Interactions of sleep and clonidine on daytime prolactin secretion in humans.

The suppressive roles of adrenergic stimulation and rapid eye movement (REM) sleep on human prolactin (PRL) secretion are controversial. We examined the effects of sleep, clonidine (an alpha 2-adrenergic agonist), and their interaction on PRL secretion. Two groups of normal men (nine each) were studied in two morning sessions. Each group received either placebo or clonidine in both sessions. Subjects remained awake in the first session and in the next session they were asked to sleep for 3 h after the test dose was given. Blood samples were drawn at 30-min intervals and polysomnographic recordings were obtained at each session. PRL concentrations remained at baseline and no clonidine effect was detected while awake. PRL concentrations increased in placebo and clonidine groups during sleep. Despite significant suppression of REM sleep in the clonidine group, no differences were detected between the placebo and clonidine groups in peak PRL or mean PRL concentrations during the study. Also, no significant difference was detected in comparing PRL responses during non-REM sleep in both groups. The results suggest that alpha 2-adrenergic stimulation does not have a significant role in modulating human PRL secretion during sleep.     

Growth hormone (GH) response to clonidine and growth hormone releasing factor (GRF) in normal controls

To investigate the relationship between the plasma growth hormone (GH) response to provocative challenge with the hypothalamic peptide growth hormone-releasing factor (GRF) and the alpha 2-adrenergic agonist clonidine, we administered GRF (1 microgram/kg), clonidine (2 micrograms/kg), and placebo to 21 healthy normal controls (13 men and eight women). Both clonidine and GRF caused significant increases in plasma GH levels over baseline. The peak GH-responses to GRF and clonidine were similar (GRF = 8.7 +/- 6.7 ng/ml; clonidine = 6.5 +/- 5.9 ng/ml; Wilcoxon test: s = 361, z = -1.31, p = NS). The GH responses to GRF and clonidine were significantly correlated (rs = 0.62, n = 20, p = 0.004). Unexpectedly, we found that five of the 21 (26%) normal controls had no GH secretory response to either GRF or clonidine. There was a modest gender effect with clonidine (men greater than women; p less than 0.06) and a negative correlation between GH secretion and age with both GRF and clonidine. Neither GRF nor clonidine had an effect on cortisol levels (DRUG x TIME interaction: F(8,152) = 0.60, p = NS). These findings are consistent with animal studies suggesting that the GH response to clonidine is mediated by GRF. The age and gender effects underscore the importance of careful matching for these factors in studies measuring the GH secretory response.     

Growth hormone-releasing factor stimulation test in depression

The authors administered the growth hormone-releasing factor (GRF) stimulation test to 19 patients with major depression and 19 age- and sex-matched control subjects to test the hypothesis that a blunted growth hormone (GH) response to clonidine reflects a central alpha 2-adrenergic receptor subsensitivity in depression. GH response to GRF was significantly higher in patients with depression than in control subjects. This group difference was mainly attributable to three of the 19 depressed patients who exhibited markedly high GH responses to GRF. These results suggest that the blunted GH response to clonidine seen in patients with depression is not due to a pituitary defect in GH secretion.     

Noradrenergic function in obsessive-compulsive disorder: behavioral and neuroendocrine responses to clonidine and comparison to healthy controls

To evaluate noradrenergic (NE) function in obsessive-compulsive disorder (OCD), behavioral, physiological, and neuroendocrine responses to the alpha 2-adrenergic agonist clonidine were examined in 18 patients with OCD and 10 healthy subjects. Subjects received single i.v. doses of 2 micrograms/kg of clonidine administered under double-blind, placebo-controlled, random-assignment conditions. Following clonidine, but not following placebo, patients transiently experienced a significant reduction of obsessions and compulsions. Significant drowsiness and a reduction in anxiety were also noted, but the antiobsessional effect appeared independent of the soporific and antianxiety effects. Growth hormone (GH), cortisol, and 3-methoxy-4-hydroxyphenylglycol responses to clonidine did not differentiate patients from healthy controls. Blood pressure and pulse in response to clonidine did not differ between groups. Improvement in OCD symptoms after clonidine significantly correlated with GH response to clonidine, suggesting specific noradrenergic mediation. This finding lends only partial support for a primary defect of noradrenergic function in OCD.     

