Neuroendocrine responses to psychological stress in adolescents with anxiety disorder

Neurotransmitter-neuroendocrine and cardiovascular responses to the administration of a psychologically stressful mixed-model test (Mental Arithmetic, Stroop Color Word Interference Task, Trier Social Stress Test) were examined in 20 male peripubertal subjects affected by anxiety disorder (group A: 14 with generalized anxiety disorder, 6 with generalized anxiety disorder and separation anxiety disorder) and 20 junior school adolescents, matched for age, without overt psychological disorders (group B). Plasma levels of norepinephrine (NE), epinephrine (EPI), adrenocorticotropic hormone (ACTH), beta-endorphin (beta-EP), cortisol (CORT), growth hormone (GH), prolactin (PRL) and testosterone (Te) were measured immediately before the beginning of the tests and 30 min later at their end. Mean prestress values of GH, PRL, beta-EP and ACTH were significantly higher in anxious subjects than in controls. There was no difference in NE, EPI, CORT and Te prestress levels in the two groups. After the psychological stress session NE, GH and Te concentrations increased significantly in anxious subjects (A), but not in controls. In contrast, beta-EP and PRL decreased significantly during the psychological stress session in anxious subjects, and were unaffected by stress in the subjects without anxiety. No significant changes were found in ACTH, CORT and EPI during the challenge either in anxious subjects or in controls, which may be attributed to the late time of poststress blood sampling. In contrast to controls, heart rate and systolic blood pressure increased significantly in anxious subjects after psychological stress testing. Our data support the hypothesis that the hyperactivity of the noradrenergic system in response to stress is associated with anxiety disorders in adolescents and might influence the responses of GH and Te. High prestress basal values of stress hormones seem to be induced in anxious subjects by the anticipation of the task or by a persistent hyperactivity of the noradrenergic system. Further studies are needed to investigate in more detail the involvement of the HPA axis in anxious adolescents by a more refined resolution of time points of blood sampling.     

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.     

Effects of electroconvulsive therapy on neuropsychological function and circulating levels of ACTH, cortisol, prolactin, and TSH in patients with major depressive illness

Thirteen patients with major depressive illness received unilateral electroconvulsive therapy (ECT). Memory and some other neuropsychological functions were studied concomitantly with changes in clinical symptoms. ACTH in plasma and cortisol, prolactin (PRL) and TSH in serum were measured 30 min before and 1, 5, 15, 30 and 60 min after treatment. Memory functions, impaired after the ECT series, were completely regained 1 month later. ACTH, cortisol, PRL and TSH were significantly increased by ECT. The maximum hormone level after ECT was lower at the last ECT in the series as compared with the first. After the last treatment, nonverbal memory performance was negatively associated with the maximum ACTH level after ECT and verbal learning was negatively correlated to the maximum cortisol level. The reason for these relationships is not known. Since both the ACTH secretion and memory function may be dependent upon the intracerebral catecholamines, the present findings may reflect variations in central monoaminergic receptor function.     

Neuroendocrine responses to experimentally-induced psychological stress in healthy humans

Previous studies of hormonal and neurophysiological changes in response to psychological stress in humans have produced contrasting findings due to differing experimental procedures and consistent individual variability. Habituation effects, which influence physiological coping in response to exposure to repeated stress, need to be investigated more extensively. In the present study, twenty healthy male subjects were each exposed twice to the same psychosocial stressor (Stroop Color Word Interference task, public speaking and mental arithmetic in front of an audience) during a first session (day 1) and a second session (day 8). Plasma concentrations of norepinephrine (NE), epinephrine (EPI), adrenocorticotropic hormone (ACTH), cortisol (CORT) and prolactin (PRL) were measured immediately before the beginning of the tests and at their end, 30 min later, on both experimental days. For the total group, NE, EPI, ACTH, and CORT levels were significantly elevated, and PRL levels were significantly decreased, after stress exposure on day 1. ACTH and CORT levels showed less significant increases after stress on day 8. In contrast, NE and EPI responses to stress were not significantly blunted, and PRL response was unchanged on day 8. Cluster analysis revealed two groups of subjects who showed different habituation patterns for ACTH and CORT. The first group (n=12) of subjects showed a reduction of ACTH and CORT responses to stress on day 8. The subjects of the second group (n=8) displayed a significant increase of ACTH and cortisol in response to stress on day 8, without any habituation effect. These results increase the evidence concerning the involvement of the HPA axis and catecholamines in response to psychological stress, and suggest that possible individual differences in the neuroendocrine coping mechanisms may affect mood regulation and the state of health.     

