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R A Donald

Publications and source records attributed to R A Donald.

At least 37 records · Page 2Linked to original sources
PubMed1997

Atrial natriuretic peptide and C-type natriuretic peptide do not acutely inhibit the release of adrenocorticotropin from equine pituitary cells in vitro.

It has been suggested that atrial natriuretic peptide (ANP) is the long-sought inhibitor of corticotropin (ACTH) secretion, but the evidence is conflicting. We have examined the effect of ANP and C-type natriuretic peptide (CNP) on the secretion of ACTH by perifused equine pituitary cells in an in vitro milieu intended to mimic the in vivo milieu in the horse. Corticotropin-releasing hormone (20 pM) and cortisol (0 or 100 nM) were perifused continuously and 7 pulses of arginine vasopressin (AVP; 10 nM) applied for 5 min at 30-min intervals. ANP (1 nM) or CNP (1 nM) were perifused continuously for 75 min, beginning before the 3rd AVP pulse. Neither ANP nor CNP, with or without cortisol, significantly altered the ACTH secretory response to the AVP pulses. We conclude that these natriuretic peptides are unlikely to act at the pituitary as rapid inhibitors of ACTH secretion in the horse.

Adrenocorticotropic Hormone↗
PubMed1997

Hypothalamo-pituitary-adrenal axis response to coronary artery embolization: an ovine model of acute myocardial infarction.

Although previous studies have described the hypothalamo-pituitary-adrenal (HPA) response to the stress of acute myocardial infarction, it is not possible to study the hormone changes immediately after infarction in humans. Accordingly, we have examined the HPA response to microembolization of coronary arteries in 13 sheep compared with 5 sham control sheep. Plasma vasopressin (AVP; P < 0.001), ACTH (P = 0.005) and cortisol (P = 0.005) were all increased 2 h (first sample time) after embolization. Plasma ACTH and cortisol levels returned to baseline levels by 6 h but plasma AVP levels did not return to baseline levels until more than 12 h after embolization. Plasma corticotrophin-releasing hormone (CRH) showed no significant change in response to embolization. In a subset of six animals which were sampled more frequently, the peak responses for plasma AVP, ACTH and cortisol occurred at 40 min after embolization. The maximum responses in any individual sheep observed at this time point were 744 pmol/l for AVP, 144 pmol/l for ACTH and 492 nmol/l for cortisol. CRH levels tended to increase across the first hour but these changes were not statistically significant. In conclusion, the stress hormone responses to microembolization of the coronary arteries have been defined in an ovine model of myocardial infarction. This model is suitable for studying the effects of novel treatments to reduce the stress of myocardial infarction.

Adrenocorticotropic Hormone↗
PubMed1996

IGF-1 and IGFBP-3 screening for disorders of growth hormone secretion.

AIM: To assess the value of plasma assays of insulin like growth factor (IGF-1) and insulin like growth factor binding protein 3 (IGFBP-3) in the diagnosis of growth hormone disorders in children and adults. METHODS: Plasma IGF-1 and IGFBP-3 were measured in 47 children referred for the assessment of short stature, 26 adult subjects with hypopituitarism and in 10 adult subjects with acromegaly. Findings were compared with results obtained in 148 normal children and 124 normal adult subjects who comprised the reference range. RESULTS: Levels of both growth factors and especially IGF-1 are highly age dependent in normal children and adults. Six of 47 short children had growth hormone deficiency and in these cases both IGF-1 and IGFBP-3 were close to the lower limit or below the normal reference range. In young children ( < 10 yr) IGFBP-3 was more informative than IGF-1, distinguishing normal short children from those with growth hormone deficiency. IGF-1 levels were raised in all 10 acromegalic adults, eight of whom had normal levels of IGFBP-3. Similarly growth hormone deficient adults were better identified (23 of 26 patients) by IGF-1 whereas IGFBP-3 was subnormal in only eight cases. CONCLUSIONS: Provided results are reviewed in relation to an age related normal reference range, both IGF-1 and IGFBP-3 are simple and convenient screening tests for assessing growth hormone deficiency in children. In adults plasma IGF-1 is the diagnostic test for a disorder of growth hormone excess. Low IGF-1 in an adult with a history of pituitary disease strongly suggests the presence of growth hormone deficiency.

Acromegaly↗
PubMed1996

Dynamics of the regulation of the hypothalamo-pituitary-adrenal (HPA) axis determined using a nonsurgical method for collecting pituitary venous blood from horses.