Effect of naloxone on the growth hormone response to clonidine in normal women during the mid-luteal phase

We studied the effect of the opiate antagonist naloxone on the peripheral GH response to the alpha 2-receptor agonist clonidine in eight normally cycling women during the mid-luteal phase. In a randomized, double-blind, cross-over design, each subject received clonidine and naloxone on one occasion and clonidine and placebo on the other. In seven of eight subjects, an attenuation of the GH response was associated with naloxone administration. The maximal GH increment above baseline (delta GHMAX) of 7.8 +/- 2.0 micrograms/L (mean +/- SEM) with placebo was higher than the delta GHMAX of 4.2 +/- 0.9 micrograms/L with naloxone (p = 0.05). Likewise, the area above baseline under the GH level-time curve following clonidine (delta GHAREA) was higher with placebo compared to naloxone (477 +/- 175 micrograms/L x min vs. 228 +/- 62 micrograms/L x min), although this difference was not quite statistically significant (p = 0.09). As expected, with placebo the increase in GH following clonidine was statistically significant by repeated measures analysis of variance (p = 0.001). The smaller increase in GH levels when naloxone was given was not significant. Both delta GHMAX and delta GHAREA values were significantly positively correlated with estradiol levels when placebo was given, but not when naloxone was given. GHRH was not detectable following clonidine administration under either the placebo or the naloxone conditions. Our data support the hypothesis that estrogen enhances the response of GH to provocative stimuli in women, at least in part by increasing endogenous opioid tone in the hypothalamus.     

Mirtazapine, but not fluvoxamine, normalizes the blunted REM sleep response to clonidine in depressed patients: implications for subsensitivity of alpha(2)-adrenergic receptors in depression

To determine whether alpha(2)-adrenergic receptor (alpha2AR) subsensitivity is a state or a trait marker of depression, we consecutively challenged 32 drug-free depressed patients with a clonidine REM suppression test (CREST). We then treated the patients with fluvoxamine, a selective serotonin reuptake inhibitor, or mirtazapine, a selective alpha(2)-adrenergic receptor antagonist. The first 10 patients from each treatment group who recovered were given a second challenge test. The CREST values of the two treatment groups at each time point were compared, and also compared with the CREST values of a group of 10 normal subjects. Before treatment, the REM sleep response to clonidine in the two groups of patients was significantly blunted compared with the REM sleep response in the healthy subjects. After treatment, there was still an abnormal REM sleep response to clonidine in the fluvoxamine-treated patients, despite clinical recovery, but there was a normalized REM sleep response in the mirtazapine-treated patients. These results are compatible with the hypothesis that alpha2AR subsensitivity is a trait marker of depression and suggest that the effects of these two antidepressants on alpha2AR sensitivity may not be linked to the alleviation of depression.     

Noradrenergic responses to clonidine in acute and remitted depressed male patients.

To investigate noradrenergic function in depression, plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), plasma norepinephrine (NE), mean arterial pressure (MAP), and heart rate responses to intravenous clonidine (2 micrograms/kg), an alpha 2-adrenergic agonist, were measured in 27 acutely depressed patients, 18 remitted depressed patients, and 27 normal control subjects; a placebo infusion was administered to a subgroup. Clonidine compared with placebo, over a 150-minute time course, decreased plasma NE, MAP, and heart rate, but not plasma MHPG, in the control subjects. Plasma MHPG, plasma NE, MAP, and heart rate at baseline or in response to clonidine and placebo over 150 minutes did not indicate any group differences. The only significant plasma MHPG response to clonidine in the normal control subjects occurred 60 minutes after the infusion. A significantly diminished plasma MHPG response to clonidine at 60 minutes was found in the acutely depressed group compared with the normal control subjects. These results suggest that peripheral inhibitory noradrenergic responses to clonidine are normal in depressed patients, while plasma MHPG responses to clonidine, which have a limited central contribution, appear to be a weak reflection of central noradrenergic function and appear insufficiently robust for a meaningful evaluation of hypothetical group differences in central inhibitory alpha 2-adrenergic activity in this population.     

