Effects of melatonin on PRL secretion during different photoperiods of the day in prepubertal and pubertal healthy subjects

The effect of melatonin on PRL secretion has not been established yet. In an attempt to establish whether PRL response to melatonin changes in relation to the photoperiods of the day and pubertal maturation, we evaluated PRL plasma levels after melatonin administration in 19 prepubertal and pubertal healthy subjects of both sexes in two different periods of the day: in the morning, when the sensitivity to melatonin is low, and in the afternoon, when the responsiveness to melatonin is higher. Melatonin was given im at a dose of 0.2 mg/kg BW PRL plasma levels were determined with double antibody RIA method. When melatonin was administered in the morning, all pubertal subjects and 7 of 9 prepubertal ones showed no significant variation of PRL levels; a significant decrease was observed in the other 2 prepubertal subjects. On the contrary, when melatonin was given in the afternoon, a significant increase in PRL plasma levels was seen in all pubertal subjects; no significant changes were found in 6 prepubertal ones, while in the other 3 a marked decrease could be observed. The results reveal that the response of PRL to melatonin depends upon the times of day of administration and on pubertal development.     

Gonadal and adrenal secretion of dehydroepiandrosterone sulfate in prepubertal and pubertal subjects

The Authors have evaluated the relationship between the secretion of dehydroepiandrosterone sulfate (DHA-S) by the adrenal glands and by the gonads in a group of prepubertal and pubertal subjects ("short normal"), both males and females. In the male subjects of a hCG test and an ACTH test were performed; in the female subjects only the latter test was carried out. The behavior of DHA-S under basal conditions was also assessed in both sexes and related to bone age and chronological age in the prepubertal period and during the early stages of puberty. Plasma levels of DHA-S in both sexes increase progressively with chronological age and bone age. A negative correlation was found between DHA-S and bone delay (expressed in percent relative to chronological age) in prepubertal subjects, both males and females. A significant increase in DHA-S after hCG stimulation was found both in prepubertal and pubertal boys. After ACTH stimulation DHA-S increased significantly in prepubertal and pubertal males and females; throughout the test no difference was found between prepubertal and pubertal subjects nor between male and female subjects. Our data confirm that DHA-S is produced both by the adrenals and by the testes.     

Ketanserin without effects on basal anterior pituitary hormone secretion in healthy subjects

The effect of ketanserin, a selective serotonin-2 (5-HT2) receptor blocking agent, on the secretion of anterior pituitary hormones was studied in 4 healthy volunteers. Ketanserin (10 mg) was administered as a slow iv injection and its effect was compared with that of saline. Ketanserin influenced neither the basal plasma levels of HGH, ACTH, TSH, LH or prolactin, nor the plasma levels of T4, T3, cortisol or glucose. Even if a single dose of ketanserin had no hormonal effects, this must also be studied after long term use.     

LH and melatonin secretion patterns in pubertal boys.

Four normal pubertal boys had plasma LH and melatonin measured at 20-minute intervals for 24-hours. All four subjects showed a significant augmentation of LH and melatonin during nocturnal sleep. There was also a significant correlation between the LH and melatonin levels (P less than 0.001). These data indicate that the peripheral concentrations of melatonin which occur during sleep are insufficient to prevent spontaneous LH secretion during puberty.     

Mechanisms of action of beta-endorphin on the secretion of hypophyseal hormones

The purpose of the study was to investigate some mechanisms of the effect of beta-endorphin on somatotropic and lactotropic function of the hypophysis, adrenal activity and the content of catecholamines in the cerebral tissues. Activation of the hypophyseoadrenal system, lactotropic and somatotropic functions 5-20 min after beta-endorphin administration was established in experiments on male rats. At the same time a decrease in the content of catecholamines in the hypothalamus, cerebral cortex was observed. It was most significant for dopamine participating in the regulation of ACTH, prolactin and somatotropin secretion.     

Adrenomedullary response to caffeine in prepubertal and pubertal obese subjects.

OBJECTIVE: To investigate whether blunted adrenomedullary responsiveness to stimuli is a primary feature of human obesity in childhood and adolescence DESIGN: Comparison of plasma catecholamine response to caffeine in obese and lean subjects before and after puberty onset. SUBJECTS: Twelve lean prepubertal subjects (six males and six females), 15 prepubertal obese subjects (seven males and eight females), 12 pubertal lean subjects (six males and six females) and 24 pubertal obese subjects (12 males and 12 females) MEASUREMENTS: Plasma levels of Luteinizing hormone (LH), follicle-stimulating hormone (FSH), 17beta-estradiol and testosterone were used to validate Tanner score. Systolic and diastolic blood pressure, pulse rate and plasma catecholamines before and after caffeine administration (4 mg/kg of ideal body weight). RESULTS: Caffeine administration significantly stimulated adrenaline release in all subjects studied. The incremental area of adrenaline response to caffeine, analysed by multiple comparison test, was lower in pubertal obese subjects with respect to other groups. CONCLUSIONS: At variance with what is observed in adulthood obesity, prepubertal obese subjects show an intact adrenomedullary response to caffeine.     