Endocrinological effects of high-dose Hypericum perforatum extract WS 5570 in healthy subjects

In this single-blind study, the effects of acute oral administration of high-dose Hypericum perforatum extract WS 5570 on the cortisol (COR), adrenocorticotropic hormone (ACTH), growth hormone (GH), and prolactin (PRL) secretions were examined in 12 healthy male volunteers. In a randomized order, the subjects received placebo or WS 5570 at several dosages (600, 900, and 1,200 mg) at 08.00 h on 4 different days. After insertion of an intravenous catheter, blood samples were drawn 1 h prior to administration of placebo or WS 5570 (600, 900, or 1,200 mg), at the time of administration, and during 5 h thereafter at intervals of 30 min. The serum concentrations of COR, GH, and PRL as well as the plasma levels of ACTH were determined in each blood sample by means of double antibody radioimmunoassay, fluoroimmunoassay, and chemiluminescence immunometric assay methods. The area under the curve value was used as parameter for COR, ACTH, GH, and PRL responses. Repeated-measures Anova revealed a significant stimulatory effect of WS 5570 on the ACTH secretion, whereas COR and PRL secretions were not significantly influenced. Moreover, there was a stimulatory peak of GH release 240 min after challenge with WS 5570 in some but not all volunteers, without reaching statistical significance in comparison with placebo. Mean arterial blood pressure and heart rate remained unchanged after administration of WS 5570. Apparently, WS 5570 at the dosages given in this study inconsistently causes endocrinological effects in healthy subjects by influencing central neurotransmitters.     

Adrenocorticotropin and growth hormone secretions after intracerebroventricular administration of neostigmine in rats: their relationships to hypothalamic monoaminergic neuronal activities

Serum adrenocorticotropic hormone (ACTH) and growth hormone (GH) concentrations were assessed simultaneously with hypothalamic neuronal activities of norepinephrine (NE), dopamine (DA), and serotonin (5-HT) 60 min after the third cerebroventricular administration of neostigmine (a cholinesterase inhibitor) in awake rats. Serum ACTH and GH concentrations were significantly increased and decreased, respectively. Neostigmine caused significant increases in hypothalamic NE and DA activities and a significant decrease in hypothalamic 5-HT activity. The reciprocal changes of serum ACTH and GH cencentrations were similar to those of hypothalamic NE and 5-HT activities. Multiple regression analyses with stepwise procedure revealed that hypothalamic NE and 5-HT activities were respectively significant determinants of serum ACTH and GH concentrations. Apart from the direct influence of neostigmine on ACTH and GH secretions, it is suggested that the changes in hypothalamic monoaminergic activities play an important role in modulating ACTH and GH secretions following the administration of neostigmine.     

电抽搐治疗引发精神分裂症患者血清催乳素和生长激素水平的改变

目的 探讨电抽搐治疗（ECT）精神分裂症时血清催乳素（PRL）,生长激素（GH）水平的变化情况。方法 采用放射免疫法对21例精神分裂症患者在第1、4、6次ECT前后各15分种的血清PRL、GH水平进行比较研究。结果 ECT和PRL和GH水平较ECT前显著升高;各次ECT后PRL和GH的释放值无显著区别。结论 支持精神分裂症的多巴胺功能亢进的假说,ECT具有神经阻滞样抗多巴胺能作用,导致这两种激素水平一过性升高。     