Twenty-four hour growth hormone secretion in patients with panic disorder

BACKGROUND: Patients with panic disorder have blunted growth hormone (GH) responses to clonidine, suggesting subsensitivity of post-synaptic alpha(2)-adrenoreceptors, presumably in response to excessive central noradrenergic outflow. However, basal levels of GH release over a full circadian cycle have not been examined in panic. Reduced basal GH release would suggest an overall hypo-active GH system rather than a specific alpha-adrenergic abnormality. METHODS: To determine whether panic patients show reduced basal GH secretion, 20 patients and 12 healthy controls were studied. Blood samples were drawn every 15 min for 24 h and plasma was assayed for GH. Patients were restudied during successful treatment with alprazolam. Groups were compared on overnight and daytime GH secretion and circadian patterns of release. RESULTS: Patients showed normal levels on all measures of GH release. Treatment may have reduced nocturnal GH release slightly, but treated patients still did not differ from controls. The normal predominance of sleep over waking GH secretion was seen in both groups. CONCLUSIONS: Panic patients, in contrast to depressed patients, have normal somatotrophic axis activity when measured in a resting state over a full circadian cycle. GH dysregulation may only be evident in these patients in activation paradigms and has been most consistently demonstrated by challenges with the alpha(2)-noradrenergic agonist, clonidine.     

Neuroendocrine evidence for decreased function of alpha 2-adrenergic receptor after electroconvulsive therapy.

Growth hormone (GH) and hypotensive responses to clonidine (150 micrograms, i.v.) were investigated before and after electroconvulsive therapy (ECT) in 16 depressed patients. Because of high baseline serum GH concentrations, results from only 10 patients could be evaluated. The level of GH secretion induced by clonidine was significantly reduced after ECT, but the hypotensive responses to clonidine remained unchanged. The results indicate downward regulation of the sensitivity of alpha 2-adrenergic receptors in the hypothalamus after ECT.     

Growth hormone response to clonidine predicts aggression in Alzheimer's disease

OBJECTIVE: The neurobiology of aggression in Alzheimer's Disease (AD) remains unknown. The objective of this study was to determine if altered central noradrenergic (NE) responsiveness is related to aggression in AD. METHODS: Fifteen institutionalized, non-depressed elderly (11 males, four females, mean age 81.5 +/- 5.5) with probable AD, severe cognitive impairment (MMSE mean 3.3 +/- 4.6) and significant behavioral disturbances (Neuropsychiatric Inventory (NPI) score > or = 8) were studied. Growth Hormone (GH) response to clonidine challenge (5 microg/kg) was used as an index of central alpha(2)-adrenergic function. RESULTS: When patients were divided into those with preserved GH response (GH maximum change from baseline > 0, n = 6) and those with blunted GH response (GH maximum change from baseline < or = 0, n = 9) there were significant differences in levels of aggression as measured by the Cohen-Mansfield Agitation Inventory (CAMI) physical aggression subscale (p = .026). Patients with blunted GH response also had significantly higher levels of aggression against others on the retrospective Overt Aggression Scale (p = 0.027). CONCLUSIONS: Certain types of physically aggressive behaviors are associated with a blunted GH response to clonidine challenge. This finding is consistent with compensatory down-regulation of post-synaptic alpha(2)-adrenergic receptors in response to enhanced NE outflow in aggressive AD patients.     

Effect of growth hormone-releasing stimuli in streptozotocin diabetic rats

The dynamics of growth hormone (GH) secretion in response to different GH secretagogues has been studied in adult freely moving male rats one month after induction of diabetes by single i.v. injection of streptozotocin (60 mg/kg). Baseline plasma GH concentrations and pituitary GH content were not different in streptozotocin-diabetic (St-D) rats and controls. Clonidine (0.15 mg/kg i.v.), an alpha 2-adrenergic agonist, failed to evoke GH release in St-D rats. Substitution therapy with insulin (1 IU/100 g b.wt.daily) delivered through subcutaneously implanted minipumps, allowed re-institution of a normal GH responsiveness to clonidine. At odds with clonidine, FK 33-824 (0.1 mg/kg i.v.), a potent analog of the opioid peptide Met-enkephalin, induced a similar rise in plasma GH levels in control and St-D rats. Finally, administration of a synthetic replicate of a GH-releasing hormone of human pancreatic origin, hpGRF-40 (2.5 micrograms/kg i.v.) elicited a higher GH response in St-D rats than in controls. These data indicate that in St-D rats: (1) an impaired function of noradrenergic pathways controlling GH release is present; (2) contrary to previous beliefs, an alpha 2-adrenergic mechanism is not involved in the GH-releasing effect of opioid peptides; and (3) pituitary GH responsiveness to hpGRF is increased.     