Since 1985, we have applied our nonsurgical technique for collecting pituitary venous (PitVen) blood from ambulatory horses to investigate the regulation of adrenocorticotropic hormone (ACTH) secretion. This method offers particular advantages for studying the hypothalamo-pituitary-adrenal axis since its benign nature enables hypothalamic and pituitary interactions to be monitored without disturbing the animal, and the horse's large blood volume allows 3- to 4-ml samples to be collected as frequently as every 20s for prolonged periods so that the secretion patterns of ACTH and its secretagogues can be precisely defined. When PitVen blood was sampled every 20 or 30s during the circadian maximum, arginine vasopressin (AVP) and ACTH secretion patterns were complex and irregular, with mean interpeak intervals of approximately 5 min. Despite their erratic patterns, AVP and ACTH secretions were closely coupled on cross-correlation analysis. By contrast, PitVen corticotropin-releasing hormone (CRH) concentrations were low, relatively stable, and not consistently related to ACTH secretion. However, when cortisol negative feedback was reduced acutely by metyrapone infusion, CRH and AVP secretion were stimulated. Mathematical modeling suggested that CRH had become the more effective secretagogue and that much of the ACTH response was mediated by increased pituitary responsiveness to CRH. Elevated blood osmolality triggered synchronous AVP and ACTH secretion, without altering PitVen CRH. In this case, the source of PitVen AVP was presumably the magnocellular/neurohypophysial pathway, which is thought to respond primarily to changes in blood osmolality and pressure. Our results suggest that this pathway also participates in ACTH regulation. We have studied the effect of several perturbations and found, as have others, that the secretagogues released vary with the stimulus given. For example, vigorous exercise promptly raised PitVen AVP and ACTH, but not PitVen CRH. Hypoglycemia provoked both CRH and AVP secretions, with the CRH increment being inversely proportional to the glucose nadir. Administration of the opioid antagonist, naloxone, increased PitVen ACTH; however, changes in AVP and CRH were variable and overall could not account for the ACTH response. This suggests that endogenous opioids inhibit a third ACTH secretagogue, stimulate an inhibitory factor, or also act at the pituitary. Chronic social stress, induced by confining newcomers with aggressive, resident mares, caused most introduced horses to become submissive. In such horses, plasma cortisol declined to levels similar to those during metyrapone infusion. Despite hypocortisolemia, PitVen ACTH was low, whereas PitVen CRH tended to be elevated. Moreover, chronically stressed horses did not respond to exogenous CRH. We conclude that at rest and during some perturbations AVP is the immediate stimulus for ACTH release. Even ACTH micropulses, previously thought to occur spontaneously, appear to be regulated by AVP in horses. On the other hand, CRH secretion and pituitary responsiveness to CRH rise when cortisol falls, suggesting that a major role for CRH is to fix the cortisol setpoint. However, during chronic stress, these relationships become disturbed, with results to date pointing toward the existence of an ACTH-release inhibiting factor.

Adrenal Glands↗
PubMed1996

The effect of beta-endorphin on basal and insulin-hypoglycaemia stimulated levels of hypothalamic-pituitary-adrenal axis hormones in normal human subjects.

