Megestrol attenuates the hormonal response to CCK-4-induced panic attacks

Progestational hormones may have anxiolytic properties. CCK-4 (cholecystokinin tetrapeptide) can be used pharmacologically to induce panic attacks both in normal controls and patients suffering from panic disorder. In this study we compared the effects of pretreatment with the progestational hormone megestrol and placebo on CCK-4-induced panic attacks and stress hormone release in healthy male controls. Using a double-blind balanced design, we pretreated 10 medically and psychiatrically healthy male controls with placebo or megestrol 160 mg at 11 p.m. and 8 a.m. (sigma=320 mg) prior to the experiment. Following 1 h of rest, 12 blood samples were drawn between 1,000 h and 1,300 h and analyzed for ACTH and cortisol levels. At 1,100 h, subjects received an intravenous injection of 50 microg CCK-4. Clinical ratings were performed at 1,045 h and 1,110 h, and included the Acute Panic Inventory (API), International Diagnostic Checklist (IDCL), as well as a visual analog scale (VAS) for anxiety and tension. CCK-4 significantly increased anxiety and tension. Pretreatment with megestrol showed no significant effect on clinical ratings. Baseline ACTH and cortisol levels, as well as ACTH and cortisol levels after administration of CCK-4, were significantly reduced after pretreatment with megestrol. In a sample of healthy male controls, pretreatment with megestrol had a profound effect on the hypothalamic-pituitary-adrenal (HPA) axis, whereas the clinical effects on panic attacks were weak. Further studies in a larger sample of subjects, including both females and patients suffering from panic disorder, seem warranted.     

Intravenous C-type natriuretic peptide augments behavioral and endocrine effects of cholecystokinin tetrapeptide in healthy men.

Given the anxiogenic effects of the type-B natriuretic peptide receptor agonist C-type natriuretic peptide (CNP) in rodents, we investigated the influence of CNP pretreatment upon the behavioral and endocrine action of the panicogen cholecystokinin tetrapeptide (CCK-4) in healthy men. In a randomized double-blind balanced design, 20 male volunteers were given an intravenous infusion of 300 microg of CNP vs. placebo followed by 25 microg of CCK-4. The behavior was assessed using panic, anxiety, and dissociation questionaires before the infusion and after the CCK-4 stimulus. Furthermore, the stress-sensitive hormones adrenocorticotropic hormone (ACTH), cortisol, and prolactin were measured. CNP pretreatment enhanced the anxiogenic and prodissociative effects of CCK-4 and significantly augmented the ACTH surge after CCK-4. However, no effect of CNP was seen upon panic symptoms. Our preliminary data support a role of type-B natriuretic peptide receptors in anxiety modulation in normal man.     

Psychoimmunoendocrine aspects of panic disorder.

Immunological, neuroendocrine and psychological parameters were examined in 14 psychophysically healthy subjects and in 17 panic disorder patients before and after a 30-day course of alprazolam therapy. T lymphocyte proliferation in response to the mitogen phytohemagglutinin, lymphocyte beta-endorphin (beta-EP) concentrations, plasma ACTH, cortisol and beta-EP levels were examined in basal conditions and after corticotropin-releasing hormone (CRH) stimulation. Cortisol inhibition by dexamethasone (DST) and basal growth hormone (GH) and prolactin levels were also examined. Depression, state or trait anxiety, anticipatory anxiety, agoraphobia, simple and social phobias, severity and frequency of panic attacks were monitored by rating scales. The immune study did not reveal any significant difference between patients and controls, or any effect of alprazolam therapy. The hormonal data for the two groups were similar, except for higher than normal basal ACTH and GH plasma levels, lower than normal ratios between the ACTH and cortisol responses to CRH, and blunted DST in some patients. All the impairments improved after alprazolam therapy, in parallel with decreases in anxiety and in severity and frequency of panic attacks.     

Behavioral and endocrine response to cholecystokinin tetrapeptide in patients with posttraumatic stress disorder.

