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.     

Effects of mirtazapine on growth hormone, prolactin, and cortisol secretion in healthy male subjects.

In the present study the effects of acute PO-administration of 15 mg mirtazapine on the growth hormone (GH), prolactin (PRL), and cortisol (COR) secretion were examined in eight physically and mentally healthy male subjects, compared to placebo. Mirtazapine is a new antidepressant agent which does not inhibit the reuptake of norepinephrine or serotonin but is an antagonist of presynaptic and, presumably, postsynaptic alpha 2-receptors as well as an antagonist of postsynaptic 5-HT2 and 5-HT3-receptors. After insertion of an i.v. catheter, blood samples were drawn 1 h prior to the administration of mirtazapine or placebo, at time of application, and during the time of 4 h after application in periods of 30 min. Plasma concentrations of GH, PRL, and COR were determined in each blood sample by double antibody RIA methods. The area under the curve (AUC) value was used as parameter for the GH, PRL, and COR response. With respect to GH and PRL secretion, mirtazapine did not show any effects in comparison with placebo. However, in all subjects, the COR concentrations were remarkably lower after mirtazapine compared to placebo, the difference being obvious in the mean value graphs 60 min after the application up to the end of the measurement period. The t-test for paired samples revealed a highly significant difference (P < 0.01) in COR-AUC-values between the mirtazapine group (mean COR-AUC: 1558.07 micrograms/100 ml x 240 min) and the placebo group (mean COR-AUC: 2698.86 micrograms/100 ml x 240 min). Further studies have to elucidate the question whether the demonstrated inhibition of COR secretion after application of 15 mg mirtazapine is caused by central or peripheral effects of this substance.     

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.     

Neuroendocrine effects of Hypericum extract WS 5570 in 12 healthy male volunteers

In the present study, the effects of acute p.o. administration of placebo at 300 mg and 600 mg of WS 5570 Hypericum perforatum extract on cortisol (COR), growth hormone (GH) and prolactin (PRL) secretion were examined in twelve physically and mentally healthy subjects. WS 5570 is a hyperforin containing extract of St. John's Wort which has been proven effective in mild to moderate depression. After inserting an i.v. catheter, blood samples were drawn one hour prior to the administration of WS 5570 or placebo, at the time of application and up to five hours after application in 30-minute intervals. Plasma concentrations of COR, GH, and PRL were determined in each blood sample by double-antibody RIA methods. No PRL stimulation could be observed after placebo or after WS 5570 (300, 600 mg). A small but statistically significant elevation in GH AUC values occurred after 300 mg of WS 5570. After 600 mg of WS 5570, a clear-cut COR stimulation was observed, occurring from 30 up to 90 minutes after the application. In this period of time (from t = 30 min to t = 90 min), the mean COR concentrations were significantly higher after 600 mg of WS 5570 compared to placebo. 300 mg of WS 5570 did not show any effects on COR secretion. We propose that the Hypericum extract WS 5570 is able to influence central neurotransmitters, thereby causing COR stimulation in a dose-dependent manner.     

Triiodothyronine administration reduces serum growth hormone levels and growth hormone responses to thyrotropin-releasing hormone in patients with anorexia nervosa

The aim of this study was to test the hypothesis that low serum T3 concentrations may promote an abnormal growth hormone (GH) response to thyrotropin-releasing hormone (TRH) in patients with anorexia nervosa. Eight anorexic women and two anorexic men, ages 15-25 years, with low free T3 circulating levels (mean +/- SEM = 2.8 +/- 0.3 pmol/l) were studied. A TRH test (200 micrograms IV) was carried out under basal conditions and repeated following treatment with oral T3 (1.5 micrograms/kg BW/day) for eight days. Following T3 administration, GH levels dropped significantly from a baseline of 7.1 +/- 1.3 micrograms/l to 3.1 +/- 0.7 micrograms/l (p less than 0.02), as did GH peak responses to TRH (9.0 +/- 1.0 micrograms/l vs 4.4 +/- 0.8 micrograms/l, p less than 0.01). ANOVA and analysis of area under the curve (AUC) confirmed that after T3 treatment there was a significant reduction in TRH-induced GH release in these patients (GH AUC: 902 +/- 132 micrograms/l vs. 456 +/- 91 micrograms/l, p less than 0.02). TSH responses to TRH, which were normal prior to T3 treatment, completely disappeared following it, and PRL responses to TRH also were diminished. Although our experimental approach does not permit a conclusion that low T3 levels were the primary reason for these changes, the data support the theory that low T3 circulating levels may facilitate abnormal GH secretion and the GH-releasing activity of intravenous TRH.     