OBJECTIVE: It has been demonstrated that beta-endorphin reduces CRH production and hypoglycaemia-induced ACTH secretion in the rat. We aimed to determine whether supraphysiological levels of beta-endorphin inhibit the ACTH and CRH response to insulin-induced hypoglycaemia in human subjects. DESIGN: Plasma glucose, prolactin, cortisol, ACTH, CRH and AVP were measured at intervals over a 3-hour period. Intravenous beta-endorphin 5 mg/50 ml or an equal volume of normal saline was infused between 30 and 90 minutes, with soluble insulin 0.15 units/kg administered i.v. at 60 minutes in a cross-over design. SUBJECTS: Six healthy male volunteers aged 20-35 years. MEASUREMENTS: Prolactin was measured by a fluoroimmunometric assay, ACTH, CRH and AVP by radioimmunoassay, and cortisol was measured by enzyme-linked immunosorbent assay. Haemodynamic measurements were recorded prior to each blood sample. Results are expressed as mean +/- standard error of the mean. RESULTS: beta-Endorphin resulted in a significant decrease in baseline cortisol (P < 0.05) but not ACTH. Plasma glucose (P < 0.001) and CRH (P < 0.05) and PRL (P < 0.05) increased significantly during beta-endorphin compared to normal saline. After insulin administration, glucose reached a similar nadir during beta-endorphin and normal saline (2.1 +/- 0.1 and 1.9 +/- 0.15 mmol/l, respectively) but the fall in plasma glucose was delayed during beta-endorphin (P < 0.01 by ANOVA). This resulted in a significantly altered time-course for the ACTH and cortisol responses (P < 0.05 for each), but no difference overall in the magnitude of the response. In contrast, neither the timing nor the magnitude of the CRH and AVP responses were affected. Prolactin also reached a similar peak value after the administration of insulin, while the haemodynamic responses to hypoglycaemia were not significantly altered during beta-endorphin. CONCLUSIONS: While beta-endorphin has been shown to be inhibitory to basal ACTH and cortisol secretion in humans, we note a significant increase in plasma CRH in response to beta-endorphin, which may be arising from a peripheral source. Intravenous beta-endorphin increases plasma glucose and delays the onset of hypoglycaemia following insulin but does not result in significant inhibition of the ACTH and cortisol response. This may reflect the poor penetration of beta-endorphin into the central nervous system, although a hypothalamic effect of beta-endorphin is implied by the increased PRL. The significantly delayed time course in ACTH and cortisol secretion noted during beta-endorphin is not explained by a later response of either CRH or AVP. Although peripheral levels of these hormones may be a relatively insensitive measure of hypothalamic function, an additional factor may influence ACTH release during hypoglycaemia.

Adrenocorticotropic Hormone↗
PubMed1996

Plasma cortisol, PRL, ACTH, AVP and corticotrophin releasing hormone responses to direct current cardioversion and electroconvulsive therapy.

OBJECTIVE: We aimed to evaluate and contrast the hypothalamo-pituitary-adrenal (HPA) response to direct current (DC) cardioversion and electroconvulsive therapy (ECT). SUBJECTS: Six male subjects (mean age 61.2 years, range 46-74) with chronic atrial fibrillation were selected for cardioversion. Six subjects with depression (one male, five female; mean age 43.2 years, range 31-59) were selected for ECT. Those taking glucocorticoid drugs, opiates or beta-adrenoceptor antagonists were excluded. MEASUREMENTS: Patients attended for serial blood sampling on the day of cardioversion or ECT, and for an equivalent time period on a control day at least one week before. Intravenous propofol was given to each subject for anaesthesia on the day of cardioversion or ECT. On both study and control days, blood samples were taken at -30, -15, 0 (just prior to cardioversion or ECT), +5, +10, +15, +30, +60, +90 and +120 minutes for assay of cortisol, PRL, ACTH, AVP and CRH. RESULTS: For cardioversion: plasma cortisol increased from 252.5 +/- 39.8 to a maximum of 721.3 +/- 50 nmol/l at 30 minutes (P < 0.0001 compared with control day). ACTH increased from 12.8 +/- 2.8 to a maximum of 64 +/- 14 pmol/l at 5 minutes (P < 0.0001 compared with control day). AVP increased from 6.6 +/- 3.3 to a maximum of 42.9 +/- 16 pmol/l at 5 minutes post-cardioversion (P < 0.005 compared with control day). PRL increased from 141 +/- 28 mlU/l to a maximum of 873 +/- 219 mlU/l at 10 minutes (P < 0.001 compared with control day). There was no significant difference in CRH responses between cardioversion and control days. There was no significant correlation between total electrical energy delivered and maximum ACTH and AVP responses (R = 0.54 and -0.13, respectively). For ECT: on the day of ECT plasma cortisol increased from 419.5 +/- 25.9 to a maximum of 614.7 +/- 26.9 nmol/l (P < 0.002 compared with control day). ACTH increased from 22.7 +/- 6.2 to a maximum of 77.8 +/- 19.1 pmol/l (P < 0.0003 compared with control day). PRL increased from 771 +/- 317 to a maximum of 3152 +/- 703 mlU/l (P < 0.001 compared with control day, and significantly greater than the peak response to cardioversion, P < 0.03). AVP increased from 13.0 +/- 10.8 to a maximum of 35.1 +/- 5.6 pmol/l (P < 0.02 compared with control day). There was no significant difference in CRH responses between ECT and control days. Peak cortisol and ACTH responses did not differ significantly between ECT and cardioversion. Baseline cortisol levels, however, were significantly higher in the depressed group compared with the cardioversion group, P < 0.02, but not ACTH or AVP. CONCLUSION: Significant hypothalamic-pituitary-adrenal activation and PRL release occur in response to both cardioversion and ECT. AVP may have an important role in mediating the acute ACTH response to electrical stimulation.