Prolactin secretion in pubertal and adult male subjects

Prolactin, LH and FSH circadian secretion were studied in a group of 20 boys in various pubertal stages and in 13 normal male adults. Prolactin 24-hour integrated concentration was similar in all groups except in stage 2 boys, in which it was significantly higher with respect to stage 3-4 boys. This pattern was observed also for nocturnal, but not for diurnal concentration. As already described by other authors, LH showed and amplified circadian secretion in stage 2 and 3-4 boys, particularly during night time. FSH increase was less evident, and reached the peak 24-hour mean concentration in stage 2 subjects. Our results suggest that during puberty the hypothalamic pituitary system increases its activity not only with regard to gonadotropins but also to prolactin secretion.     

Effect of melatonin on the oxidative stress in erythrocytes of healthy young and elderly subjects

The disturbances in pro- and antioxidant balance may play an important role in the pathomechanism of aging. The pineal hormone melatonin, which exerts effective antioxidative properties, is suggested to be involved in the aging process. The aim of this study was to compare the oxidative stress in erythrocytes of healthy young adults and elderly people, and to determine the influence of melatonin supplementation on measured parameters in both examined groups. The malondialdehyde (MDA) and reduced glutathione levels as well as Cu-Zn superoxide dismutase (SOD-1), catalase, glutathione peroxidase (GSH-Px), glutathione S-transferase (GST) and glutathione reductase (GR) activities in erythrocytes and morning serum melatonin concentration in 14 healthy young adults and 14 healthy elderly people at baseline and after the 30th day of melatonin (5 mg daily) supplementation were determined. A significant age effect on increasing the MDA level and decreasing SOD-1, GSH-Px and GR activities as well as melatonin concentration was observed. Melatonin supplementation resulted in a significant increase in melatonin concentration, SOD-1 and GR activities and a decrease in the MDA level in both examined groups. These data indicate an age-related augmentation of oxidative stress in erythrocytes and the improvement of erythrocytic antioxidative defense by melatonin administration. These results might suggest melatonin supplementation to prevent age-related diseases and to prolong the lifespan and improve the quality of life of elderly people.     

Sex hormone changes during the prepubertal and pubertal development of healthy boy]

The size of testis, testosterone, LH, FSH were measured in 463 healthy boys, ages 5-18 years old. Our results showed that the values of the developmental indices increased with the age, and abruptly elevated at 13 years old indicating the beginning of puberty. At 17, all has indices had achieved the level of adulthood and did not further increase. It suggested the maturity of sex development at 17. The linear correlation analysis revealed a positive correlation between LH, FSH and testosterone (P less than 0.001, P less than 0.05-0.01, separately). The kinetic curves of LH and testosterone were also similar. The rise of LH preceded one age group than that of testosterone. The correlation between LH, FSH and testis size were positive correlation (before 14, P less than 0.001, P less than 0.01, separately; after 14, no significant difference in P values) and LH was positive correlation since 5 years old, but FSH was positive correlation since 7 years old. These finding suggest that the prepubertal testicular enlargement is primarily due to the action of LH and afterwards, FSH and testosterone combined with LH also contribute to the enlargement of testes. The clinical significance of sex hormone measurement was discussed.     

Effect of cimetidine on histamine- and pentagastrin-stimulated gastric secretion in healthy subjects.

Cimetidine-induced inhibition of gastric acid and pepsin secretion in response to histamine and pentagastrin simulation was studied in four healthy young subjects. Different doses of histamine and pentagastrin were administered alone and in combination with cimetidine on separate days; the order of administration was randomized. As the dose of histamine increased, the inhibitory effect of 0.6mg.kg-1h-1 of cimetidine on acid output decreased. With supramaximal histamine stimulation the inhibition was completely overcome. These results are consistent with competitive inhibition of histamine-stimulated acid output by cimetidine in man. After pentagastrin stimulation inhibition of acid output by cimetidine could not be overcome by increasing the dose of the stimulant, suggesting a noncompetitive inhibition of pentagastrin-evoked acid output. It is concluded that the kinetics of cimetidine-induced inhibition of histamine- and pentastrin-stimulated gastric acid output are different. At approximately half maximal stimulation of acid secretion, cimetidine was a more potent inhibitor of histamine than of pentagastrin. Pepsin output in response to both histamine and pentagastrin stimulation was also inhibited by cimetidine.     

Effect of carbacholine and urecholine on pentagastrin-stimulated gastric secretion in healthy subjects.