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.     

Testosterone, androstenedione and dihydrotestosterone concentrations are elevated in female patients with major depression

Hyperactivity of the HPA-system in major depression is reflected by an increased secretion of adrenal hormones especially cortisol and dehydroepiandrosterone (DHEA). In women for whom androgenicity is associated with cardiovascular disorders the dominant source of androstenedione and testosterone secretion are the adrenal glands. To date, there is only sparse information about the regulation of androstenedione, testosterone and dihydrotestosterone (DHT) concentrations in women with severe major depression.Therefore, 11 pre- and postmenopausal, severely depressed, hypercortisolemic women (Hamilton Depression Scale, 31.3+/-5.9; age, 28-77 yrs; mean, 48. 1+/-18.1 yrs) and 11 age-matched healthy female controls (age, 24-81 yrs; mean, 47.9+/-21.5 yrs) underwent a 24 hour (h) blood sampling starting at 0800 h with 30-minute sampling intervals.By applying multivariate analysis of covariance with age as covariate, androstenedione, testosterone and DHT plasma levels at 0900 h show a trend for elevated concentrations in depressed women compared to controls (F(1,19)=2.7; P=0.057). Univariate F tests reveal a significant difference between the groups for androstenedione (4. 19+/-1.571 vs 2.584+/-1.257 nmol/l; P<0.05) testosterone (1.110+/-0. 278 vs 0.833+/-0.347 nmol/l; P<0.05) and DHT (0.656+/-0.207 vs 0. 483+/-0.242 nmol/l; P<0.05). Mean ACTH (16.4+/-10.4 vs 10.4+/-2.4 pmol/l; P=0.89), LH (13.5+/-11.8 vs 8.9+/-9.2 IU/l; P=0.12), FSH (35. 2+/-33.1 vs 31.3+/-35.7 IU/l; P=0.67) and estradiol (135.4+/-157.4 vs 82.2+/-85.1 pmol/l; P=0.20) plasma levels did not differ between patients and controls. Further, there was a trend towards an age related decline in testosterone secretion in healthy controls (r=-0. 24; P=0.08) which did not occur in depressed patients (r=0.17; P=0. 96), while the calculated ratio of DHEA to testosterone was similar in both groups (0.2+/-0.14 vs 0.13+/-0.7; P=0.21, unpaired t-test). In conclusion, androstenedione, testosterone and DHT concentrations all were increased in hypercortisolemic women with severe major depression. These findings are best explained as a consequence of an overstimulation of the adrenal glands through pituitary and hypothalamic sites of the HPA-system.     

d-Lys-GHRP-6 does not modify the endocrine response to acylated ghrelin or hexarelin in humans

Acylated ghrelin exerts numerous endocrine and non-endocrine activities via the GH Secretagogue receptor type 1a (GHS-R1a). D-Lys-GHRP-6 has been widely studied in vitro and in vivo in animal studies as GHS-R1a antagonist; its action in humans has, however, never been tested so far. Aim of our study was to verify the antagonistic action of D-Lys-GHRP-6 on the endocrine responses to acylated ghrelin and hexarelin, a peptidyl synthetic GHS, in humans. The effects of different doses of D-Lys-GHRP-6 (2.0microg/kg iv as bolus or 2.0microg/kg/h iv as infusion) on both spontaneous and acylated ghrelin- or hexarelin (1.0microg/kg iv as bolus) -stimulated GH, PRL, ACTH and cortisol levels were studied in six normal volunteers (age [mean+/-SEM]: 25.4+/-1.2yr; BMI: 22.3+/-1.0kg/m(2)). The effects of D-Lys-GHRP-6 (2.0microg/kg iv as bolus+4.0microg/kg/h iv) on the GH response to 0.25microg/kg iv as bolus acylated ghrelin was also studied. During saline, spontaneous ACTH and cortisol decrease was observed while non changes occurred in GH and PRL levels. Acylated ghrelin and hexarelin stimulated (p<0.05) GH, PRL, ACTH and cortisol secretions. D-Lys-GHRP-6 administered either as bolus or a continuous infusion did not modify both spontaneous and acylated ghrelin- or hexarelin-stimulated GH, PRL, ACTH and cortisol secretion. D-Lys-GHRP-6 did not modify even the GH response to 0.25microg/kg iv acylated ghrelin. In conclusion, D-Lys-GHRP-6 does not affect the neuroendocrine response to both ghrelin and hexarelin. These findings question D-Lys-GHRP-6 as an effective GHS-R1a antagonist for human studies.     