Adrenocorticotropic Hormone↗
PubMed1996

Low-dose growth hormone replacement lowers plasma leptin and fat stores without affecting body mass index in adults with growth hormone deficiency.

OBJECTIVE: The ob gene product, leptin, is considered to be a marker of adipose tissue mass and a possible homeostatic regulator of body mass. Our objective was to examine the effect of GH replacement on adipose tissue stores and leptin in adult hypopituitarism. SUBJECTS: Twenty adults, mean age 47 years (range 20-69) with proven GH deficiency were randomly allocated to either GH (up to 0.25 U/kg/week in daily doses) or placebo for 3 months before cross-over to the opposite treatment. MEASUREMENTS: Body composition was measured by dual-energy X-ray absorptiometry (DEXA) in the whole body, trunk and limbs. Plasma leptin was measured by radioimmunoassay at baseline and +2, +4, +8 and +12 weeks in each treatment arm. RESULTS: Total body tissue fat (mean +/- SE) was 30.1 +/- 2.2% after GH compared with 31.9 +/- 2.2% after placebo, P < 0.001 (ANOVA). There were no significant changes in BMI (kg/m2), 29.1 +/- 1.3 after placebo vs 28.8 +/- 1.2 after GH; or waist to hip ratio (WHR), 0.91 +/- 0.01 after both placebo and GH. Baseline plasma leptin showed a significant correlation with baseline BMI, r = 0.67, P < 0.005 and baseline percentage total body fat, R = 0.89, P < 0.001. Plasma leptin (adjusted by using baseline percentage total body fat as a covariate) showed a significant linear decrease with time on GH compared with placebo (P = 0.03, ANOVA). CONCLUSIONS: Plasma leptin and total body fat fall promptly in response to low-dose replacement of GH in GH-deficient subjects. Hormone-induced changes in leptin can occur in humans in the absence of change in body mass index.

Adipose Tissue↗
PubMed1996

Adaptation of the hypothalamopituitary adrenal axis to chronic exercise stress in humans.

Repeated acute or chronic exposure to a particular stress results in adaptation whereby the hypothalamopituitary adrenal (HPS) axis becomes less responsive to subsequent or continued exposure to that particular stress. To investigate the adaptive changes that occur in the HPA axis in response to chronic stress in humans, we studied the effect of chronic exercise stress on basal activity of the HPA axis in six highly trained male ultramarathon athletes and six healthy male controls matched for body mass index. After 3-5 of abstention from intense physical activity, the subjects were admitted to a metabolic study ward at 1600 h. Peripheral blood was sampled initially at 0300 h, at 20-min intervals from 0400 to 0900 h, hourly from 0900 to 1200 h, and then every 2 h from 1200 to 1600 h. A 24-h urine collection was completed during the admission. Peripheral blood adrenocorticotropic hormone (ACTH) was measured by radioimmunoassay. Plasma and urinary cortisol were measured by enzyme-linked immunoassay. Plasma and injury cortisol were measured by enzyme-linked immunosorbent assay (ELISA). Plasma ACTH and cortisol levels showed the expected diurnal change in athletes and control subjects (P = 0.00001). However, the early morning ACTH and cortisol surge occurred earlier in the athletes than in the controls (P = 0.026). Plasma ACTH levels were significantly higher in the athletes than in the control subjects (P = 0.0026). There was, however, no significant overall difference in plasma cortisol levels between the athletes and the control subjects, and urinary excretion of free cortisol was similar in the two groups. These data show that intense physical training leads to adaptive changes in basal HPA function, including a phase shift and increased pituitary in basal HPA function, including a phase shift and increased pituitary ACTH secretion, but also blunting of the adrenal cortisol response.

Adaptation, Physiological↗
PubMed1996

The integrative control of adrenocorticotrophin secretion: a critical role for corticotrophin-releasing hormone.