BACKGROUND: Given the relationship between posttraumatic stress disorder (PTSD) and panic, it was of interest to examine whether panic provoking agents affect PTSD symptoms. We therefore investigated the behavioral and endocrine response of PTSD patients to the panicogen cholecystokinin tetrapeptide (CCK-4). METHODS: Eight patients with PTSD (DSM-IV) received 50 micrograms CCK-4 intravenously in a placebo-controlled, double-blind balanced design. Provocation of panic, anxiety, and flashbacks was assessed. Plasma adrenocorticotropin (ACTH) and cortisol levels after CCK-4 were measured and compared to healthy subjects matched for age, gender, and provoked symptoms. RESULTS: Despite significant effects of CCK-4 on anxiety and panic symptoms, no significant provocation of flashbacks emerged. CCK-4-induced panic symptoms showed an inverse correlation to trait dissociation. The ACTH response after CCK-4 was significantly lower in PTSD patients than in controls. Cortisol was similarly increased in both groups after CCK-4, but PTSD patients showed a more rapid decrease of stimulated cortisol concentrations. CONCLUSIONS: Panic symptoms or heightened anxiety are not necessarily conditioned stimuli for the provocation of posttraumatic flashbacks. Further studies in PTSD with different panicogens should be controlled for the potential interference of trait dissociation. Our hormone data show further evidence for a corticotropin-releasing hormone (CRH) overdrive and enhanced negative glucocorticoid feedback in PTSD patients.     

Neuroendocrine effects of diazepam in panic and generalized anxiety disorders.

The adrenocorticotropic hormone (ACTH), cortisol, and growth hormone responses to four consecutive, logarithmically increasing doses of intravenous diazepam compared with placebo given at 15-min intervals were examined in patients with panic disorder (n = 13), generalized anxiety disorder (n = 8), and healthy controls (n = 13). Diazepam caused dose-dependent decreases in cortisol and increases in GH and dose-independent decreases in ACTH. There were no patient-control differences, possibly due to either the small sample size of the experimental paradigm, which tested subjects in an upright, sitting position in mildly arousing circumstances.     

Behavioral,cardiovascular, and neuroendocrine profiles following CCK-4 challenge in healthy volunteers: A comparison of panickers and nonpanickers

Healthy subjects who panic following systemic cholecystokinin-tetrapeptide (CCK-4) challenge typically exhibit a symptom profile reminiscent of that evident among panic patients. However, the biological concomitants of CCK-4-induced panic in healthy subjects remain obscure. Accordingly, we evaluated the behavioral, cardiovascular, and neuroendocrine effects of CCK-4 in panickers and nonpanickers. Predictably, subjects who panicked with CCK-4 experienced more intense symptoms of panic and greater increases in ratings of fearful and anxious mood than did subjects who did not panic. CCK-4-induced increases in diastolic blood pressure, adrenocorticotropic hormone, prolactin, and growth hormone secretion were also significantly enhanced in subjects who panicked. The results of this study demonstrate that the behavioral experience of CCK-4-induced panic in healthy individuals is accompanied by marked biological changes and provide confirmation that CCK-4 is a useful model of panic for research among nonclinical subjects. Depression and Anxiety 8:1–7, 1998. © 1998 Wiley-Liss, Inc.     

Effects of citalopram treatment on behavioural, cardiovascular and neuroendocrine response to cholecystokinin tetrapeptide challenge in patients with panic disorder.

Eight patients with panic disorder were administered 20 micrograms of cholecystokinin tetrapeptide (CCK-4) before and after 8 weeks of treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram. All patients responded to treatment by showing a significant general improvement and reaching a panic-free state for 2 weeks. At the rechallenge with CCK-4, patients displayed a marked reduction in the intensity and number of panic symptoms. The frequency of panic attacks induced with CCK-4 decreased by 50% after treatment. Citalopram treatment had no substantial effect on cardiovascular (heart rate and blood pressure) or hormonal (cortisol, prolactin and growth hormone) responses to CCK-4. Patients who still had panic attacks after treatment demonstrated a blunted growth hormone response to CCK-4 that was not seen in those who did not have panic attacks. This study suggests that treatment with an SSRI can reduce an enhanced sensitivity to CCK-4 without modifying cardiovascular and neuroendocrine responses to CCK-4 in patients with panic disorder.     