The glutamate antagonist riluzole and its effects upon basal and stress-induced activity of the human hypothalamus-pituitary-adrenocortical system in elderly subjects

There is preclinical evidence that CRH is released in response to a glutamatergic stimulation. However, it is not clear, whether glutamate plays a role in the physiological stress response. We tested whether the antiglutamatergic drug riluzole dampens the response of the hypothalamus-pituitary-adrenocortical (HPA) system to both a mental and a physical stressor. Nine male elderly healthy subjects received placebo and 150 mg riluzole for 2 days in a randomized balanced order. Blood was withdrawn every 15 min for estimation of cortisol and ACTH from 14.00 to 20.00 h. Between 16.00 and 16.45 h, the subjects were subjected to a cognitive challenge paradigm. Further, between 19.02 and 19.15 an individually adapted physical stress test was performed. After riluzole treatment, baseline ACTH and cortisol concentrations were unchanged when compared to placebo treatment. Also, after the mental stressor, there was no difference between both treatment conditions. In contrast, the cortisol (riluzole vs. placebo: 148 +/- 60 vs. 183 +/- 98 nmol/l) and ACTH response (20.2 +/- 11.9 vs. 40.7 +/- 61.9 pmol/l) to the physical stressor tended to be lower after riluzole pretreatment. In conclusion, the antiglutamatergic drug riluzole did not have any effects upon HPA system activity under baseline and cognitive-stress-induced conditions in elderly subjects. However, a trend for dampening the endocrine response to physical stress emerged.     

Sleep, clonidine, and their interactive effect on growth hormone secretion in normal men

Central alpha 2-adrenergic function is often inferred from the growth hormone (GH) response to clonidine, despite the drug's known hypnotic effect and the accepted cholinergic mechanism for sleep-related GH secretion. We examined the effect of daytime sleep on GH secretion in normal men taking placebo or clonidine orally, using a two-group blind design (placebo, clonidine; n = 9 each). Each subject participated in two morning sessions monitored by polysomnography: wake (sleep actively prevented) and sleep (subjects asked to sleep for 3 hr after receiving placebo or clonidine). Blood samples were drawn at times -15 min, 0, and every 30 min for 3 hr after the test dose was given. The total sleep time was similar for both groups. The placebo/wake group had lower GH responses than the other three groups. None of the GH responses in the clonidine/sleep group were significantly different from those in the placebo/sleep group; and the peak GH micrograms/L, mean +/- SD) was 16.9 +/- 10.9 vs. 14.6 +/- 10.5, respectively. We conclude that the GH response to clonidine may not be indicative of alpha 2-adrenergic function if sleep is permitted during the test.     

Evidence of basal pituitary-adrenal overactivity in first episode, drug naïve patients with schizophrenia