Adrenergic receptor sensitivity in depression. Effects of clonidine in depressed patients and healthy subjects

Several recent investigations have raised the possibility that the sensitivity of alpha 2-adrenergic receptor may be of etiologic importance in depression. To assess whether abnormalities in presynaptic alpha 2-adrenergic receptor exist in depressed patients not taking drugs, the effects of an alpha 2 agonist, clonidine, on plasma 3-methoxy-4-hydroxyphenelethyleneglycol (MHPG) and on blood pressure (BP) were evaluated in 15 depressed patients and 12 healthy controls of similar age. The ability of clonidine to increase growth hormone (GH) secretion was also assessed. The effect of clonidine on plasma MHPG and BP was not different between the depressed patients and controls. However, the GH response to clonidine was blunted in the depressed patients. These results suggest that in depression (1) the sensitivity of the presynaptic alpha 2-adrenergic receptor is not abnormal, and (2) the sensitivity of postsynaptic adrenergic receptors may be decreased.     

A novel hypothalamic-dispersed pituitary co-perifusion model for the study of growth hormone secretion.

This study presents a novel, in vitro, hypothalamic-dispersed pituitary co-perifusion system (HPPS) developed to examine the influence of the hypothalamus on pituitary growth hormone (GH) secretion in a controlled environment. In this perifusion system, dispersed rat pituitary cells were loaded onto Biogel P-2 (P-2) beads in a 0.5-ml plexiglas chamber and were submerged in a 37 degrees C water bath. After stabilization, two hypothalami were placed into each chamber on a thin layer of P-2 beads and the chamber was re-equilibrated. To test the system, pituitary cells were stimulated either directly with growth hormone-releasing factor (GRF) or indirectly via the hypothalamus, with clonidine, an alpha 2-adrenergic (alpha 2) receptor agonist. Perifusion of HPPS or pituitary cells with GRF (40 ng/ml) induced a substantial endogenous GH surge. Clonidine (2 x 10(-8) M) treatment stimulated a GH surge in HPPS chambers, but not in chambers containing only pituitary cells. Thus, somatotrophs respond to hypothalamic factors released in response to clonidine and not directly to alpha 2 stimulation. To determine if the components involved in GH feedback are present in the perifusion system, HPPS chambers were sequentially perifused with hGH, clonidine, and GRF. hGH pretreatment suppressed the clonidine but not the GRF-induced GH surge(s) observed in chambers perifused with clonidine and GRF only. In chambers only containing pituitary cells, GH was only increased in response to GRF when sequentially perifused with all three substances. This study demonstrates the dynamic interaction between the hypothalamus and pituitary in the regulation of GH secretion in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reboxetine acutely stimulates cortisol, ACTH, growth hormone and prolactin secretion in healthy male subjects

In this single-blind study the effects of acute oral administration of the selective noradrenaline reuptake inhibitor reboxetine on the cortisol (COR), ACTH, growth hormone (GH) and prolactin (PRL) secretion were examined in 12 healthy male volunteers. In a randomized order, the subjects received placebo or reboxetine (4 mg) at 0800 h on two different days. After insertion of an intravenous catheter, blood samples were drawn 1 hour prior to the administration of placebo or reboxetine, at time of administration, and during the time of 5 hours thereafter at periods of 30 minutes. Serum concentrations of COR, GH, and PRL as well as plasma levels of ACTH were determined in each blood sample by means of double antibody RIA, fluoroimmunoassay and chemiluminescence immunometric assay methods. The area under the curve (AUC) value was used as parameter for the COR, ACTH, GH, and PRL response. Using t-tests for paired samples, statistical analysis revealed significant stimulatory effects of reboxetine on COR, ACTH, GH, and PRL secretion, compared to placebo (mean AUC values+/-S.E.M. (a) reboxetine: COR 127893.20+/-8125.75 nmol/l x min; ACTH 2385.68+/-387.19 pmol/l x min; GH 56026.59+/-15594.87 pmol/l x min; PRL 113961.60+/-10280.44 pmol/l x min; (b) placebo: COR 83672.19+/-5225.20 nmol/l x min; ACTH 1449.83+/-190.67 pmol/l x min; GH 9308.16+/-3402.75 pmol/l x min; PRL 64663.28+/-7283.62 pmol/l x min). Mean arterial blood pressure and heart rate were significantly increased by reboxetine, too. Our results suggest that besides COR, ACTH and GH secretion, the release of PRL is also under the control of the noradrenergic systems in man.     

