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The Hormonal Response to Exercise Henrik Galbo Department of Medical Physiology B, The Panum Institute, University of Copenhagen, 2200 Copenhagen N, Denmark Introduction . . . .. . . . . ... . . . . . . . ....................................... Sympathoadrenal Activity During Exercise . . . . . .. ... . . .. . . . . . . . . . . . . . . . . . . . . The Renin-Angiotensin System. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . .. . .. Gastroenteropancreatic (GEP) Hormones ............. .................... A. Insulin. .. .. . . . . . . .. .. .. . ..... ..._..... . .. .. . . .. . . .. . . .. . . ... . .. .. .. .. .. .. B. Glucagon.. .. . . . . . .. . . . .. . .. . . . . .. . . .. . . . . . .. . .. . .. . . .. . . .._...._...... . .. C. Somatostatin (SRIF) and Pancreatic Polypeptide (PP) . . . . . . . . . . . . . . . . . . . . D. Other GEP Hormones.. . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Parathyroid Hormone (PTH). . . . . . . . . . . . . . . . . . .. . . ... . . . . . . . . . .. . . . . . . . . . . . . . VI. The Pituitary Gland.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII . Growth Hormone (GH). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VIII. Prolactin (PRL) . . . . . . . . . . . . . . . . . . . . . . .. . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lx. Adrenocorticotropic Hormone (ACTH) and Adrenal Glucocorticoids . .... . .. X. Endogenous Opioid Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XI. TSH and Thyroid Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . .. . . . . . . XII. Pituitary Gonadotropins (LH and FSH) and Gonadal Hormones . . . . . . . . . . . . XIII. The Postexercise Period. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XIV. Unifying Scheme for the Control of the Hormal Response to Exercise.. . . . . . xv. Accuracy of Fuel Mobilization in Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I. 11. 111. IV. 385 385 388 389 389 391 392 392 392 393 393 394 394 396 396 397 399 399 401 I. INTRODUCTION In the present paper, the hormonal (including autonomic neuroendocrine) changes elicited during exercise are outlined. A unifying hypothesis concerning the control of the hormonal response to exercise is advanced. The influence of this response on metabolism is discussed in terms of whether the hormonal changes are compatible with an accurate adjustment of fuel delivery to the energy needs of the working muscles. Some areas which are likely to attract future research attention are pointed out. The present exposition is an updated review and the reader is referred to References 13, 17, 126, and 127 for a more extensive quotation of these older studies and a detailed bibliography. 11. SYMPATHOADRENAL ACTIVITY DURING EXERCISE During exercise an increase in sympathoadrenal activity is the most important autonomic neuroendocrine response. If sympathetic (adrenergic) activity is impeded, exercise capacity is reduced.'I2 The increase in sympathoadrenal DiabetesMetaboIism Reviews, Vol. 1, No. 4, 385-408 (1986) CCCO742-4221/86/040385-24$04.00 0 1986 by John Wiley & Sons, Inc. 386 EXERCISE ENDOCRINOLOGY activity is of major importance for the cardiovascular adaptation and thermoregulalion that occurs during exercise. The heart rate and force of contraction are enhanced, the tone of arterioles in the splanchnic area, kidneys and noncontracting muscles is increased, and the spleen-at least in dogs-brought to contract. In this way cardiac output is enhanced and blood volume and flow redistributed to skin and working muscle. Stimulation of sweat glands increases evaporative heat loss. Sympathoadrenal activity also influences water and electrofyte balances by facilitating muscular uptake of potassium, by activating the renin-angiotensin axis (see below), and by a direct effect on the kidney to decrease and redistribute renal blood flow and to directly enhance tubular sodium reabsorption. In this way the loss of water and electrolytes caused by sweating is counterbalanced. The secretion of hormones (see below) and substrate mobilization are profoundly influenced by adrenergic activity. Adrenergic activity also enhances contractility in skeletal muscle, as it does in heart. Finally, studies with epinephrine infusion3 and p-receptor blockade4,' suggest that augmented sympathetic activity at the onset of exercise increases the rate of ventilation and pulmonary gas exchange by enhancing circulatory adjustments and thereby delivery of CO, from the working muscles to the lungs. A direct effect of sympathetic activity on respiration or airway resistance during exercise6 have not been found. In humans, the best practical way to assess sympathoadrenal activity during exercise is to measure the concentrations in plasma of free norepinephrine and epinephrine. At rest about 80% of circulating catecholamines are sulfate conjugates. During exercise the concentrations