The diurnal variations in plasma ACTH levels were concordant with those of cortisol in the two groups. However, unlike cortisol, plasma ACTH levels were significantly higher in the athletes than in the control subjects (main effect for group, P = 0.0026).
In highly trained male ultramarathon runners, compared to control subjects, we demonstrated a phase shift in the early morning increase in activity of the HPA axis and elevated peripheral plasma ACTH levels, without increase in peripheral plasma levels of cortisol or in 24-h urinary cortisol excretion. It is unlikely that we are seeing persistent activation of the HPA axis due to the effects of the marathon, as indices of HPA axis activity are reported to return to baseline within 24 h of a marathon (6).
To our knowledge a phase shift in activation of the HPA axis in athletes compared to controls has not been reported previously. The group of athletes studied, all amateur ultramarathoners, regularly arose early (0400-0500 h) to train before going to work, compared to the control subjects, who arose between 0630 h and 0800 h. Light clearly has a major synchronizing effect on human circadian rhythms (11). While it is possible that the phase shift is due to the differences in light exposure in the two groups, nonphotic cues also influence circadian rhythms in humans. For example, human rhythms in continuous darkness may be entrained by a rigorous schedule of bedtimes, mealtimes, and performance tasks (1). Furthermore, it has recently been shown that exercise itself can result in phase shifts of the human circadian clock (28).
In this study we chose to measure ACTH primarily during the diurnal activation of the HPA axis in order to determine the relationships between ACTH and cortisol at that time. Plasma ACTH levels were higher in the athletes than in the controls at all times during the entire 13-h period of sampling, including the late afternoon. Although we do not know whether these relationships would be maintained at the nadir of the circadian rhythm, the mean plasma cortisol levels, at least, are likely to be similar between the two groups since 24-h urinary cortisol levels did not differ.
While persistently elevated ACTH levels in the athletes indicate activation of the HPA axis, neither plasma nor urinary free cortisol levels were significantly different between the groups. Since exercise has not been shown to have any significant effect on cortisol-binding globulin (CBG)(23,29) or on the clearance rates of cortisol(29), it seems most likely that there is a reduced adrenal sensitivity to ACTH. This has previously been suggested in trained humans (18,25). Furthermore, it has recently been shown that cortisol responses to exercise in amenorrheic runners are blunted at the adrenal level (8).
Elevated basal plasma ACTH levels without increased cortisol levels have previously been reported in ultramarathon athletes compared to controls, although these observations were based on single prerace plasma samples(25). Luger et al. (22) reported elevated basal plasma ACTH and cortisol levels in highly trained subjects compared to controls. However, this observation was based on two plasma samples 15 min apart in the evening, and 24-h urinary free cortisol data were not available. In contrast to our findings, Loucks et al.(21) found no difference in plasma ACTH levels or ACTH pulsatility over 24 h in either eumenorrheic or amenorrheic women compared to sedentary controls. Overall cortisol secretory dynamics and 24-h urinary excretion in eumenorrheic athletes were similar to those of control subjects. On the other hand, amenorrheic athletes had persistent elevation of plasma cortisol throughout the 24-h sampling period and increased 24-h urinary cortisol excretion, suggesting a closer association of hypercortisolism with amenorrhea than with exercise itself. Similar findings of hypercortisolism in amenorrheic but not eumenorrheic athletes have been reported by others(8). However, increased cortisol production in eumenorrheic as well as amenorrheic runners has also been reported(29). In addition to menstrual status, increased basal activation of the HPA axis may correlate better with type of exercise and duration of training (5,8,14) rather than physical conditioning as such, suggesting that other factors may be important in the persistent activation of the HPA axis noted in some athletes. Recently, the promoter region of the corticotropin-releasing hormone gene was demonstrated to contain an estrogen response element, and sexual dimorphism in the regulation of the HPA axis has been described (26). Therefore, sexual dimorphism in the adaptation to chronic stress may also occur.
Hypercortisolemia may in fact reflect failure of adaptation of the HPA axis to exercise, and HPA axis dysfunction has been shown to be a feature of overtraining rather than intensive training in itself(2). Compulsive running has been suggested to be an analogue of anorexia nervosa (32), and some highly trained runners, as well as anorectic and depressed patients, may represent subjects in whom different stressors (excessive running, perceived environmental changes, weight loss, or emotional stress) may exceed a putative threshold, leading to sustained hypercortisolism(22).
The occurrence of adaptive responses of the HPA axis to training in humans is also suggested by studies showing that the response of the HPA axis to acute exercise to the same absolute workload is attenuated by physical training (4,18,22). Luger et al.(22) have shown convincingly that this is the consequence of a decreased ˙VO2max and have suggested that the altered responsiveness to acute exercise stress is the consequence of changes in afferent input to the HPA axis. The mechanism by which changes in baseline activity of the HPA axis occur in response to training is not known. Possible mechanisms include reduced adrenal responsiveness(7,18,25) and decreased sensitivity to the negative glucocorticoid feedback signal (14). The results of the current study suggest reduced adrenal responsiveness, since decreased sensitivity to glucocorticoid negative feedback would be expected to result in increased levels of plasma cortisol as well as ACTH.
The reason why reduced adrenal responsiveness to ACTH should occur in response to chronic exercise but not other states of ACTH excess is not clear. However, a number of factors, including corticotropin-releasing hormone(27), vasoactive intestinal polypeptide(3), and splanchnic nerve activity(12), have been shown to affect adrenal responsiveness to ACTH. Splanchnicectomy reduces the adrenal sensitivity to exogenous and endogenous ACTH (12). The splanchnic nerve carries both sympathetic and parasympathetic innervation to the adrenal gland. Norepinephrine has been found in nerve fibers and terminals within the adrenal cortex (24) and has been shown to stimulate corticosteroid secretion (30). Trained athletes have been shown to have lower plasma noradrenaline levels than those who become overtrained (15). Therefore, training-induced alterations in splanchnic nerve activity may account for reduced responsiveness of the adrenal to ACTH. An alternative explanation for the disparity between the elevated ACTH levels but normal cortisol levels in the athletes might be that the ACTH has reduced bioactivity. It is not known whether excessive exercise modifies the processing of the propiomelanocortin(POMC) message. In this study we measured ACTH by radioimmunoassay; however, we used an immunoradiometric assay to confirm our findings in a separate group of athletes (16).
Taken together these findings suggest that the normal adaptive response of the HPA axis to chronic exercise stress includes enhanced ACTH secretion but attenuated adrenal response, possibly to protect from the deleterious effects that may occur from sustained hypercortisolemia. Maladaptive responses rather than exercise per se may be responsible for the hypercortisolemia that occurs in such syndromes as the amenorrhea of exercise, hypogonadism in males, and the overtraining syndrome, which have similarities to the pathophysiological changes of anorexia and depression.
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ULTRAMARATHON; ACTH; CORTISOL; ADAPTATION