Differential effects to CCK-4-induced panic by dexamethasone and hydrocortisone

Abstract Objectives. Peripheral administration of the cholecystokinin (CCK) receptor agonist CCK-4 generates panic and activates the hypothalamic-pituitary-adrenal (HPA) axis. Direct effects at the pituitary and CCK-HPA interactions at higher regulatory sites have been suggested. According to preliminary data, ACTH response to CCK receptor agonists may differ from its response to exogenous CRH by its resistance to cortisol feedback inhibition. To further explore this resistance and to better characterize CCK-4 sites of action, the effects of different glucocorticoid pretreatments on CCK-4-induced panic were compared. Methods. Using a double-blind placebo-controlled design we pretreated healthy males with either dexamethasone (peripheral action) or hydrocortisone (central-peripheral action) each followed by a CCK-4 challenge. Blood levels of ACTH and cortisol were analyzed and panic symptoms were assessed. Results. We found a blunted response of ACTH release following CCK-4 injection only after hydrocortisone pretreatment. Dexamethasone however did not affect CCK-4-induced ACTH release relative to baseline. In contrast to dexamethasone, hydrocortisone reduced the severity of CCK-4-induced panic as measured by the Acute Panic Inventory on a trend level. Conclusions. Findings suggest that CCK-4-induced stress hormone release seems susceptible to cortisol-feedback inhibition and argues for a suprapituitary site of CCK action. Effects on panic anxiety were weak but congruent with studies showing that CCK-4-induced HPA axis inhibition is accompanied by a reduction of anxiety after CCK-4.     

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.     

Differential effects to CCK-4-induced panic by dexamethasone and hydrocortisone

Abstract

Objectives. Peripheral administration of the cholecystokinin (CCK) receptor agonist CCK-4 generates panic and activates the hypothalamic–pituitary–adrenal (HPA) axis. Direct effects at the pituitary and CCK-HPA interactions at higher regulatory sites have been suggested. According to preliminary data, ACTH response to CCK receptor agonists may differ from its response to exogenous CRH by its resistance to cortisol feedback inhibition. To further explore this resistance and to better characterize CCK-4 sites of action, the effects of different glucocorticoid pretreatments on CCK-4-induced panic were compared. Methods. Using a double-blind placebo-controlled design we pretreated healthy males with either dexamethasone (peripheral action) or hydrocortisone (central-peripheral action) each followed by a CCK-4 challenge. Blood levels of ACTH and cortisol were analyzed and panic symptoms were assessed. Results. We found a blunted response of ACTH release following CCK-4 injection only after hydrocortisone pretreatment. Dexamethasone however did not affect CCK-4-induced ACTH release relative to baseline. In contrast to dexamethasone, hydrocortisone reduced the severity of CCK-4-induced panic as measured by the Acute Panic Inventory on a trend level. Conclusions. Findings suggest that CCK-4-induced stress hormone release seems susceptible to cortisol-feedback inhibition and argues for a suprapituitary site of CCK action. Effects on panic anxiety were weak but congruent with studies showing that CCK-4-induced HPA axis inhibition is accompanied by a reduction of anxiety after CCK-4.     

Lower cortisol and higher ACTH levels in individuals with autism

Blood concentrations of pituitary hormones adrenocorticotropin (ACTH), prolactin, growth hormone, and adrenal hormone–cortisol were measured in 36 autistic and 27 control individuals. Individuals with autism had significantly lower serum concentrations of cortisol (p < 10^–6), and significantly higher concentrations of ACTH (p = 0.002) than control age- and sex-matched subjects. Also, prolactin concentrations in autistic patients with epilepsy were significantly higher when compared with normal subjects. The observed hormonal changes may indicate dysfunction of the hypothalamo-pituitary-adrenal axis in individuals with autism.     