BACKGROUND: Evidence for basal hypothalamic-pituitary-adrenal (HPA) axis dysfunction in schizophrenia is less consistent than that seen in major depression. Potential reasons include sampling procedures and the use of patients on antipsychotic medications which may suppress the HPA axis. Therefore, the objective of this study was to determine whether first episode, drug na?ve patients with schizophrenia have evidence of basal HPA axis dysfunction by measuring plasma levels of AVP, ACTH and cortisol from 13:00 to 16:00 h, a time frame which is believed to reflect 24 h concentrations of HPA axis activity. METHOD: In this cross-sectional study, plasma levels of AVP, ACTH and cortisol were measured in 12 (7 males and 5 females) (mean age +/-SD=33.6+/-12.6 years) patients with DSM-IV schizophrenia and compared with those found in age- and sex-matched healthy controls. RESULTS: Patients and controls did not differ in terms of their 13:00 h cortisol and AVP. However, patients with schizophrenia had higher levels of ACTH as compared to control subjects at 13:00 h (41.3+/-14.6 vs. 12.4+/-1.1 pg/ml respectively; t=1.99, df=11, p <0.05). In comparison to controls subjects, patients with schizophrenia, had higher mean (+/-SE) AUC of ACTH (26.3+/-6.2 vs. 13.9 nmol/l, respectively; t=2.86, df=11, p <0.02) and cortisol (279.4+/-26.0 vs. 213.1+/-18.4 nmol/l, respectively; t=3.72, df=11, p <0.01). Though, patients with schizophrenia, in comparison to control subjects, had lower mean (+/-SE) AUC of AVP (0.87+/-0.24 vs. 1.42+/-0.34 pmol/l, respectively; t=2.29, df=11, p <0.02). CONCLUSIONS: First episode, drug na?ve patients with schizophrenia show evidence of basal overactivity of the pituitary-adrenal axis.     

Effects of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and Vasoactive Intestinal Polypeptide (VIP) on Prolactin, Luteinizing Hormone and Growth Hormone Secretion in the Ewe

This study was undertaken to investigate the roles of PACAP and VIP in the control of pituitary hormone secretion in the ewe. The first experiment was designed to identify any direct effects at the level of the pituitary and was conducted during the luteal phase of a prostaglandin-synchronized oestrous cycle. PACAP (0.008, 0.04, 0.2 and 1.0 nmol/min) or VIP (0.06, 0.2, 0.6 and 1.8 nmol/min) was infused into the carotid artery over a 10 min period. Blood samples were taken before and after the infusions so that plasma PRL, LH and GH concentrations could be measured. Blood pressure was also monitored to determine if the doses used were biologically active. In no case was an effect on hormone secretion observed. In contrast, the highest dose of each peptide induced an increase in heart rate to almost three-fold the resting value. Although both peptides are active in vivo, this result suggests that neither peptide has a direct effect on hormone release from the pituitary of prostaglandin-synchronized ewes. In a second experiment, we investigated whether the peptides had central effects on hormone secretion. Intracerebroventricular (ICV) injection of PACAP or VIP at the dose 10nmol was tested in ovariectomized ewes. After injection, PACAP suppressed PRL and GH secretion so that plasma hormone concentrations from 1–3 h after injection were significantly different from the control (P<0.05 for PRL, P<0.01 for GH). In addition, PACAP significantly reduced mean LH concentration (P<0.05) and LH pulse frequency (P<0.01). A similar suppressive effect on LH secretion was also observed after ICV injection of VIP (P<0.05 for both parameters), although PRL and GH release were not affected. These results suggest a possible role for PACAP in the neuroendocrine control of PRL, GH and LH secretion in sheep. In addition, VIP may be involved in the control of LH secretion. In contrast, there is no evidence to suggest that either peptide is a hypophysiotropic factor for PRL, LH or GH in prostaglandin-synchronized ewes.     

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.     

Neuroendocrine effects of citalopram infusion in anorexia nervosa

Because of the role of serotonin (5HT) in regulating food intake and mood, several studies have focused their attention on the assessment of serotonergic activity in eating disorders, and in particular in anorexia nervosa, but the results have been inconsistent. Citalopram, a highly selective 5HT reuptake inhibitor, has been recently reported as a neuroendocrine probe to assess the serotonergic function in physiological and pathological conditions. We evaluated the adrenocorticotropic hormone (ACTH), cortisol, prolactin (PRL) and growth hormone (GH) secretion during placebo or citalopram IV infusion (20 mg over 120 min), in six women with anorexia nervosa restricter type, and in six healthy women, in order to test the hypothesis that this neurotransmitter system is abnormal in this group of patients. ACTH and PRL secretion was higher during citalopram infusion compared to placebo (p<0.05) in both groups, while cortisol secretion was higher during citalopram infusion only in healthy controls (p<0.05), but not in anorexic patients. GH levels were unaffected by citalopram in both groups. These results demonstrate that serotonergic activation by citalopram affects corticotroph and lactotroph but not somatotroph secretion in anorexic as well as in normal subjects. Our preliminary findings do not support the existence of remarkable alterations in the serotonergic control of anterior pituitary function in anorexia nervosa, while there seems to be an impairment of the adrenal function in this group of patients.     