Prolactin and thyrotropin in serum during electroconvulsive therapy in patients with major depressive illness

Thirty-three patients with major depressive illness received electroconvulsive therapy (ECT), and serum prolactin (PRL) and thyrotropin (TSH) levels were measured 30 min before and 1, 5, 15, 30, and 60 min after the treatment. There was a threefold increase in PRL levels with a maximum after 15 min. The TSH plasma levels rose significantly with a maximum at 30 min after ECT. No change in PRL and TSH concentrations was seen in control experiments when the patients received anaesthesia only. In 15 patients the hormone levels were studied both during the first and sixth (last) ECT. The PRL and TSH levels were significantly higher following the first as compared to the sixth ECT. Patients on phenothiazines had higher PRL and lower TSH levels than those on other drugs or without medication, but there was no significant difference in the mean increment by ECT. Dopamine depresses PRL and TSH secretion. The diminished hormone release after a series of ECT may be explained by ECT-induced increase of postsynaptic dopamine receptor function leading to inhibition of PRL and TSH release from the pituitary gland.     

Parental divorce and neuroendocrine changes in adolescents

Plasma noradrenaline (NE), adrenocorticotrophic hormone (ACTH), growth hormone (GH), prolactin (PRL) and luteinizing hormone (LH) concentrations were examined in basal conditions and after stimulation by the step test in two groups of psychophysically healthy adolescent girls, 18 from divorced families and 16 from non-divorced families. Basal NE, ACTH, GH, PRL values did not differ in the two groups, whereas those of LH were significantly lower in the adolescents from divorced parents than in those from non-divorced families. Responses of NE and ACTH to the stimulus were normal, of GH and PRL were weaker, and of LH slightly weaker in children of divorced parents. An impaired catecholaminergic and serotoninergic tonus in children of disrupted families might underly the hormonal alterations.     

Effect of dexamethasone implanted in different brain areas on the morphine-induced PRL, GH and ACTH/corticosterone secretion

We studied the effect of dexamethasone (DEX) implantation in male Wistar rats to elucidate the site of action of morphine-induced prolactin (PRL), growth hormone (GH), adrenocorticotropic hormone (ACTH) and corticosterone (B) secretion. DEX or cholesterol was implanted in the close vicinity of the paraventricular (PVN), or the arcuate nuclei (ARN) of the hypothalamus or into the hippocampus. Five days after implantation blood samples were taken 30 min after i.p. morphine by decapitation or through an indwelling cannula 15, 30, 60 min after i.v. injection. DEX implanted near the PVN resulted in a blockade of morphine-induced ACTH and B secretion. In contrast, GH response to morphine was enhanced, while that of PRL was unchanged. DEX implanted near the ARN significantly inhibited the PRL-releasing effect of morphine, but was without any influence on the PRL secretion induced by haloperidol. There was a partial reduction in the B response to morphine, and GH secretion was unchanged. Dorsal hippocampal implants were without any effect on the morphine-induced GH, PRL or B secretion. We suggest that the site of glucocorticoid inhibitory action in the hypothalamus is the PVN for the opiate-induced ACTH/B secretion, and the ARN for the morphine-induced PRL release. The enhanced GH response to morphine observed in DEX-PVN implanted rats might be due to a decreased somatostatin tone.     

