Margaret M. Walters

Effects of simvastatin on blood lipids, vitamin E, coenzyme Q10 levels and left ventricular function in humans

Background  As statin therapy has been reported to reduce antioxidants such as vitamin E and coenzyme Q10 and there are indications that this reduction may cause impairment of left ventricular function (LVF), we studied the influence of simvastatin on LVF and serum vitamin E and coenzyme Q10 levels in humans.

Hypersensitivity of the hypothalamic-pituitary-adrenal axis to naloxone in post-traumatic stress disorder

Naloxone, which increases endogenous corticotropin-releasing hormone (CRH) release by blocking an inhibitory opioidergic tone on the hypothalamic-pituitary-adrenal (HPA) axis, was administered in a dose-response protocol to seven healthy volunteers and 13 patients with treated posttraumatic stress disorder (PTSD). Six of the PTSD patients showed an increased hormonal response to the lowest naloxone dose (6 micrograms/kg) compared to both the control subjects and the other PTSD patients. This difference persisted on detailed subgroup analysis, although it was less marked at the highest naloxone dose (125 micrograms/kg). The responses of the other seven PTSD patients were indistinguishable from those of the control group. The greater responses of the six PTSD patients could not be explained on the basis of associated psychiatric illnesses or psychotropic drug therapy, and did not correlate with standard psychological testing or severity of PTSD. The results of this preliminary study therefore suggest that a hypersensitivity of the HPA axis to endogenous CRH stimulation may occur in PTSD.

A Synergistic Adrenocorticotropin Response to Naloxone and Vasopressin in Normal Humans - Evidence That Naloxone Stimulates Endogenous Corticotropin-Releasing Hormone

Naloxone stimulates pituitary-adrenal function by blocking an endogenous inhibitory opioidergic tone which modulates pituitary adrenocorticotropin (ACTH) release. In animals, this action of naloxone is mediated by increased corticotropin-releasing hormone (CRH) secretion, but such a mechanism is disputed in humans. CRH and arginine vasopressin (AVP) are known to have a synergistic effect on ACTH secretion in both humans and animals. In vitro, this synergism is independent of L-type voltage-dependent Ca2+ channel function. The aims of this study were therefore: (i) to determine if the combined administration of naloxone and AVP is synergistic regarding ACTH release; (ii) to assess the effect of nifedipine, which blocks L-type Ca2+ channels, on the ACTH response to combined naloxone/AVP stimulation. Seven healthy volunteers were studied using a placebo-controlled, single-blind protocol. Naloxone (125 micrograms/kg) and/or AVP (10 units) were given in all four possible combinations, and oral nifedipine (20 mg) was also given with naloxone and AVP as an additional test. The mean AUC and the mean peak change in ACTH levels following combined naloxone/AVP administration were both significantly greater than the arithmetic sum of the ACTH responses to naloxone and AVP given on separate occasions (AUC: 1,576.4 +/- 417.9 vs. 567.1 +/- 106.1 pmol.min.l-1, p < 0.002; peak change: 37.9 +/- 14.0 vs. 11.8 +/- 2.0 pmol/l, p < 0.007). Nifedipine reduced the ACTH response to combined naloxone/AVP stimulation by 43% (AUC: 1,576.4 +/- 417.9 vs. 897.0 +/- 186.2; p < 0.05), but it remained greater than the sum of the individual responses (897.0 +/- 186.2 vs. 576.1 +/- 106.1, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The Insulin Hypoglycemia Test: Hypoglycemic Criteria and Reproducibility

The insulin hypoglycemia test (IHT) is widely regarded as the ‘gold standard’ for dynamic stimulation of the hypothalamic‐pituitary‐adrenal (HPA) axis. This study aimed to investigate the temporal relationship between a rapid decrease in plasma glucose and the corresponding rise in plasma adenocorticotropic hormone (ACTH), and to assess the reproducibility of hormone responses to hypoglycemia in normal humans. Ten normal subjects underwent IHTs, using an insulin dose of 0.15 U/kg. Of these, eight had a second IHT (IHT2) and three went on to a third test (IHT3). Plasma ACTH and cortisol were measured at 15‐min intervals and, additionally, in four IHT2s and the three IHT3s, ACTH was measured at 2.5‐ or 5‐min intervals. Mean glucose nadirs and mean ACTH and cortisol responses were not significantly different between IHT1, IHT2 and IHT3. Combined data from all 21 tests showed the magnitude of the cortisol responses, but not the ACTH responses, correlated significantly with the depth and duration of hypoglycemia. All subjects achieved glucose concentrations of of ≤ 1.6 mmol/l before any detectable rise in ACTH occurred. In the seven tests performed with frequent sampling, an ACTH rise never preceeded the glucose nadir, but occurred at the nadir, or up to 15 min after. On repeat testing, peak ACTH levels varied markedly within individuals, whereas peak cortisol levels were more reproducible (mean coefficient of variation 7%). In conclusion, hypoglycemia of ≤ 1.6 mmol/l was sufficient to cause stimulation of the HPA axis in all 21 IHTs conducted in normal subjects. Nonetheless, our data cannot reveal whether higher glucose nadirs would stimulate increased HPA axis activity in all subjects. Overall, the cortisol response to hypoglycemia is more reproducible than the ACTH response but, in an individual subject, the difference in peak cortisol between two IHTs may exceed 100 nmol/l.