Dose-response studies of pentagastrin-stimulated gastric secretion were performed in 6 healthy volunteers. On different days pentagastrin was given in doses of 0.15, 1.5, and 15 mug/kg/hr either alone or in combination with carbacholine, 2 mug/kg/hr, or urecholine, 60 mug/kg/hr. Carbacholine and urecholine increased acid and pepsin secretion evoked by the lowest dose of pentagastrin while there was no augmentation at the highest dose. The dose of pentagastrin required to elicit half maximal acid output (Km) tended to decrease by simultaneous infusion of carbacholine or urecholine, suggesting that the cholinomimetics increased the sensitivity of the parietal cells to pentagastrin stimulation. Km for pentagastrin alone was higher than previously found in unoperated duodenal ulcer patients.     

Effect of short dexamethasone suppression on plasma steroids in prepubertal and pubertal girls

In 40 girls aged from 2 to 14 years, subdivided into groups according to age and pubertal development, and in 6 adult female volunteers, plasma cortisol (F), pregnenolone (delta 5), dehydroepiandrosterone (DHA) progesterone (P), 17-hydroxyprogesterone (17P), androstenedione (A), testosterone (T) and estradiol (E2) were measured before and after short dexamethasone (DXM) suppression. The results confirmed the capacity of DXM to inhibit plasma steroids in all age groups, except T in 2-9 year old and P1 Tanner's stage girls. The percentage suppression of each given steroid was constant over the age groups from 6-9 years to P4-5 Tanner's stage, while lower suppression was found in 17P, P and DHA in 2-5 year old girls and in 17P, DHA and E2 in adult women. These results emphasize the fundamental role of ACTH as the overall stimulating factor of adrenal steroidogenesis but do not negate the possibility of another factor responsible for the development of the adrenal androgen secreting cells throughout prepuberty and puberty.     

Exercise-induced GH secretion is enhanced by the oral ingestion of melatonin in healthy adult male subjects.

There is evidence that melatonin may play a role in modulating pituitary secretion, although the mechanisms are unclear. We examined the effects of a single dose of oral melatonin (5mg) on exercise-induced GH secretion. In a randomised, double-blind, placebo-controlled study, seven healthy male subjects undertook an initial period of graded bicycle ergometric exercise to determine maximum workload and oxygen uptake (VO(2max)). Subjects were subsequently studied on two further occasions, receiving either melatonin or placebo in random order at the onset of each study (-60min). At 0 min a period of bicycle exercise was performed for 8 min at a workload corresponding to 70% of that achieved at VO(2max). Serum GH and IGF-binding protein-1 (IGFBP-1) concentration was measured at 15-min intervals from the onset of the study until 120 min post-exercise. Blood was also sampled for the measurement of plasma glucose, insulin, non-esterified fatty acids, IGFBP-3, melatonin and vasopressin concentration. There was an exercise-induced increase in GH concentration following melatonin which was greater compared with placebo as assessed by both area under the curve (P<0.01) and peak increase in GH levels (P<0.01). The peak increase in IGFBP-1 levels post-exercise was also significantly greater following melatonin compared with placebo (P<0. 01) but did not quite reach levels of significance as measured by area under the curve (P=0.07). Since exercise-induced GH secretion is thought to be mediated predominantly through a hypothalamic pathway, it seems likely that melatonin facilitates GH secretion at a hypothalamic level.     

Effect of cholinergic, adrenergic, and dopaminergic blockade on gastrin secretion in healthy subjects

The effects of receptor blockers on the cholinergic, adrenergic, and dopaminergic nervous system have been tested on basal and meal-stimulated gastrin secretion in six normal subjects. Basal gastrin secretion was unaffected by all agents, as was gastrin secretion after food when alpha- and beta-adrenergic blockers were applied. Both atropine and haloperidol significantly enhanced the meal-induced secretion of gastrin. Dopamine had no effect on gastrin secretion. It is suggested that this effect of haloperidol is mediated by blockade of dopaminergic receptors, supporting the idea that the dopaminergic nervous system may influence gastrin secretion. It is concluded that the adrenergic nervous system does not influence gastrin secretion under physiological conditions, whereas both cholinergic and dopaminergic receptors may play an inhibitory role.     