Interleukin regulation of prolactin and corticotropin from pituitary adenoma

Recent findings indicate that lymphokines, leukocyte-derived hormones, interact with the hypothalamic-pituitary axis. We examined the role of neurotrophic lymphokines in the neuroendocrine system. Specifically, the action of Interleukin (IL)-1b, IL-2 and IL-6 upon the anterior pituitary hormones, growth hormone (GH), prolactin (PRL) and adrenocoticotropic hormone (ACTH) were studied in rodent pituitary adenoma cell lines. Hormone release by GH and PRL-producing rat adenoma cells (GH3) and ACTH-producing mouse adenoma cells (AtT-20) was analyzed by radioimmunoassay (RIA). Recombinant (r) IL-1beta decreased PRL release from GH3 in a dose-dependent fashion. IL-1 inhibition of PRL production occurred in parallel with IL-1 inhibition of DNA synthesis in GH3 as measured by [(3)H] thymidine incorporation. This result strongly indicates that IL-1 alters PRL production by adenoma cells at the translational level. Low dose IL-2 (10 U/ml) enhanced ACTH production from AtT-20, but higher concentrations of IL-2 failed to affect the release of ACTH. IL-2 did not change the incorporation of [(3)H] thymidine in AtT-20. Previous studies showed that IL-1 and IL-6 induce a significant secretion of ACTH via the hypothalamic-pituitary axis. However, IL-1 and IL-6 failed to affect ACTH secretion by AtT-20. Blood-derived cytokines have direct effects on hormone secretion by pituitary adenoma cells in vitro.     

Neuroendocrine evidence for dopaminergic actions of hypericum extract (LI 160) in healthy volunteers.

BACKGROUND: We studied the effect of a single dose of a formulation of a methanolic extract of Hypericum perforatum (HP), also known as St. John's wort, on plasma concentrations of growth hormone (GH), prolactin (PRL), and cortisol (CORT) in 12 healthy male volunteers. METHODS: Subjects received 9 tablets of the finished product Jarsin 300 and placebo in a double-blind, balanced-order, cross-over design. RESULTS: Following HP relative to placebo, there was a significant increase in plasma GH and a significant decrease in plasma PRL. Plasma CORT levels were unchanged. CONCLUSIONS: Taken together with data from animal experimental studies, the findings suggest that this dose of HP may increase some aspects of brain dopamine function in humans.     

Hormone response to repeated electroconvulsive therapy: effects of naloxone

Plasma prolactin (PRL), cortisol, and growth hormone (GH) were measured before, and at 15-min intervals for 1 hr after, electroconvulsive therapy (ECT). This was repeated over a series of 6 consecutive treatments for each of 12 depressed drug-free inpatients. Patients received naloxone, 2 mg or 20 mg, by intravenous infusion before the third and fifth treatment. ECT was consistently followed by a release of PRL and cortisol, although two patterns of PRL response could be distinguished. In eight patients, the PRL response did not change significantly with repeated ECT, whereas in four patients, the plasma PRL increased tenfold after the first treatment and decreased after each successive treatment. The GH level varied widely, with no evidence of a reliable response to ECT. Opiate receptor blockade with low- or high-dose naloxone did not alter the release of PRL or cortisol after ECT. These findings demonstrate a reliable PRL and cortisol response to ECT, but do not support a role for endogenous opiates in these hormonal changes.     

Differential Response of Growth Hormone, Cortisol, and Prolactin to Seizures and to Stress

Plasma concentrations of growth hormone (GH), cortisol, and prolactin (PRL), following a spontaneous generalized seizure in epileptic men were compared with similar measurements made in nonepileptic, stressed men to determine the role of stress in the hormonal response to seizures. Nonepileptic, nonstressed men served as control subjects. GH concentrations increased significantly within 60 min postictally, and as expected, so did cortisol and PRL. A subgroup of alcoholic patients exhibited a smaller GH response to seizures. Stressed patients had significantly less elevated cortisol and PRL plasma values, but no rise of GH. The data suggest that neurogenic stimuli responsible for the postictal release of GH, cortisol, and PRL are, at least in part, independent of stress mechanisms and that GH response is blunted in alcoholic patients.     