Perifused equine anterior pituitary cells were used to investigate the relationships between the secretion of ACTH and substances known to either stimulate (corticotrophin-releasing hormone (CRH), and arginine vasopressin (AVP)) or inhibit (cortisol) ACTH secretion. The experiments were designed to mimic the hormone milieu present in vivo in the horse, with cortisol (0 or 100 nmol/l) and CRH (0 or 0.02 nmol/l) perifused continuously, and pulses of AVP (10 nmol/l) applied for 5 min at 30-min intervals. In columns perifused with 0.02 nmol CRH/l there was no significant overall effect of 100 nmol cortisol/l on the ACTH responses to pulses of AVP, although there was a significant interaction between AVP pulse number and cortisol showing that ACTH total area (pmol ACTH proportional to area under response curve) in response to AVP pulses 1 and 2 was significantly (P < 0.05) decreased in columns perifused with 100 nmol cortisol/l. However ACTH incremental area (pmol ACTH proportional to the area above the CRH-induced baseline) was not affected by cortisol at any AVP pulse. This contrasts with the effect of cortisol in columns perifused with 0 nmol CRH/l, where 100 nmol cortisol/l significantly decreased ACTH total area (P = 0.0075) and incremental area (P = 0.049) at all AVP pulses compared with the responses in columns receiving 0 nmol cortisol/l. There was a fall off in ACTH responsiveness with time during the experiment which, in the presence of 0.02 nmol CRH/l, was significantly (P < 0.001) greater with 0 nmol cortisol/l than with 100 nmol cortisol/l and if 6 (rather than 3) pulses of AVP were given, whereas with 0 nmol CRH/l there was no difference in the fall off with time between columns receiving 0 and 100 nmol cortisol/l. These results show that the control of ACTH secretion is influenced not only by independent action of secretagogues such as CRH and AVP, or inhibitors such as cortisol, but by a complex interaction of these factors with one another. CRH may have a role in 'protecting' the ACTH response to pulses of AVP in the presence of cortisol. It follows that, in vivo, 'background' CRH could allow an increase in ACTH in response to AVP released by a new stress, despite the presence of elevated cortisol.

Adrenocorticotropic Hormone↗
PubMed1995

Central C-type natriuretic peptide augments the hormone response to hemorrhage in conscious sheep.

The effect of intracerebroventricular infusions of C-type natriuretic peptide (CNP-22, 5 micrograms/h for 3 h) or vehicle on the neurohumoral response of conscious sheep (n = 7) to acute moderate hemorrhage (15 ml/kg in 15 min performed 1 h after start of CNP) was studied. CNP alone (prehemorrhage) induced a transient rise (after 30 min) in heart rate (p = 0.0005), plasma aldosterone (p = 0.007), ACTH (p = 0.049), and cortisol (p = 0.049), with values returning to control levels immediately prehemorrhage. Hemorrhage caused arterial pressure to fall (15 mmHg) and heart rate to rise similarly on both study days. Compared with vehicle, posthemorrhage responses of AVP (p = 0.05) and cortisol (p = 0.004) were greater during CNP. Thus, central CNP-22 augmented the hypothalamic-pituitary-adrenal axis at baseline and in response to hemorrhage in conscious sheep.

Animals↗
PubMed1995

The effects of alcoholism on the hypothalamic-pituitary-adrenal axis: interaction with endogenous opioid peptides.