of these decrease for reasons unknown. However, the concentrations of free norepinephrine and epinephrine have been shown to increase during exercise in humans8, similarly in men and women, as well as in several other mammalian species, including dog9,"' and rat"*'2, and primitive vertebrates. During exercise the main source of plasma norepinephrine is skeletal rnu~cle~,'~. However, the relationship between sympathetic nervous activity and tissue overflow of norepinephrine to the blood stream is obscure and the organ distribution of electrical impulses within the sympathetic nervous system is unknown.14 The kinetics of epinephrine in plasma are easier to interpret than those of norepinephrine. It has been shown that during exercise the increase in epinephrine concentration closely reflects increased adrenomedullary secretion, since epinephrine clearance varies little.I5 At low work loads clearance increases slightly (15%),whereas at high workloads it decreases slightly (20%) and is inversely related to the relative work intensity." In man, increases in catecholamine concentrations have been found during static (isometric) as well as during dynamic exercise. Norepinephrine and epinephrine concentrations in plasma vary exponentially with work intensity and VO, during dynamic exercise. Norepinephrine levels increase significantly at work loads lower than those that cause an increase in epinephrine levels.'6 At a certain VO, catecholamine levels are higher during work with small muscle than during work with large groups with a low muscle group specific V02max Furthermore, the rise in plasma epinephmuscle groups with a high V02max.18 rine is larger relative to that of norepinephrine during static than during dynamic e~ercise.'~,'~ Comparison between dynamic and static exercise performed GALBO 387 with the same muscle group reveals that the increase in plasma norepinephrine is larger relative to the increase in heart rate during the former type of exercise.” The duration of exercise also appears to be an important regulator of sympathoadrenal activity. Thus, at a constant VOz, norepinephrine and, more markedly, epinephrine levels in plasma increase continuously up to the time of exhaustion. 1,15,19 Availability of oxygen and norepinephrine concentration in plasma appear to be closely associated, but the exact mechanism is not known. Studies performed at rest and during exercise in patients with ischemic heart disease as well as in healthy subjects have shown that the concentration of norepinephrine in plasma varies inversely with (is negatively correlated to) the oxygen saturation of mixed venous blood. Furthermore, catecholamine concentrations in plasma are higher and lower, respectively, when exercise is performed during hypoxia20,21 and hyperoxia, than when it is performed during normoxia. It has been claimed that the close relationship between plasma norepinephrine concentration and relative VO, is essentially unaffected by hypoxemia.” However, catecholamine levels tend to be higher, at comparable relative loads, during hypoxia than during normoxia” indicating an effect of hypoxemia per se on sympathetic activity. A number of factors have been shown to moderate sympathetic nervous systems activity during exercise. Stimulation of temperature receptors (either hot or cold) enhances sympathetic activity.22Pressure and volume receptors also appear to modulate sympathoadrenal activity during exercise. Epinephrine secretion also is very sensitive to a decrease in plasma glucose concentration during exercise while stimulation of norepinephrine secretion by hypoglycemia is less conspicuous.~7~’9~23 In dogs, both infusion of glucose into the carotid artery or the lateral cerebral ventricle2*and infusion into the portal veinz5reduce the increase in plasma norepinephrine observed during prolonged exercise, indicating that cerebral and hepatic glucoreceptors participate in the control of sympathetic activity during exercise. The responsiveness of these centers may depend on insulin availability in the time preceding exercise. The evidence underlying this view is that the catecholamine response to exercise is exaggerated in states of insulin deficiency such as fasting,26 intake of a high fat-low carbohydrate diet, and poorly controlled diabete~.’~ Furthermore, in diabetic subjects the catecholamine response to exercise is gradually normalized during 2 weeks of optimum insulin treatment.27Glycogen availability in working muscles does not influence catecholamine levels when the plasma glucose concentration remains constant. During a period of vigorous endurance training a significant reduction in catecholamine response to a given absolute work load is seen within one week. The reduction is more readily apparent for norepinephrine than for epinephrine.28After training, the norepinephrine concentration in plasma is lower than before whether exercise is carried out with trained or untrained muscles. The resting norepinephrine concentration in plasma, as well as the vasoconstrictor activity in sympathetic fibers innervating skeletal muscle, are unaffected by trainingz9 However, the resting level of epinephrine and the epinephrine response to insulin-induced hypoglycemia is higher in endurance athletes than in sedentary subject^.