Dose-dependent growth hormone, prolactin and cortisol stimulation after i.v. administration of desimipramine in human subjects

In previous studies it was shown that the tricyclic antidepressant desimipramine (DMI) had different stimulatory effects on growth hormone (GH), prolactin (PRL), ACTH and cortisol secretion in healthy subjects, depending on the mode of administration. The present study examined the effects following i.v. administration of placebo and DMI (5, 15, 25, 50 and 75 mg) on GH, PRL and cortisol secretion in male subjects (n = 6). This primarily noradrenergic and secondarily serotonergic reuptake-inhibiting substance was found to stimulate the secretion of GH, PRL and cortisol in a dose-dependent manner. Compared to placebo, significant increases occurred in GH (p less than 0.05) and in PRL (p less than 0.05) from a dose of DMI 25 mg on, and in cortisol (p less than 0.05) from 15 mg on. The results indicate that, in addition to the dose, the method of administration influenced the effects of DMI on the three hormones.     

Plasma pattern of adrenocorticotropin and cortisol during electroconvulsive therapy in patients with major depressive illness

Thirty-three patients with major depressive illness were treated with electroconvulsive therapy (ECT) and plasma adrenocorticotropin (ACTH), and cortisol levels were measured 30 min before and 1, 5, 15, 30 and 60 min after ECT. There was an immediate release of ACTH with a maximum after 5 min. The maximum cortisol plasma levels were measured 30 min after ECT. No change in ACTH and cortisol concentrations was seen in control experiments when the patients received only anaesthesia. ACTH release was seen in patients treated with ECT in the morning and in the evening. In 15 patients the levels were studied at the first and sixth (last) ECT. ACTH and cortisol levels were significantly higher after the first ECT as compared with the sixth. This alteration in ACTH release might reflect ECT-induced changes in the central monoaminergic transmission with stimulation of beta-adrenergic pathways leading to inhibition of ACTH-release.     

Immune cells and the hypothalamic-pituitary axis in major depression

To explore changes in immune cell status with changes in the hypothalamic-pituitary (HP) axis in 20 patients with major depression as compared with 20 age-, sex-, and race-matched control subjects, we examined peripheral blood mononuclear cells (PBMC) for total T-cells (T3), total B-cells (B1), two T-cell subsets (T4 and T8), and natural killer cells (NKH1), and we measured the plasma level of cortisol, adrenocorticotropic hormone (ACTH), growth hormone (GH), and prolactin (PRL). The ratio of T4/T8 was increased in the patients. Within the group of control subjects only, increasing age correlated significantly with decreasing plasma PRL. Within the group of patients only, GH positively correlated significantly with T8 and NKH1, as did PRL with NKH1. No between-groups difference was found for T3, B1, T4, T8, NKH1, cortisol, ACTH, GH, or PRL.     

Endocrinological effects of mirtazapine in healthy volunteers

Objective: Unlike other antidepressants, mirtazapine does not inhibit the reuptake of norepinephrine or serotonin (5-HT) but acts as an antagonist at presynaptic ₂-receptors and at postsynaptic 5-HT₂, 5-HT₃ and histamine H₁-receptors. In the present investigation, the influence of acute oral administration of 15-mg mirtazapine on the cortisol (COR), adrenocorticotropin (ACTH), growth hormone (GH) and prolactin (PRL) secretion was examined in 12 healthy male subjects, compared to placebo. Methods: After insertion of an intravenous catheter, both the mean arterial blood pressure (MAP) and the heart rate were recorded and blood samples were drawn 1 h prior to the administration of mirtazapine or placebo (7:00 a.m.), at time of administration (8:00 a.m.) and during 5 h thereafter in periods of 30 min. Concentrations of COR, ACTH, GH and PRL were measured in each blood sample by double antibody radioimmunoassay and chemiluminescence immunoassay methods. The area under the curve (AUC; 0–300 min after mirtazapine or placebo administration) was used as parameter for the COR, ACTH, GH and PRL response. Furthermore, the urinary free cortisol excretion (UFC) was determined beginning at 8:00 a.m. (time of administration of placebo or mirtazapine) up to 8:00 a.m. the day after. Results: Two-sided t-tests for paired samples revealed significantly lower COR AUC, ACTH AUC, UFC and PRL AUC values after 15-mg mirtazapine compared to placebo, whereas no significant differences were found with respect to GH AUC, MAP and heart rate. Conclusions: Since the acute inhibition of COR secretion in the healthy volunteers was paralleled by a simultaneous decrease of ACTH release, central mechanisms (e.g., inhibition of hypothalamic corticotropin releasing hormone (CRH) output) are suggested to be responsible for the inhibitory effects of mirtazapine on COR secretion. Our results are of particular interest in the light of the hypercortisolism observed in depressed patients and new pharmacological approaches such as CRH₁ receptor antagonists.     

