of TRH administered continuously. The response to TRH is reduced on the second consecutive day of TRH treatment, using either the pulsatile or continuous pattern of administration.

Effect of peptide YY on prolactin and on FSH and LH release in man

Effect of peptide YY on prolactin and on FSH and LH release in man

Sustained inhibitory actions of a potent antagonist of gonadotropin-releasing hormone in postmenopausal women.

The inhibitory time course and dose-related characteristics of a new potent GnRH antagonist peptide, [N-acetyl-D-pCl-Phe1,2-D-Trp3-D-Lys6-D-Ala10]GnRH, on gonadotropin secretion were studied in nine postmenopausal women. Effective suppression of gonadotropin secretion was correlated with increased circulating concentrations of immunoassayable GnRH antagonist. Inhibition of gonadotropin secretion was achieved by a parenteral dose of 300 micrograms/kg GnRH antagonist. This dose reduced plasma bioactive LH concentrations by 49-59%, immunoactive LH by 41-46%, and immunoactive FSH by 25-40%. Blockade of gonadotropin secretion was sustained for 10-28 h after a single injection of the synthetic decapeptide. This prolonged action was associated with significant plasma protein binding of the GnRH antagonist and mean plasma half-times of disappearance of 1.5 and 21 h for the fast and slow components, respectively. In summary, we have described the biological actions of a potent GnRH antagonist that binds avidly to serum proteins, has a prolonged plasma residence time, and exerts sustained inhibitory effects on bio- and immunoactive LH release in man. The extended duration of action of this compound may reflect in part its significant binding to circulating plasma proteins.

Sex steroids and pulsatile luteinizing hormone release in men. Studies in estrogen-treated agonadal subjects and eugonadal subjects treated with a novel nonsteroidal antiandrogen.

This study evaluated the effects of estrogens and androgens on LH pulse frequency and amplitude in male subjects. To assess the role of estrogens we compared the serum LH pulse frequency and amplitude between 3 groups: 8 agonadal subjects receiving no steroid treatment; 6 agonadal subjects continuously treated with 50 micrograms ethinylestradiol/day; and 17 eugonadal men. Mean serum LH levels and LH pulse amplitude were significantly lower in the agonadal subjects receiving estrogens (14.8 +/- 5.4 (SD) U/L and 4.1 +/- 1.5 U/L, respectively) than in the group of agonadal subjects not receiving sex steroid treatment (35.7 +/- 8.4 U/L and 7.3 +/- 2.0 U/L, respectively). The mean LH pulse frequency was 7.1 +/- 1.5/7 h in the group not receiving sex steroid treatment and 6.0 +/- 1.4/7 h in the group receiving estrogens (P NS). The LH pulse frequency in the eugonadal men (3.8 +/- 1.3/7 h) was significantly lower than the frequency in both groups of agonadal subjects. The LH pulse amplitude was of the same magnitude in the estrogen-treated agonadal subjects and in eugonadal men (4.1 +/- 1.5 U/L and 3.5 +/- 1.2 U/L, respectively). The role of androgens was studied in 15 eugonadal male subjects (who presented for female role reassignment) by determining the effects of a novel nonsteroidal androgen receptor blocker, Anandron, on basal and LH-releasing hormone (LHRH)-stimulated serum LH/FSH levels; LH pulse frequency and amplitude; sex steroid and sex hormone-binding globulin levels; and serum PRL levels during an 8-week period. Basal and LHRH-stimulated LH levels and testosterone rose progressively during the first 6 weeks and reached a plateau thereafter, while estradiol levels continued to increase somewhat. The LH pulse amplitude and frequency had increased after 6 weeks (3.1 +/- 0.6 vs. 4.5 +/- 1.2 U/L and 4.4 +/- 2.4 vs. 6.6 +/- 1.1 pulses/7 h, respectively). Basal FSH levels were not affected while LHRH-stimulated FSH levels progressively decreased from 2 to 6 weeks, after which they did not change. Along with the rise of estradiol levels an increase of sex hormone-binding globulin and PRL levels occurred.(ABSTRACT TRUNCATED AT 400 WORDS)

Selective β1-adrenergic receptor-blockade with atenolol enhances growth hormone releasing hormone and mediated growth hormone release in man

The growth hormone (GH) responses to a single bolus injection of the growth hormone releasing hormone (GRH) were examined in the basal state and in the presence of β-adrenergic receptor blocking agents of different specificity in ten normal men. During a constant five-hour infusion of 56 μg/min of propanolol (nonselective β-adrenergic receptor-blocker) in seven subjects studied, there was a significant augmentation of the GH release in response to exogenous GRH compared to the GH response during saline infusion, as measured by the peak serum GH concentrations after GRH ( P = 0.019) and the integrated GH values ( P = 0.019). A similar significant enhancement of GH responses to exogenous GRH as compared to the control day was observed with the specific β 1-adrenergic receptor-blocker atenolol in all seven subjects studied (four of whom also participated in the propanolol study). Both the peak GH response to a GRH bolus and the integrated GH values were significantly greater with atenolol ( P = 0.019 for both). There was no difference in serum GH concentrations after β-adrenergic receptor-blocking drugs during a three-hour sampling period before GRH administration compared to placebo. Our results support the concept that β-adrenergic receptors may modulate either the release or action of hypothalamic somatostatin in the control of GH secretion in man. We suggest the effect is mediated by specific β 1-adrenergic receptors.

Effect of insulin on motilin release in man.

The effect of insulin on motilin release was investigated by use of the euglycemic glucose clamp technique. By use of this technique plasma glucose concentration was maintained constant at 80-90 mg/100 ml, and plasma insulin immunoreactivity (IRI) was increased from 15 +/- 6 microU/ml to 171 +/- 22 microU/ml in 10 min, and remained at this level for 2 hr. Plasma motilin like immunoreactivity (MLI) concentration decreased within 10 min from 199 +/- 36 pg/ml to 120 +/- 28 pg/ml and remained low during the course of study. A significant negative correlation between MLI and IRI concentrations (r = -0.72, p less than 0.01) was observed. The present results indicate that the suppressive effect of insulin on motilin release is a direct action of insulin and is not mediated by glucose.