A. Viru M.

Viru

Cortisol Essential Adaptation Hormone in Exercise

Physiology & Biochemistry

In 1986 Adlercreutz and coworkers [1] focused attention to the ratio testosterone/cortisol. They proposed using the ratio between free testosterone and cortisol as an indication of overstrain if the ratio decreases more than 30 % or if the ratio is less than 0.35 103. This way, an extreme situation in the balance of anabolic and catabolic stimuli may be detected. However, the proposed quantitative measure was later forgotten and any decrease in the ratio was considered as a bad indication including an association with overtraining. Attention has not paid to the fact that Adlercreutz et al. [1] considered free but not total testosterone concentration in the blood. Moreover, Adlercreutzs team focused on the overreaching rather than overtraining. Actually, in a number of studies the decreased ratio was associated with improved performance of athletes [17, 32]. In high-level rowers, the cortisol response to all-out exercise increased in conjunction with improved performance during a training year [28]. The purpose of the present editorial is to comment the actual significance of cortisol in exercise and to correct several misunderstandings in evaluation of cortisol responses in athletes.

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Protein synthesis is controlled at three levels: pre-translation level (induction), translation level, and post-translation level [2]. The post-translation control consists of adjusting the number of protein molecules to the actual need. Specific protein catabolism is also necessary for this task. The contribution of the cortisol catabolic effect is not excluded in the post-translation control as well as in all other needs for catabolism. The metabolic control is actualized by the interplay of various hormonal and metabolic factors. The integral whole of these related influences determine the resultant change in metabolic processes. It is not wise to make conclusions based only on a description of changes in the level of a single hormone.

Affiliation Institute of Exercise Biology, University of Tartu, Estonia Correspondence A. Viru Institute of Exercise Biology, University of Tartu Ylikooli 18 Tartu 51041 Estonia E-mail: atko.viru@ut.ee Accepted after revision: May 12, 2004 Bibliography Int J Sports Med 2004; 25: 461 464  Georg Thieme Verlag KG Stuttgart New York DOI 10.1055/s-2004-821068 ISSN 0172-4622

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Classical studies of H. Selye [27] on the general adaptation syndrome evidenced involvement of the adrenal cortex in adaptation processes. Accordingly, cortisol has been nominated as the adaptation hormone. However, during the past 15 20 years several researchers in exercise physiology and sports medicine have had the opinion that the decreased ratio of testosterone/cortisol indicates a predominance of catabolism that is undesirable for adaptation and improvement of performance in athletes. In their opinion, an increased cortisol concentration is guilty of association with maladaptation.

Cortisol Function
This hormone has a wide spectrum of tasks in metabolic control (Fig. 1). Indeed, activation of catabolic processes and anti-anabolic action are included. However, these are essential tools for adaptation in the stress situation. The adaptive significance of catabolic changes consists, first of all, in creation of an increased pool of free amino acids. Therefore, branched chain amino acids can be used as additional substrate of oxidation. Moreover, free amino acids are available as building blocks for protein synthesis. Synthesis of several ultimately needed proteins is necessary during stress situation (including exercise), but it will be the dominating process during the late recovery period. Among metabolic inductors are those, which are produced in protein degradation (see Mader [20]). Catabolic processes continue also during the recovery period [35] ensuring the destruction of physiologically exhausted elements of protein structures in order to make possible their substitution by newly synthesized proteins.

CORTISOL Protein Metabolism

Protein degradation Anti-anabolic action (connective tissue, smooth muscle, resting skeletal muscle) (connective and muscle tissues) Pool of free amino acids Protein synthesis (liver)

Fig. 1 Main effects of cortisol in metabolic control.