Influence of clenbuterol, a β-adrenergic agonist, on desipramine induced growth hormone, prolactin and cortisol stimulation

We report herein the effects of the β-adrenergic agonist clenbuterol on desipramine(DMI)-induced growth hormone (GH), prolactin (PRL) and cortisol secretion in healthy male subjects. In the first study, nine subjects were treated with either clenbuterol (0.04 mg, p.o.) or placebo. In the second study, 12 subjects received either DMI (50 mg, i.v.) alone or in combination with clenbuterol (0.04 mg, p.o.) given 60 min prior to DMI administration.

Clenbuterol alone had no influence on GH, PRL, or cortisol concentrations, compared to placebo. DMI alone caused GH stimulation (mean MAXIMUM = 15.7±3.4 ng/ml), which was significantly lower after combined administration of DMI and clenbuterol (mean MAXIMUM = 7.7±1.6 ng/ml) (p≤0.01). DMI-induced PRL and cortisol stimulation was not influenced by clenbuterol pretreatment.

These results indicate the inhibiting influence of noradrenergic β-receptors on GH stimulation.     

Immunoreactive corticotropin-releasing factor and corticotropin during pregnancy, labor and puerperium

Concentrations of immunoreactive corticotropin releasing factor (CRF) and corticotropin (ACTH) in the plasma were studied in healthy pregnant women. Concentration of CRF was near the detection limit of the assay (2.5 pmol/l) until the 16th week of pregnancy, increasing thereafter significantly towards term: the mean values (+/- S.E.) at weeks 8-11, 12-15, 16-19, 20-23, 24-27, 28-31, 32-35, and 36-40 were 2.9 +/- 0.42, 2.9 +/- 0.72, 5.2 +/- 1.1, 10.2 +/- 5.8, 14.6 +/- 2.0, 32.8 +/- 4.8, 63.6 +/- 9.2, and 187 +/- 39 pmol/l, respectively. The mean concentration of CRF did not increase during labor, and it decreased rapidly after delivery. On the contrary, the mean plasma level of ACTH increased only slightly during late pregnancy, but during labor the increase was significant. These findings suggest that CRF in maternal circulation is not primarily involved in the regulation of maternal ACTH secretion, and the stress of labor does not increase the release of CRF, which probably originates mainly from the placenta.     

Repeated administration of the combined dexamethasone-human corticotropin releasing hormone stimulation test during treatment of depression.

Human corticotropin releasing hormone (h-CRH) was administered to 14 patients with major depression, after premedication with an overnight dose of 1.5 mg dexamethasone. Cortisol response, expressed as area under the time course curve (AUC), was significantly higher in the 14 patients than in a group of 13 age-matched control subjects (9.4 +/- 7.6 ng x min x 1,000/ml vs. 3.1 +/- 3.6 ng x min x 1,000/ml). Corresponding AUC values for plasma adrenocorticotropic hormone (ACTH) were also significantly higher in patients than in control subjects (4.9 +/- 1.4 pg x min x 1,000/ml vs. 2.6 +/- 0.9 pg x min x 1,000/ml). After patients were treated with trimipramine (200 mg/day) for 6 weeks, the combined dexamethasone/h-CRH test was repeated. At that time, depression scores were significantly improved and the patients' cortisol response pattern became indistinguishable from that of controls. While plasma cortisol output normalized during treatment with trimipramine, ACTH release remained exaggerated. The combined dexamethasone/h-CRH challenge test may be of particular value in the detection of state-dependent changes of pituitary-adrenocortical neuroregulation.     

