R. A. Donald

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.

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.

The plasma ACTH, AVP, CRH and catecholamine responses to conventional and laparoscopic cholecystectomy

OBJECTIVES We compared the responses of the stress hormones, Cortisol, ACTH, vasopressin (AVP), corticotrophin releasing hormone (CRH) and catecholamines to elective conventional and laparoscopic cholecystectomy.

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 horses 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.

Arginine vasopressin is associated with hypercortisolemia and suicide attempts in depression

Activation of the hypothalamic–pituitary–adrenal (HPA) axis is commonly seen in patients suffering from depression (Charlton and Ferrier 1989). Raised plasma concentrations of cortisol may be present (Butler and Besser 1968; Deuschle et al 1997), along with increased 24-hour urinary free cortisol levels (Carroll et al 1976). Detailed analysis of plasma adrenocorticotropic hormone (ACTH) reveals an increase in pulse frequency (Mortola et al 1987; Deuschle et al 1997). In approximately 40–50% of all patients with depression, plasma cortisol is not normally suppressed by dexamethasone (Arana et al 1985). The mechanism of the hypercortisolemia is believed to be related to increased hypothalamic secretion of corticotropinreleasing hormone (CRH) (Charlton and Ferrier 1989; Licinio and Gold 1991), and increased adrenal sensitivity to ACTH (Charlton and Ferrier 1989). Since most studies of the HPA axis in depression concentrate on CRH as the predominant ACTH secretagogue, there are relatively few data concerning the role of arginine vasopressin (AVP), which is also a potent stimulus to ACTH secretion (Gillies et al 1982). The aim of this study was to determine whether there was any relationship between afternoon plasma levels of cortisol, ACTH, and AVP in depressed subjects, particularly in those displaying biochemical hypercortisolemia. We also sought to determine if any relationship existed between severity of depression and suicidal behavior and activation of the HPA axis.

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 oplold peptides have been postulated to have an aetiological role In alcohol addiction.

Plasma corticotrophin releasing factor and vasopressin responses to exercise in normal man

Summary. objective To evaluate the hypothalamo‐pitultary‐adrenal (HPA) response to both mild and Intense exercise.

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.

PLASMA CORTICOTROPHIN‐RELEASING FACTOR AND VASOPRESSIN RESPONSES TO HYPOGLYCAEMIA IN NORMAL MAN

The plasma Cortisol, ACTH, AVP and corticotrophin‐releasing factor (CRF) responses to insulin‐induced hypoglycaemia were investigated in six normal men using a controlled, randomized, cross‐over design. Hormonal concentrations were determined following insulin or saline injection. The maximum Cortisol response was seen at 90 min while plasma ACTH, AVP and CRF concentrations peaked at 45 min following insulin injection. The responses of the insulin‐treated and control groups were compared by assessing the incremental response from baseline (pre‐injection) to peak hormone levels. A significant increase was observed for each hormone following insulin injection. The mean of the incremental responses between 30 and 120 min in each subject was also statistically greater for each hormone in the insulin‐treated group when compared with the control group. These results are consistent with the hypothesis that AVP and CRF are both physiological mediators of ACTH secretion induced by a hypoglycaemic stress.

Neurohormonal response to head-up tilt and its role in vasovagal syncope.

In a controlled study, 26 patients with a history of recurrent syncope were found to have increased arginine vasopressin, corticotrophin, and atrial natriuretic factor levels after 5 minutes of 60 degrees head-up tilt, long before they became hypotensive. The exaggerated neurohormonal response in these patients may indicate a greater sensitivity to central hypovolemia which may predispose to vasovagal syncope, mediated by the vasodilatory effects of atrial natriuretic factor or the sensitization of mechanoreceptors by arginine vasopressin.