BACKGROUND: Abnormal baseline hypothalamic-pituitary-adrenal axis function and dexamethasone suppressibility seen in withdrawing alcoholics returns to normal on abstinence, but some studies report blunting of the ACTH response to CRH persisting during the early abstinence phase. Reduced central levels of endogenous opioid peptides have been postulated to have an aetiological role in alcohol addiction. AIMS: To evaluate hypothalamic-pituitary-adrenal axis function in a group of recently abstinent alcoholics using basal hormone data, naloxone (an opioid receptor antagonist), and ovine CRH. SUBJECTS: Nine alcoholics (age 41.4 +/- 3.1 years) studied more than one week after the acute withdrawal period but within 6 weeks of cessation of drinking, and nine age and sex matched non-alcoholic controls. PROTOCOL: Cortisol, ACTH, CRH and AVP levels were measured every 20 minutes for 2 hours between 0900 and 1100h Twenty mg naloxone i.v. was administered at 1100h (0 minutes) and further samples for the above hormones were taken at 15, 30, 45, 60, 90 and 120 minutes. On a separate occasion, again at 1100h, oCRH 1 microgram/kg (n = 7 alcoholics, n = 6 controls) was administered, with samples for cortisol, ACTH and AVP taken at the same times. STATISTICS: Results were examined by analysis of variance for repeated measures (ANOVA), while incremental hormone response and area under the secretory curve (AUC) in alcoholics versus controls were compared by the two-tailed Student's t-test. Linear regression analysis was carried out to examine the relation between basal cortisol and hormone responses to naloxone and oCRH. RESULTS: Basal hormone levels did not differ between the groups. The alcoholics had a blunted ACTH incremental response to naloxone (11.4 +/- 3.0 vs 21.1 +/- 2.5 pmol/l, P < 0.05) but the cortisol response was not significantly different (205 +/- 51 vs 305 +/- 42 nmol/l, P = 0.15). The alcoholics also had a blunted ACTH incremental response to oCRH (28.7 +/- 4.2 vs 41.2 +/- 3.7 pmol/l, P = 0.052) and by ANOVA a significant main effect of group (alcoholic vs control) was seen (P < 0.02) for the ACTH response to oCRH. There was no difference between the groups in the cortisol incremental response to oCRH. In the control subjects, a negative correlation was found between basal cortisol and the cortisol increment (r = -0.82, P < 0.05) and ACTH increment (r = -0.81, P = 0.052) following oCRH, while in contrast, basal cortisol correlated positively with cortisol increment (r = 0.72, P < 0.05) following naloxone. There was also a trend for basal cortisol to correlate positively with ACTH increment following naloxone in the controls (r = 0.63, P < 0.07). In the alcoholics, the normal negative effect of basal cortisol on the cortisol increment after oCRH was reversed, with a positive correlation between basal cortisol and cortisol increment (r = 0.75, P = 0.05). CONCLUSIONS: Recently abstinent alcoholics with normal basal HPA axis hormone levels have a blunted ACTH response to naloxone and oCRH. While reduced levels of central endogenous opioid peptides may be a factor in the blunted ACTH response to naloxone in the alcoholics, it is proposed that the alcoholics have reduced pituitary responsiveness to CRH. This may be via a direct pituitary effect of the chronic ethanol exposure or by a reduction in hypothalamic-hypophyseal vasopressin levels.

Adrenocorticotropic Hormone↗
PubMed1995

The acute effects of oral ethanol on the hypothalamic-pituitary-adrenal axis in normal human subjects.

OBJECTIVE: To evaluate the acute effects of oral ethanol on the hypothalamic-pituitary-adrenal axis in normal human subjects and, in particular, to examine the effect of background alcohol intake and gastrointestinal side-effects on this response. DESIGN: Plasma ethanol, cortisol, ACTH, corticotrophin-releasing hormone (CRH) and AVP were measured half-hourly for 4 hours following 1.1 ml/kg of 95% ethanol or placebo in a cross-over study. At least one week elapsed between each procedure. SUBJECTS: Twelve healthy non-alcoholic volunteers with a wide range of background alcohol intakes. MEASUREMENTS: Peptide hormones were measured by radioimmunoassay, cortisol by ELISA and blood ethanol by headspace gas chromatography. Results are expressed as mean +/- SEM. RESULTS: Blood ethanol levels peaked at one hour post ethanol ingestion. Three subjects developed significant gastrointestinal (GI) side-effects, with two vomiting and one experiencing moderate to severe nausea. There was no difference between peak blood ethanol levels in the groups with and without GI side-effects (34.5 +/- 2.4 mmol/l vs 34.3 +/- 1.7 mmol/l respectively). ACTH and cortisol rose in those subjects who experienced GI side-effects (P < 0.0001 for each). The remaining subjects had a tendency for ACTH and cortisol to be higher on the placebo day. The group with GI side-effects following ethanol administration had a significant rise in AVP (P < 0.02) that was synchronous with ACTH and cortisol. No consistent alcohol related changes were seen in peripheral CRH levels, although there was a significant increase over time on both active and placebo days (P < 0.0001). In the group with no GI side-effects, AVP did not significantly fall in the first half hour following ethanol, while a significant fall did occur following placebo (P < 0.05). Plasma renin activity was, however, increased by ethanol (P < 0.05). The background alcohol intake of the group with GI side-effects was significantly lower than the group without (18 +/- 7 vs 235 +/- 51 g/week, P < 0.05), but no hormonal response was seen in two subjects with a relatively low alcohol intake (< 100 g/week) who did not experience GI side-effects. CONCLUSION: Intoxicating levels of ethanol per se do not result in activation of the hypothalamic-pituitary-adrenal axis in humans. However, gastrointestinal side-effects induced by the ethanol do result in such activation, which appears to be mediated by AVP as the dominant ACTH secretagogue. One of the factors which influences the blood ethanol level at which GI side-effects occur appears to be background alcohol intake.