In vivo and in vitro effects of cholecystokinin on gonadotropin, prolactin, growth hormone and thyrotropin release in the rat

Varying doses of cholecystokinin (CCK) dissolved in 2 μl of 0.9% NaCl or 2 μl of saline alone were injected into the third ventricle of conscious ovariactomized (OVX) rats bearing 3rd ventricular cannulae. Plasma luteinizing hormone (LH), prolactin (PRL), growth hormone (GH), thyrotropin (TSH) and follicle stimulating hormone (FSH) levels were measured by RIA in jugular blood samples drawn through an indwelling silastic cannula. Control injections of saline i.v. or into the 3rd ventricle did not modify plasma hormone levels. Intraventricular injections of 4, 40 and 500 ng CCK produced a significant suppression of plasma LH within 5 min of injection. Injection of 4 or 500 ng doses of CCK has no effect on plasma PRL levels, but injection of the 40 ng dose produced a significant elevation of plasma PRL within 15 min. Plasma GH levels increased significantly within 15 min of the 3rd ventricular injection of each dose of CCK. The 40 ng dose of CCK caused a progressive reduction of plasma TSH which was significant by 15 min and lasted through the 60 min of experimentation. The highest dose of 500 ng reduced plasma TSH levels within 5 min. Plasma FSH was not altered by any dose of CCK. Intravenous injection of CCK caused a dose-related increase in plasma prolactin levels within 5 min, but only the highest dose of 1000 ng produced a significant decrease in plasma LH. No significant changes in GH, TSH or FSH levels were observed after i.v. injection of CCK. In vitro incubation of hemipituitaries from male rats with doses of CCK ranging from 10 ng to 5 μg had no effect on pituitary hormone release into the medium. The results indicate that CCK can alter pituitary hormone release via a hypothalamic action and suggest that it may act as t transmitter or modulator of neuronal activity controlling the release of hypothalamic releasing and/or inhibiting hormones.     

Growth hormone and somatomedin serum levels in patients with major depressive illness undergoing electroconvulsive therapy

Thirty-three patients with major depressive illness received electroconvulsive therapy (ECT), and serum growth hormone (GH) levels were measured 30, min before and 1, 5, 15, 30 and 60 min after treatment. Six of the patients were studied 2 days before the first ECT (ECT-1) while receiving anaesthesia only. The anaesthesia given appeared to depress GH levels, which were significantly lower at 1 and 5 min after ECT than before treatment. When ECT was given there was a recovery of the GH level at 60 min, indicating a stimulatory effect of ECT on GH secretion. In 26 of the patients also investigated during the sixth and last ECT (ECT-6) in a series, no such recovery was observed. This may be due to changes in the sensitivity of intracerebral monoaminergic receptors in neurons controlling GH secretion from the pituitary gland. Since inhibition of GH secretion is mediated via beta-adrenergic pathways, the depression of GH secretion may be due to ECT-induced supersensitivity of postsynaptic beta-adrenergic receptors. In 27 of the patients serum somatomedin A, measured by radioreceptorassay (SMA-RRA), was analysed before ECT-1 and in 19 patients before ECT-6. In seven subjects the SMA-RRA was measured 30 min before and 1, 5, 15, 30, and 60 min after ECT-1. SMA-RRA levels were mainly within the normal range for age and did not change during ECT. No difference in SMA-RRA levels was observed before ECT-1 and ECT-6. This indicates that, although abnormalities in the GH-response to challenge stimuli have been reported in adults with major depressive disorder, their GH production is normal.