The Possible Role of Androgenic Hormones in Maturation of Alpha2-Adrenergic Mechanisms in the Rat

In order to get better characterization of androgenic hormones on the functionality of the α₂-adrenergic system and widen our previous studies, we investigated the effect of clonidine on the growth hormone (GH) secretion in male Wistar rats of various ages: 7-, 14- and 30-day old and adult, adult male castrated rats with and without testosterone treatment. Two different patterns of the GH response to clonidine have been observed in the control and testosterone-treated young animals: clonidine at the dose 15 μg/kg intraperitoneally had no effect on the GH secretion in 7- to 14-day old rat pups. In contrast, its effect appeared following the increase in the plasma testosterone concentration induced by pretreatment with testosterone (5 mg/kg subcutaneously for 4 days) in these animals. In 30-day old rats clonidine affected GH secretion and this influence was more pronounced in the testosterone-treated animals than in the controls. The decrease in the circulating testosterone levels caused by castration in adult male rats caused a decreased GH response to clonidine. Moreover, there was a tendency for the GH response to return in 4-week old animals. The effect of clonidine has been restored by testosterone replacement of castrates. Testosterone administration decreased basal plasma GH levels in the pups. However, it triggered the ultradian surges of GH secretion which were absent in the young animals. Clonidine had no effect on the corticosterone secretion in 7-day old animals. Testosterone treatment induced a response in the 7-day old rat and markedly potentiated its effect on the secretion of this hormone in 14- and 30-day old animals, respectively. Neither progesterone nor hydrocortisone influenced the GH-releasing effect of clonidine. Hydrocortisone markedly inhibited the basal- and clonidine-induced corticosterone secretion. The results of the present study indicate an important role of androgenic hormones in inducing and/or maintaining the effectiveness/sensitivity of the α₂-adrenergic receptor system and suggest a possible role for the androgenic hormones in the maturation of α-adrenergic mechanisms in the rat.     

Ghrelin alone or co-administered with GHRH or CRH increases non-REM sleep and decreases REM sleep in young males

Ghrelin activates the somatotropic and the hypothalamic-pituitary-adrenal axes, being crucially involved in sleep regulation. Simplified, growth hormone releasing hormone (GHRH) increases slow-wave sleep and REM sleep in males, whilst corticotropin-releasing hormone (CRH) increases wakefulness and decreases REM sleep. Ghrelin's role in sleep regulation and particularly its interactions with GHRH and CRH are not entirely clear. We aimed to elucidate the interactions between ghrelin, GHRH and CRH in sleep regulation and the secretion of cortisol and GH. Nocturnal GH and cortisol secretion and polysomnographies were determined in 10 healthy males (25.7+/-3.0 years) four times, receiving placebo (A), ghrelin (B), ghrelin and GHRH (C), or ghrelin and CRH (D) at 22:00, 23:00, 00:00, and 01:00h, in this single-blind, randomized, cross-over study. Non-REM sleep was significantly (p<0.05) increased in all verum conditions (mean+/-SEM: B: 355.3+/-7.4; C: 365.4+/-8.1; D: 371.4+/-3.9min) compared to placebo (336.3+/-6.8min). REM sleep was decreased (B: 84.3+/-4.2 [p<0.1]; C: 74.2+/-7.0 [p<0.05]; D: 80.4+/-2.7min [p<0.05]) compared to placebo (100.9+/-8.3). CRH+ghrelin decreased the time spent awake and enhanced the sleep efficiency; furthermore, the REM latency was decreased compared to the other treatment conditions. CRH enhanced the ghrelin-induced cortisol secretion but had no relevant effect on GH secretion. In turn, GHRH enhanced the ghrelin-induced GH secretion but had no effect on cortisol secretion. In conclusion, ghrelin exhibited distinct sleep effects, which tended to be enhanced by both GHRH and CRH. CRH had sleep-improving and REM permissive effects when co-administered with ghrelin, being in contrast to the effect of CRH alone in previous studies.     