Adrenocorticotropic Hormone↗
PubMed1995

A comparison of the naloxone test with ovine CRH and insulin hypoglycaemia in the evaluation of the hypothalamic-pituitary-adrenal axis in normal man.

OBJECTIVE: It has been suggested that naloxone might be useful in clinical testing of the hypothalamic-pituitary-adrenal (HPA) axis. We have therefore evaluated this non-selective opioid receptor antagonist, as a test of HPA axis function, and compared the results to ovine corticotrophin-releasing hormone (oCRH) and the insulin tolerance test (ITT). DESIGN: Following i.v. administration at time zero of naloxone 20 mg (n = 12) on day 1, and either oCRH 1 microgram/kg (n = 6) or soluble insulin 0.15U/kg (n = 6) on day 2, venous blood was sampled at times 120, 0, 15, 30, 45, 60, 90 and 120 minutes for cortisol, ACTH and AVP. Peripheral CRH was also measured following naloxone and insulin hypoglycaemia. SUBJECTS: Twelve normal males (age 20-57 years) with no history of hypothalamic-pituitary-adrenal axis disease. MEASUREMENTS: Peptide hormones in plasma samples were measured by radioimmunoassay and cortisol by ELISA. Results are expressed as mean +/- SEM. RESULTS: Following naloxone, there was a highly significant overall rise in ACTH (P < 0.0005) and cortisol(P < 0.0001), but 1 out of the 12 subjects failed to respond. This subject had a normal ACTH and cortisol response to oCRH, indicating normal pituitary-adrenal function. Peripheral levels of CRH also increased significantly following naloxone (P < 0.002), while AVP did not alter significantly (P = 0.38). Maximal levels of CRH were seen following the ACTH peak however, at a time when ACTH was returning to baseline. All six subjects who received oCRH had an increase in ACTH and cortisol, and the ACTH response to oCRH was greater that that to naloxone (P < 0.05). One subject who developed nausea and hypotension following oCRH had a large rise in AVP and very high levels of ACTH and cortisol. Following insulin each subject had symptomatic hypoglycaemia and significant rises in cortisol (P < 0.0001), ACTH (P < 0.0001), AVP (P < 0.0005) and CRH (P < 0.01) were seen. Both cortisol and ACTH responses to ITT were significantly greater than those to naloxone (P < 0.05 for each). CONCLUSION: The HPA axis response to naloxone is smaller in magnitude overall compared to oCRH or insulin hypoglycaemia and is variable in normal subjects. This variability probably reflects changes in central opioid tone rather than alterations in pituitary responsiveness to CRH. It is unlikely that the naloxone test will replace currently used clinical tests of HPA axis function, particularly in the setting of a possible ACTH deficiency, because some subjects wit ha normal HPA axis appear not to respond to naloxone. As the mechanism involved in the ACTH response to naloxone has not yet been defined with certainty, the naloxone test should not be regarded simply as a test of endogenous CRH release.

Adrenocorticotropic Hormone↗
PubMed1995

Elevated basal adrenocorticotropin and evidence for increased central opioid tone in highly trained male athletes.