Male patients with paranoid schizophrenia have greater ACTH and cortisol secretion in response to metoclopramide-induced AVP release

Dynamic testing of the hypothalamic-pituitary-adrenal axis in schizophrenia has yielded conflicting results, which may be related to patient selection and previous exposure to psychotropic medication. The objective of this study was to determine the pattern of corticotropin (ACTH) and cortisol release in response to metoclopramide (a dopamine antagonist), which appears to be unique in its ability to release vasopressin (AVP), in drug naive patients with schizophrenia experiencing their first episode of psychosis. In this study, we examined AVP, ACTH and cortisol release in response to metoclopramide in 10 drug-naive, first-episode male patients with a DSM IV diagnosis of paranoid schizophrenia and compared them to healthy control subjects matched for age, sex and smoking status. Patients, as compared to controls had higher levels of baseline plasma cortisol (375.5+/-47.4/l vs. 273.8+/-42.2 nmol/l, respectively; t=2.48, df=9, p< 0.02) and plasma ACTH (14.9+/-0.85 vs. 11.3+/-0.57 pg/ml, respectively; t=4.29, df=9, p<0.001). AVP levels were lower in patients though this did not reach statistical significance (0.89+/-0.09 vs. 1.3+/-0.08 pmol/l, respectively; t=1.97, df=9, p<0.07). A repeated measures 2-way ANOVA to compare responses to metoclopramide over time between the two groups yielded a significant group by time interaction for cortisol (F=11.3, df=6, 108, p<0.001) and ACTH (F=15.65, df=6, 108, p<0.002). Post hoc Tukey's test revealed significant differences between the two groups at +30, +45, +60, +90 and +120 min for cortisol (p<0.01) and at +30, +45, +60 and +90 min for ACTH (p<0.01). The group by time interactions continued to remain significant when cortisol (F=10.9, df=6, 107, p<0.001) and ACTH (F=13.04, df=6, 108, p<0.002) were entered as co-variates. There was a significant positive correlation between AVP and cortisol responses in patients (r=0.65, df=8, p<0.01). Male patients with paranoid schizophrenia release greater amounts of ACTH and cortisol in responses to metoclopramide-induced AVP secretion than control subjects.     

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.     

Cortistatin-8, a synthetic cortistatin-derived ghrelin receptor ligand, does not modify the endocrine responses to acylated ghrelin or hexarelin in humans

Cortistatin (CST), a neuropeptide with high structural homology with somatostatin (SST), binds all SST receptor (SST-R) subtypes but, unlike SST, also shows high binding affinity to ghrelin receptor (GHS-R1a). CST exerts the same endocrine activities of SST in humans, suggesting that the activation of the SST-R might mask the potential interaction with ghrelin system. CST-8, a synthetic CST-analogue devoid of any binding affinity to SST-R but capable to bind the GHS-R1a, has been reported able to exert antagonistic effects on ghrelin actions either in vitro or in vivo in animals. We studied the effects of CST-8 (2.0 microg/kg i.v. as a bolus or 2.0 microg/kg/h i.v. as infusion) on both spontaneous and ghrelin- or hexarelin- (1.0 microg/kg i.v. as bolus) stimulated GH, PRL, ACTH and cortisol secretion in 6 normal volunteers. During saline, no change occurred in GH and PRL levels while a spontaneous ACTH and cortisol decrease was observed. As expected, both ghrelin and hexarelin stimulated GH, PRL, ACTH and cortisol secretion (p<0.05). CST-8, administered either as bolus or as continuous infusion, did not modify both spontaneous and ghrelin- or hexarelin-stimulated GH, PRL, ACTH and cortisol secretion. In conclusion, CST-8 seems devoid of any modulatory action on either spontaneous or ghrelin-stimulated somatotroph, lactotroph and corticotroph secretion in humans in vivo. These negative results do not per se exclude that, even at these doses, CST-8 might have some neuroendocrine effects after prolonged treatment or that, at higher doses, may be able to effectively antagonize ghrelin action in humans. However, these data strongly suggest that CST-8 is not a promising candidate as GHS-R1a antagonist for human studies to explore the functional interaction between ghrelin and cortistatin systems.