Neuroendocrine evaluation of catecholaminergic neurotransmission in mania

Several lines of evidence suggest catecholamine overactivity (noradrenergic and/or dopaminergic) in mania. We studied the growth hormone (GH) response to clonidine (an alpha-adrenergic agonist) and apomorphine (a dopaminergic agonist) in seven inpatients meeting Research Diagnostic Criteria for mania. They had been completely drug free for at least 3 months before the neuroendocrine procedures and were age- and sex-matched to seven major depressive and seven minor depressive inpatients, drug free for at least 2 weeks. GH was assayed every 20 min for 40 min before and 120 min after either clonidine (0.15 mg i.v.) or apomorphine (0.5 mg s.c.), with an interval of at least 2 days between the tests. The three groups differed significantly in the GH peak response: after clonidine (mean +/- SD), 3.2 +/- 2.4 ng/ml in manics, 3.2 +/- 2.4 ng/ml in major depressives, and 13.2 +/- 8.7 ng/ml in minor depressives; after apomorphine, 10.5 +/- 7.4, 3.2 +/- 1.9, and 26.9 +/- 15.8, respectively. While there were significant differences between manics and minor depressives and between major and minor depressives after both clonidine and apomorphine, manics did not significantly differ from major depressives on either test. These results do not provide neuroendocrine support to the catecholaminergic hypothesis of manic disorders.     

Effects of noradrenergic agonists and antagonists on growth hormone secretion under gamma-hydroxybutyrate narco-analgesia in the rat

(1) The administration of gamma-hydroxybutyrate (GHB) has no effect on the hypothalamic concentration of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in the rat. (2) The injection of GHB induces a consistent growth hormone (immunoreactive GH) secretory episode, followed by basal levels for several hr. (3) During this period, the infusion of clonidine, an α-adrenergic agonist, elicits a dramatic GH increment, whereas basal levels are not modified by isoproterenol, a β-adrenergic agonist. (4) In animals pretreated with α- and β-adrenergic agonists, clonidine enhances the GH peak induced by GBH, which is clearly inhibited by isoproterenol. The effects of α- and β-adrenergic antagonists were also investigated in this study. (5) The data reported here could support the hypothesis that α-adrenergic receptors mediate the secretion of the GH-releasing hormone and that β-adrenergic receptors are involved in the release of somatostatin.     

Effect of clonidine on the secretion of anterior pituitary hormones in heroin addicts and normal volunteers

Neuroendocrine effects of intravenous injections of clonidine, 0.15 mg, were investigated in 13 heroin addicts and 14 normal control subjects. The study was designed to determine whether continuous opiate administration leads to the development of hypersensitive alpha 2-adrenergic receptors. The peak increments in levels of plasma growth hormone (GH) and beta-endorphin induced by clonidine did not differ between heroin addicts and normal control subjects. At no time interval could the clonidine-induced rise in GH levels in addicts be differentiated from that induced by placebo. Clonidine failed to alter plasma prolactin, gonadotropin, or thyrotropin levels in either heroin addicts or controls. Since clonidine's neuroendocrine effects are reportedly due to the activation of postsynaptic alpha 2-adrenoceptors, it appears that (1) continuous opiate use does not lead to the development of hypersensitive alpha 2-adrenergic receptors involved in neuroendocrine mechanisms and (2) brain norepinephrine does not play a role in the regulation of tonic prolactin, gonadotropin, and thyrotropin secretion in man.     

Ghrelin enhances the nocturnal secretion of cortisol and growth hormone in young females without influencing sleep

Ghrelin was shown to increase slow wave sleep (SWS) and the secretion of growth hormone (GH) and cortisol in young males. In terms of sleep, such information for females, however, is lacking. Therefore, polysomnographies were recorded (23:00-07:00 h) and nocturnal (20:00-07:00 h) secretion profiles of GH and cortisol were determined in 10 healthy females (24.9+/-2.4 years, body mass index: 21.2+/-1.1) twice, receiving four boluses of 50 microg ghrelin or placebo at 22:00, 23:00, 00:00, and 01:00 h, in this single-blind, randomized, cross-over study. No significant differences of conventionally or quantitatively analyzed sleep were observed between ghrelin and placebo condition. First administration of ghrelin caused a marked mean increase of GH by 53.3 to 64.4+/-14.2 ng/ml (placebo: 5.9+/-1.5 ng/ml) and cortisol by 54.2 to 96.4+/-15.3 ng/ml (placebo: 27.5+/-4.7 ng/ml). The following ghrelin injections were associated with smaller increases of GH and cortisol. In the ghrelin condition, GH plasma levels remained significantly (P<0.05) higher from 22:20 to 02:00 h and cortisol plasma levels from 22:20 to 02:20 h. In contrast to findings in young men, ghrelin did not affect sleep in young women, indicating a sexual dimorphism. In accordance with the findings in young men, ghrelin stimulated secretion of GH and cortisol.