Inhibition of Inflammatory Processes Immunity and Immuno Activities

Involution of lymphoid tissue, decreased output of T-cells and antibodies

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Permissive Action
Conditions for cAMP accumulation

During exercise, the catabolic changes in skeletal muscles are expressed by the accumulation of free tyrosine and 3-methylhistidine [5]. In the most active muscles and muscle fibers concentrations of free tyrosine and 3-methylhistidine increase by only a small amount if at all, compared to less active ones [33]. These results indicate that contractile activity may defend muscle tissue from exaggerated catabolism. Since 3-methylhistidine is released during degradation of myosin and actin, the lack of accumulation of this metabolite in active muscles shows that the contractile apparatus has been specially defended. In resting conditions, administration of glucocorticoids results in pronounced catabolic changes in various tissues, including skeletal muscle. However, during exercise the catabolic effects of administered glucocorticoids are inhibited in skeletal muscle [11, 25].

nucleus. Here the complex modulates gene expression related to stimulation or inhibition of specific mRNA production. In various situations, the cascade of processes constituting the hormone action, may be either up- or down-regulated [7]. Therefore, the effects of the hormone depend not only on the amount of hormone molecules available, but also on the state of receptors (number of binding sites, affinity of binding to hormone). Moreover, at the receptor level competition may exist between various hormones for binding sites of a hormone receptor. The competition between cortisol and testosterone for glucocorticoid binding sites determine the anti-catabolic action of testosterone and for the androgen receptors the anti-anabolic action of cortisol [23]. Hickson et al. [12] demonstrated that during training the affinity of muscle androgen receptors for glucocorticoids decreased in association with the reduced glucocorticoid catabolic action. The interplay of these various actions raises the question of whether cortisol is ultimately essential in metabolic control during exercise, although cortisol effects are convincing in resting conditions. Studies on adrenalectomized rats show that when exercise was performed in conditions of insufficiency of adrenocortical hormones, alanine-aminotransferase activity is low both in skeletal muscles and liver [41]; furthermore, alanine [41] and

Mechanisms of Cortisol Action

Most effects of steroid hormones, including cortisol, are actualized by specific induction of synthesis of related enzyme proteins. Therefore, the steroid hormone has to penetrate into the cell, bind to a cytoplasmic receptor protein, and the formed steroid-receptor complex has to be activated and translocated to

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Physiology & Biochemistry

Glucose-Alanine Cycle Gluconeogenesis

Alanine synthesis (skeletal muscle) Alanine desamination (liver) Glucose production (liver) Urea synthesis (liver)

An important function of glucocorticoid is the induction of enzymes of catecholamine synthesis, mainly the synthesis of phenyl-ethanolamine-N-methyl transferase that catalyzes the methylation of noradrenaline to adrenaline [24]. Rat experiments showed that decreased concentration of corticosterone in blood after prolonged swimming associated with disorders in adrenaline formation. Administration of cortisol in vivo before swimming or in vitro during incubation of adrenal glands isolated after swimming restored the ability of the adrenals to synthesize adrenaline [22]. Experiments on adrenalectomized rats confirmed also that the glucocorticoid effect on work capacity is related to protein synthesis. When RNA synthesis and thereby also protein synthesis were blocked by treatment with actinomycin D, cortisol administration no longer restored work capacity in adrenalectomized rats [38]. The metabolic effect of cortisol mediated through formation of a steroid-receptor complex is a time-consuming process. The metabolic effects of cortisol appear after a lag-period that is in some cases about half an hour, in other cases more than an hour. Therefore the product-moment correlations between cortisol levels and metabolic parameters measured at the same time points do not have any physiological meaning.

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Permissive Action
In 1952, Ingle [13] indicated that in several cases the availability of a hormone might be necessary for a certain metabolic effect, although the hormone does not contribute directly to triggering the metabolic effect. He proposed to use the term permissive action of the hormone in these cases. Glucocorticoids exert a typical permissive action on metabolic changes, which are evoked by accumulation of cAMP in target cells [8,10]. This action is founded on the glucocorticoid effects on either calcium

In short-term exercise the blood level of cortisol increases if the exercise intensity is above a certain threshold [34]. This threshold increases with endurance training and therefore at the same absolute exercise intensity the cortisol response may be lower or may disappear entirely [34]. However, with supramaximal exercise of overthreshold intensities the cortisol response is especially pronounced in endurance trained persons [29, 34]. During prolonged exercise, the cortisol response is variable [40]. The most frequent variant of cortisol dynamics is the initial increase that is substituted by a decrease to pre-exercise or lower levels after 20 30 min. During the second hour of exercise a secondary increase in the blood cortisol concentration occurs. The mechanisms triggering the initial and the secondary increase of blood cortisol concentration should be different. The initial adrenocortical activation is, plausibly, related to a nervous mechanism (see [14]). Likely, the initial activation is terminated or reduced by the feedback inhibition of the increased cortisol blood level. This possibility has been demonstrated by Brandenberger et al. [3]. The secondary increase is, plausibly, induced by feed forward influence from working muscles (the nervous discharge from