NEW DIAGNOSTIC TESTS FOR CUSHING'S SYNDROME: USES OF NALOXONE, VASOPRESSIN AND ALPRAZOLAM

1. We set out to investigate whether the administration of naloxone alone, naloxone plus vasopressin (AVP) or naloxone plus alprazolam to patients with Cushings syndrome would result in a blunted dynamic response of the pituitary‐adrenal axis compared with normal volunteers. Cushings syndrome is often difficult to diagnose. It would be helpful if new tests were available to help in the biochemical distinction between Cushings syndrome and non‐Cushings syndrome patients.

L-Type Calcium Channels and Crh-Mediated Acth and Cortisol Release in Humans

1. The effect of pretreatment with nifedipine on naloxone‐stimulated corticotrophin‐releasing hormone (CRH)‐induced adrenocorticotrophin (ACTH) release in humans was investigated. The mean peak plasma ACTH and cortisol levels and the mean peak change in cortisol levels from basal were significantly lower in the nifedipine/naloxone test than in the naloxone alone test. The integrated areas under the ACTH‐time and cortisol‐time curves were reduced by 33 and 49%, respectively, in the nifedipine/naloxone test compared with the naloxone alone test. These results correlate well with published in vitro studies.

Inhibition of Naloxone-Stimulated Adrenocorticotropin Release by Alprazolam in Myotonic Dystrophy Patients

Myotonic dystrophy (DM) is an autosomal dominant disorder causing myotonia, progressive muscle weakness, and endocrine abnormalities including hypothalamic‐pituitary‐adrenal (HPA) axis hyperresponsiveness to CRH‐mediated stimuli. This ACTH hyperresponsiveness appears directly related to the underlying genetic abnormality. Naloxone (Nal)‐mediated CRH release causes ACTH release in normal humans and an ACTH hyperresponse in DM. Alprazolam (APZ) attenuates the ACTH release in response to Nal in normal individuals, probably by inhibiting CRH release. This study investigates the effects of APZ on Nal‐induced HPA axis stimulation in DM. The ACTH response to Nal in DM subjects was significantly reduced by APZ. Despite this DM patients have a relative resistance to APZ inhibition of Nal‐induced ACTH/cortisol release. APZ caused a smaller percentage reduction in AUC for ACTH in DM compared with controls. These findings provide further insight into the mechanism(s) of the HPA axis abnormalities in DM. In DM, there may be an increase in tonic opioid inhibition to CRH release with compensatory increases in stimulatory pathways. Alternatively, these patients may have a basal increase in pituitary vasopressin levels or an enhanced AVP/CRH synergistic mechanism at the level of the corticotroph.

EFFECT OF SODIUM VALPROATE ON NALOXONE‐STIMULATED ACTH AND CORTISOL RELEASE IN HUMANS

1. Gamma‐aminobutyric acid (GABA) and endogenous opioids each inhibit hypothalamic CRH secretion. In humans, the opioid antagonist, naloxone, stimulates the release of CRH, and so of ACTH and cortisol, while alprazolam, an indirect GABAA agonist, blocks naloxone‐induced ACTH and cortisol secretion. Sodium valproate (SV) inhibits ACTH release in response to CRH, metyrapone and substance P. We hypothesized that, if this action is GABAA‐mediated, SV should also inhibit naloxone‐stimulated ACTH release.

DIURNAL EFFECTS OF FLUOXETINE AND NALOXONE ON THE HUMAN HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

1. Central serotonergic pathways are hypothesized to be involved in the stimulation of hypothalamic adrenocorticotropic hormone (ACTH) secretagogue release by both circadian‐ and stress‐induced mechanisms. We aimed to investigate this hypothesis by measuring the effect of the highly specific serotonin re‐uptake inhibitor fluoxetine (FX) on ACTH and Cortisol release in the morning and in the afternoon in humans, both by itself and in combination with the opioid antagonist naloxone (Nal). Naloxone causes ACTH release in humans by removing an endogenous inhibitory opioid tone on central noradrenergic pathways stimulatory to hypothalamic corticotropin‐releasing hormone (CRH) secretion. Serotonergic agents may act directly or indirectly through these central noradrenergic pathways and, if so, would be expected to be additive to or synergistic with Nal in causing ACTH and Cortisol release.

Pituitary-adrenal responses to combined oral D-fenfluramine and intravenous naloxone in humans

1. Fenfluramine is an optically active 5‐hydroxytryptamine (5‐HT) releaser and re‐uptake inhibitor. Increased brain 5‐HT mediates appetite suppression, the d enantiomer being more active than l‐ or dl‐fenfluramine. Fenfluramine also stimulates the hypothalamic‐pituitary‐adrenal (HPA) axis, leading to suggestions that this could act as a marker for its biological actions. However, the d enantiomer appears less active than a comparable dl racemate dose in animals, while effects of D‐fenfluramine on the human HPA axis remain unproven. The aim of the present study was to clarify this.