Effect of calcimimetic agent, KRN568, on gastrin secretion in healthy subjects

KRN568 is a calcimimetic compound which acts on the calcium sensing receptors (CaR) on the parathyroid gland to suppress secretion of PTH. A recent report has demonstrated that CaRs are expressed on cultured human antral gastrin cells and that gastrin secretion is stimulated by an increase in extracellular calcium level. However, the effect of KRN568 on serum gastrin levels has yet to be clinically assessed. We therefore studied the effect of this calcimimetic on gastrin secretion in healthy subjects enrolled in the phase 1 study for KRN568 currently carried out in Japan. Single doses of KRN568, ranging from 25 mg to 400 mg, were orally administered to 6 healthy male volunteers at fasting and after meal. One subject proved to be a poor metabolizer (PM) for this compound and showed more than 10-fold high concentrations of plasma KRN568 (fasting Cmax 90.8 and non-fasting 83.8 ng/ml) compared to the other 5 individuals (Cmax 6.5 +/- 2.2 and 7.4+/- 1.6 ng/ml, respectively). Plasma gastrin levels showed mild but apparent increase (from 30 to 125 pg/ml) in this particular subject, while there were no significant increases in the other five people (from 34 +/- 6 to 63 +/- 3 pg/ml) after oral administration of 400 mg KRN568 at fasting. In the PM, administration of KRN568 resulted in extraordinarily high serum drug levels associated with transient increase of gastrin levels. This observation suggested that calcium-induced stimulation of gastrin secretion in human was mediated by a mechanism involving CaR. Potential side effects related to the increased gastrin secretion may be warranted in the practical use of this compound.     

Regulation of fat-stimulated neurotensin secretion in healthy subjects

CONTEXT: Cholecystokinin (CCK) and neurotensin are stimulated during meal intake by the presence of fat in the small intestine. The sequence of events suggests that fat hydrolysis is crucial for triggering the release. OBJECTIVE: The aim of this study was to investigate whether CCK mediated the effect of intraduodenal (ID) fat on neurotensin secretion via CCK-1 receptors. SETTING: This was a single center study; 34 male volunteers were studied in consecutive, randomized, double-blind, cross-over studies. SUBJECTS AND METHODS: CCK and neurotensin release were quantified in: 1) 12 subjects receiving an ID fat infusion with or without 60 mg orlistat, an irreversible inhibitor of gastrointestinal lipases, in comparison to vehicle; 2) 12 subjects receiving ID long chain fatty acids (C18s), ID medium chain fatty acids, or ID vehicle; and 3) 10 subjects receiving ID C18 with and without the CCK-1 receptor antagonist dexloxiglumide or ID vehicle plus iv saline (placebo). Hormone concentrations were measured by specific RIA systems. RESULTS: ID fat induced a significant increase in CCK and neurotensin concentrations (P < 0.001-0.002). Inhibition of fat hydrolysis by orlistat abolished both effects. C18 stimulated CCK and neurotensin release (P < 0.001, respectively), whereas medium chain fatty acid was ineffective. Dexloxiglumide administration partially blocked the effect of C18 on neurotensin; the effect was only present in the first phase of neurotensin secretion. CONCLUSIONS: Generation of C18 through hydrolysis of fat is a critical step for fat-induced stimulation of neurotensin in humans; the signal is in part mediated via CCK release and CCK-1 receptors.     

Quantitative and qualitative differences in basal and glucose- and arginine-stimulated insulin secretion in healthy subjects and different stages of NIDDM

Summary To determine quantitative and qualitative differences in insulin secretion equimolar amounts of glucose and arginine were infused in 9 healthy subjects, in 8 individuals each with obesity without and with impaired glucose tolerance, and in non-obese and obese non-insulin-dependent diabetic patients (NIDDM). Insulin secretion was calculated after individual determination of metabolic clearance rate of C-peptide (MCRcp) both as the area under the C-peptide concentration curve times MCRcp, and by a mono-compartment mathematical model, both yielding identical results. MCRcp fell consistently with increasing C-peptide infusion rate (e.g.: healthy subjects: C-peptide, 10 nmol/h, 4.2±0.4; 20 nmol/h, 3.3±0.3; 30 nmol/h, 3.1±0.2 ml/kg · min; p<0.05 to p<0.01). Basal insulin secretion was 2.1-fold greater in the obese with impaired glucose tolerance than in healthy subjects, but was unchanged in non-obese NIDDM. Glucose and arginine triggered insulin release was greater than in healthy subjects at almost identical area under the respective substrate concentration curve (AUC/kg body weight) in obese subjects without (2-fold) and with impaired glucose tolerance (4-fold), and in NIDDMs following i.v. arginine (2-fold). The mean ratio of incremental insulin release to i.v. glucose and arginine was smaller in NIDDM (normal weight, 1.3±0.4; obese, 1.0±0.2) than in healthy (2.0±0.3), or obese subjects with impaired glucose tolerance (2.8±0.7). Stimulated C-peptide/insulin ratio was reduced in all patientsvs that in healthy subjects (p<0.05). We conclude that (a) MCR of C-peptide is in part a saturable process; (b) insulin clearance may be impaired in obesity and NIDDM; and (c) insulin secretion differs in obese states and NIDDM both quantitatively and qualitatively, and thereby separates the two disorders as different entities. In addition, quantitation of insulin release in obese states may also help (d) to better define primary algorithms for insulin replacement in normal- and overweight insulin-dependent diabetic patients.