Situational panic attacks. Behavioral, physiologic, and biochemical characterization

To investigate the pathophysiology of nonpharmacologically induced panic attacks, 18 drug-free agoraphobic patients and 13 matched healthy subjects underwent structured exposure to phobic situations. Heart rate, blood pressure, and plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG), cortisol, growth hormone, and prolactin levels were measured before, during, and after exposure. Fifteen patients experienced situational panic attacks during exposure. Panicking patients displayed significantly greater increases in heart rate but not blood pressure or plasma free MHPG or cortisol in comparison with the healthy subjects. Growth hormone and prolactin responses tended to be smaller in the patients. If brain noradrenergic hyperactivity occurs during situational panic attacks, it may be too brief or too restricted in regional localization to affect MHPG levels in plasma. Chronically recurrent attacks may cause an adaptation of neuroendocrine mechanisms activated by anxiety or stress.     

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.     

Growth hormone and cortisol secretion after oral clonidine in healthy adults

The purpose of this study was to evaluate oral clonidine for testing growth hormone (GH) responsiveness in healthy adults. Oral clonidine (0.15 mg) produced a satisfactory GH response (greater than 4 ng/ml from basal) in eight out of 10 subjects, which is similar to rates reported after an equivalent intravenous dose. Elevated GH levels at baseline occurred in four out of five female subjects; this did not affect the clonidine-induced GH release. There were no significant differences at any time point in plasma prolactin or cortisol levels following clonidine, compared to placebo controls. Adequate plasma clonidine levels (greater than 0.4 ng/ml) were achieved in all subjects, with corresponding reductions in mean arterial blood pressure, but with only minimal adverse effects. Results from this study indicate that oral clonidine is a reliable method for testing GH responsiveness in adult subjects.     

Carbon dioxide-induced anxiety. Behavioral, physiologic, and biochemical effects of carbon dioxide in patients with panic disorders and healthy subjects

Carbon dioxide was administered for 15 minutes to patients with panic disorders (5% CO2, n = 14) and healthy subjects (5% CO2, n = 11; 7.5% CO2, n = 8). Following administration of CO2 and air placebo, changes in behavioral ratings, vital signs, and plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol, cortisol, growth hormone, and prolactin were measured over three hours. In the healthy subjects, CO2 produced dose-related increases in anxiety, somatic symptoms, vital signs, and plasma cortisol levels. In the patients, the frequency of panic attacks (in eight of 14 patients) and the increases in anxiety and somatic symptoms induced by 5% CO2 exceeded those in the healthy subjects and were similar to those induced by 7.5% CO2 in the healthy subjects. The physiologic and biochemical measurements obtained did not elucidate the mechanisms underlying CO2-induced anxiety or the greater anxiogenic effects of CO2 seen in patients with panic disorders.     

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.     

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.     

Neuroendocrine and monoaminergic responses to acute administration of alprazolam in normal subjects

The effect of a single dose (3 mg) of alprazolam on plasma cortisol, growth hormone (GH), prolactin, norepinephrine (NE) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) was studied in 10 healthy males. Alprazolam and placebo were administered orally in a crossover design and blood was sampled for 24 h. In comparison to placebo, alprazolam significantly reduced plasma cortisol levels and raised plasma GH levels. Prolactin levels were elevated by 100% from 2 to 8 h after alprazolam administration. The robust increase in prolactin levels is less consistent with previously reported data on traditional benzodiazepines. Plasma NE levels following alprazolam were lower than following placebo administration only at one time point, and MHPG concentrations were not affected. The lack of change in NE and MHPG levels suggests that the acute effect of alprazolam in normal subjects is not mediated via the central noradrenergic system.     

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.     

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.