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urea [19] production as well as urea renal elimination [18] are reduced. Whereas swimming for 3 hours augmented liver alanineaminotransferase activity in sham-operated rats, this change was not observed in adrenalectomized rats but restored in adrenalectomized rats treated with corticosterone [36]. In untreated adrenalectomized rats arginase activity decreased during exercise in conjunction with the lack of elevation of urea levels in blood, liver, and skeletal muscles [19]. An essential contribution of glucocorticoids for hepatic gluconeogenesis and glucose output has been indicated by observations of a pronounced reduction in hepatic glycogen store and the development of hypoglycemia during prolonged exercise in adrenalectomized rats [9]. When during exercise the synthetic glucocorticoid dexamethasone was administered to adrenalectomized rats the hypoglycemia was eliminated and rats were able to continue to swim [43]. In intact rats swimming for 5 to 8 hours caused an elevated level of corticosterone in blood in association with a relative stability of liver glycogen content (the utilization of liver glycogen was, obviously, balanced by gluconeogenesis and spared by increased utilization of lipids). After swimming for 12 hours the blood corticosterone level was decreased and a prompt fall in liver glycogen was apparent [43].

fluxes in cells or inhibition of the synthesis of cAMP-phosphodiesterase [6]. In this way, cortisol promotes the action of adrenaline. This action of cortisol is relatively rapid. An example of glucocorticoid permissive action during exercise is the influence on free fatty acid release from adipose tissue. Adrenalectomy eliminates this response [9, 21, 31]. Krge et al. [15] demonstrated that during long-lasting swimming, Na,K-ATPase activity in the microsomal fraction of rat myocardium and blood corticosterone concentration changed in parallel. First, both hormone level and enzyme activity increased. When the duration of swimming was more than 10 h, they both decreased. In adrenalectomized rats, enzyme activity was low and exercise did not elevate the activity [16]. Since adrenaline activates the Na,K-pumps in the sarcolemma of muscles [4] the cortisol effect may represent a permissive action.

Physiology & Biochemistry

Cortisol Response in Exercise

Sellers et al. [26] tested the biological significance of the glucocorticoid response during prolonged exercise in rats. A corticosterone pellet was subcutaneously implanted into rats simultaneously with adrenalectomy. Adrenocortical insufficiency was avoided but these rats were not able to respond to exercise with an increased blood level of corticosterone. The duration of treadmill running until exhaustion was in sham-operated rats 138  6 min, compared to 114  9 min in adrenalectomized-implanted rats injected with corticosterone before the exercise, and 89  8 min in adrenalectomizedimplanted rats injected with corn oil as placebo. Consequently, the increased level of glucocorticoids during exercise was essential for the endurance performance of rats. However, neither stimulation (by injection of ACTH) nor blockade (with dexamethasone treatment) of adrenocortical activity before the exercise test altered the peak VO2 or power output at a heart rate of 170 beats/min [37]. Obviously, the significance of the adrenocortical response for endurance performance is related to metabolic processes during prolonged exercise rather than to changes in aerobic capacity.

muscle metaboreceptors [14] and the augmented release of interleukin-6 from contracting skeletal muscles [30]). The secondary increase is also more pronounced in endurance trained athletes than in less trained persons [40]. Consequently, endurance training enhances the cortisol responses in demanding exercise. In contrast, cortisol response becomes inversed both in acute fatigued state [42] and in very pronounced overreaching or in overtraining in association with decreased adaptability of athlete (see [39]).

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Conclusion

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The exercise-induced increase in the blood cortisol concentration is essential for the normal metabolic response to exercise and in the process of adaptation to repeated bouts of demanding exercise. Endurance training ensures augmented possibilities for increasing the cortisol production in these exercises. However, acute fatigue and overreaching/overtraining are associated with a markedly reduced blood cortisol concentration during exercise.

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Physiology & Biochemistry