Basal cortisol and ACTH levels have previously been shown to be elevated in highly trained athletes, whereas the ACTH response to ovine CRH has been reported to be diminished compared to that in nonathletic controls. Naloxone, a nonselective opioid receptor antagonist, is known to stimulate ACTH and cortisol secretion. The mechanism of this response is thought to be via increased hypothalamic CRH secretion. The aim of this study was to examine basal and naloxone-stimulated levels of hypothalamic-pituitary-adrenal axis hormones in male athletes. Ten highly trained male athletes and 10 nonathletic controls took part in the study. Peripheral venous blood was sampled for cortisol, ACTH, CRH, and arginine vasopressin (AVP) for 2 h before the administration of 20 mg naloxone, i.v., and 15, 30, 45, 60, 90, and 120 min after naloxone treatment. Body mass index was significantly lower in the athletes (P < 0.001). Basal (prenaloxone) ACTH levels were higher in the athletes (P < 0.05), whereas levels of cortisol, CRH, and AVP were similar in both groups. After naloxone treatment, there was a significantly greater rise in ACTH in the athletes (P < 0.02). There was also a trend for the cortisol response to be greater, which was not statistically significant (P < 0.07). Although in both groups, peripheral CRH rose after naloxone treatment (P < 0.005), a rise of similar magnitude occurred over the 2-h period before naloxone (P < 0.0001). Plasma AVP did not change significantly after naloxone treatment. Neither the plasma cortisol level at baseline nor the body mass index correlated significantly with the ACTH or cortisol response to naloxone. The presence of an enhanced ACTH response to naloxone is evidence that central opioid tone may be increased in highly trained athletes. However, there is no associated suppression of the hypothalamic-pituitary-adrenal axis, and basal ACTH levels are raised, without any detectable change in peripheral plasma CRH or AVP. An additional factor (other than CRH) that stimulates ACTH secretion may be released after naloxone administration.

Adrenocorticotropic Hormone↗
PubMed1994

Bone mineral density is reduced in female but not male subjects with Addison's disease.

AIMS: Bone mineral density (BMD) may be potentially reduced in Addison's disease as a result of excessive glucocorticoid replacement, loss of adrenal androgens or concomitant gonadal or thyroid disease. We have examined clinical and biochemical parameters, and BMD in a group of subjects with Addison's disease. METHODS: Fourteen patients (9 female mean age 56 years, 5 male mean age 56.6 years) with primary adrenocortical failure (median duration 8.5 yrs) on replacement therapy were studied. Four had hypothyroidism on thyroxine doses (0.1 to 0.15 mg/d). Seven of the 9 females were post menopausal. Mean plasma cortisol levels were calculated from at least five samples in each subject drawn between 3 and 5 hours post dose, and the cortisol replacement dose calculated per unit body mass (mg/kg). BMD was measured by dual energy X-ray absorptiometry (DEXA) at femoral neck and lumbar spine (L2-4) and compared with local reference data. RESULTS: For women (n = 9) at L2-4 the mean Z score was -1.21 (95% CI -1.69, -0.73), and at femoral neck -0.57 (95% CI -1.15, 0.00). For men (n = 5) at L2-4, the mean Z score was 1.32 (95% CI -0.86, 3.50) and at femoral neck 0.62 (95% CI -0.18, 1.42). For all patients, there was no significant correlation between mean plasma cortisol and Z scores at L2-4 and femoral neck, r = -0.003 and -0.095 respectively; and between duration of Addison's disease and mean Z scores at L2-4 and femoral neck r = -0.043 and 0.143 respectively. CONCLUSIONS: Women with Addison's disease therefore have a greater than expected reduction in BMD. We postulate that this may be related to loss of adrenal androgens.

Absorptiometry, Photon↗
PubMed1994

The plasma interleukin-6 and stress hormone responses to acute pyelonephritis.

The relationships between the "stress hormones" corticotrophin (ACTH), vasopressin (AVP), corticotrophin releasing hormone (CRH) and cortisol, and the cytokines, interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor were studied during an acute infection. Ten patients (7 female, 3 male, age range 16-56 years) with acute pyelonephritis and normal renal function were studied during the first 72 hours following hospital admission. Peptide hormones were measured by radioimmunoassay, cortisol and cytokines by ELISA. Reference ranges for all hormones were from samples donated by 40 or more volunteers from the electoral roll. The reference data for IL-6 was obtained from 20 normal donor sera. The mean plasma IL-6, AVP and CRH concentrations on admission to hospital were significantly raised above the mean 08:00h values of the normal volunteers (p < 0.001 for AVP and CRH, p < 0.01 for IL-6), but mean plasma ACTH and cortisol were not. Mean plasma IL-6 and AVP were raised more than two standard deviations above the mean of the reference range for 72 hours, although IL-6 tended to fall after 24 hours. No change in plasma IL-1 and tumour necrosis factor was observed in three patients. The correlation between plasma IL-6 and cortisol concentrations at all sampling times and in all subjects was highly significant (p < 0.001). Significant correlations between plasma IL-6 and AVP (p < 0.005), and IL-6 and ACTH (p < 0.05) were also observed. No correlation between IL-6 and CRH could be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