*^*^^ Furthermore, in the former subjects plasma epineph- 388 EXERCISE ENDOCRINOLOGY rine concentrations have been found to be higher at identical supramaximal relative work intensities3' as well as at the end of prolonged exhausting exercise even though the heart rate was identical to those of untrained subjects. These findings indicate that the capacity to secrete epinephrine is increased in athletes, a fact which probably improves exercise capacity. The increase in norepinephrine levels during isometric exercise has by some, but not all,32been found to increase with age. Acute administration of drugs may also influence the catecholamine levels achieved during exercise. Thus, catecholamine concentrations are increased by a- as well as by P-adrenergic receptor-blocking agents,3335 by atropine,35by opiate antagonists such as nal ~ x o n eand , ~ ~by the serotonergic antagonist, k e t a n ~ e r i nOn . ~ ~the other hand, during exercise plasma catecholamine concentrations are lower after administration of dopamine agonists and ganglionic blockade. After chronic P-adrenoceptor antagonism enhanced catecholamine responses to exercise are not always seen.% Destruction of noradrenergic nerve endings with 6-hydroxydopamine results in lower plasma concentrations of norepinephrine in exercising rats than is normally while in exercising dogs a compensatory increase in adrenomedullary secretion may increase the total plasma catecholamine concentration." The adrenergic response to exercise also is influenced by underlying disease. In diabetics, the catecholamine response to dynamic exercise is increased if they are poorly controlled, and decreased if they have autonomic neuropathy.40The sympathoadrenal response to exercise may be blunted in asthmatic subjects, whereas higher norepinephrine concentrations may be found during exercise in hyperthyroid patients compared to controls. In hypertensive subjects, the norepinephrine concentration has been reported to be higher during dynamic but lower during isometric exercise than in controls.41Patients with ischemic heart disease have high plasma norepinephrine levels during exercise and aerobic training diminishes the catecholamine response to exercise in patients with coronary arterial disease.42 In summary, many factors are known to influence sympathoadrenal activity during exercise and these have been briefly reviewed. The exact mechanisms by which they act and their quantitative importance for the sympathoadrenal response to exercise is in large part, still unknown. Several of the factors mentioned may interact, and their interplay in the regulation of sympathoadrenal activity during exercise is far from fully explored. 111. THE RENIN-ANGIOTENSIN SYSTEM During exercise increased sympathoadrenal activity, mainly via P-adrenergic mechanisms, causes secretion of the proteolytic enzyme, renin, into the circulation. Renin cuts off angiotensin 1 from the circulating globulin called angiotensinogen or renin substrate. Angiotensin 1 is converted to angiotensin 2, which directly stimulates the adrenal cortex to secrete aldosterone. Angiotensin 2 also acts on the subfornical area in the diencephalon, an area "outside the blood-brain barrier," to stimulate neural areas involved with thirst and release of antidiuretic hormone (ADH) from the posterior pituitary gland.43Aldosterone and ADH reduce sodium and water losses by their actions on the GALBO 389 kidney. Thus, the renin-angiotensin system plays an important role in this maintenance of body fluid homeostasis during acute exercise and may contribute to expansion of the extracellular volume during a period of training. The plasma concentrations of renin, angiotensin, aldosterone, and ADH are directly related to intensity and duration of e ~ e r c i s e . ~The ~ , ~hormonal ~,~~,~ responses are determined by the relative, rather than by the absolute work load. Thus, the state of physical conditioning also influences the hormonal response with the concentrations of renin, aldosterone, and ADH43in plasma being lower during exercise in trained than in untrained subjects. In accordance with the known stimulatory effect. of the sympathetic nervous system on the reninangiotensin system, serotonergic and opioid blockade have been shown to enhance the responses to exercise of renin and a n g i o t e n ~ i nand ~ ~a l d ~ s t e r o n in e~~ parallel to the magnitude of the catecholamine responses. The concentrations in plasma of angiotensinogen and converting enzyme probably do not change during e ~ e r c i s e . ~ ~ , ~ ~ Baroreceptors, especially low pressure receptors that sense reductions in extracellular fluid volume, are involved in stimulation of the renin-angiotensin system during exercise. Thus, the exercise-induced increase in renin concentration is enhanced after sodium restriction and inhibited after a high sodium intake. During prolonged exercise increases in renin and aldosterone are lower when electrolyte solutions rather than when water are administered. During exercise in a hot environment an exaggerated decrease in plasma volume is seen, and this is accompanied by an enhanced renin response. Also, at similar decreases in plasma volume, stimulation of low pressure receptors in the central circulation is probably more intense during upright than during supine exercise and the increase in plasma concentration of ADH is more pronounced under the former compared to the latter conditions. Changes in plasma osmolality are highly correlated with changes in plasma ADH during graded exercise43but it is clear that changes in osmolality and blood pressures cannot fully explain the exercise-induced changes in renin and ADH The increase in aldosterone concentration in plasma during exercise is not entirely due to increased renin levels. Increases in plasma potassium and ACTH concentrations, as well as a decrease in the clearance of aldosterone contribute to the higher aldosterone levels. IV. GASTROENTEROPANCREATIC (GEP) HORMONES A. Insulin The most important effect of sympathoadrenal activity on hormone secretion in exercise is an w-adrenergic inhibition of insulin release.35Although insulin clearance has been shown to decrease,47,the plasma insulin concentration, like that of C peptide, predictably decreases when the intensity of exercise exceeds approximately 40-50% of V 0 2max . In man, the a-adrenergic inhibition of insulin release during exercise is exerted by sympathetic nerves to the pancreas, while in sheep and rat48epinephrine contributes to the @-cellinhibition. In accordance with sympathetic inhibition of insulin secretion, it has been shown that during exercise of more than mild intensity, insulin secretion is rather insensitive to changes in plasma glucose c ~ n c e n t r a t i o n . ~ ~ 390 EXERCISE ENDOCRINOLOGY The concentrations of insulin and C peptide in plasma decrease with the and the decrease is less pronounced in trained than in duration of untrained subjects. In obese subjects and in normal subjects ingesting a carbohydrate enriched diet, insulin and C-peptide levels are higher than normal in the postabsorptive state as well as during exercise. Conversely, both at rest and during exercise insulin levels are lower after fastingZband fat diet.23Insulin levels are of course low both at rest and during exercise in insulin-deficient diabetics. It is now well established that exercise may enhance the absorption of insulin from subcutaneom depots in normal and diabetic individuals. In the postexercise period insulin concentrations are low relative to the plasma glucose concentration during oral glucose loading in man.49,50 This may be due to diminished glucose-induced secretion of gastric inhibitory polypeptide (GIP), an insulin s e c r e t ~ g o g u eor ,~~ to persistently high alpha-adrenergic tone. In sedentary rats a reduction in the sensitivity of insulin secretion to glucose per se has been demonstrated”’ and contributed to the lower plasma insulin concentrations after an intravenous glucose bolus. Following physical training the reduction in glucose-induced insulin secretion has been shown to be more pronounced when glucose is administered orally than intraven~usly.~’ Importantly, the diminished plasma insulin and C-peptide responses to oral glucose were associated with a decreased GIP response,53again suggesting that exercise may influence the enteropancreatic axis. In man an effect of physical training to reduce the plasma insulin response to oral glucose can be demonstrated 4 days after the last training session,53 indicating that the reduction in insulin secretion represents a long-term adaptive response to physical conditioning. In rats exercise training also has been shown to diminish the insulin response to intravenous glucose, tolbutamide, and arginine loads54and the effect persists well after the last bout of e~ercise.~’ A decreased intrinsic sensitivity of the P cells to stimulation by glucose has been demonstrated. Thus, the ability of glucose to stimulate insulin secretion by cultured islets isolated from trained rats has been shown to be reduced.55 These data demonstrate that training-induced hypoinsulinemia observed in vivo is not solely dependent upon alterations in the hormonal or metabolic milieu or in neurogenic stimulation of the islets, but also reflects long-term adaptations within the pancreatic (3 cells. These long-term changes in insulin secretion cannot be explained by altered glucose utilization by the islets.56Since the sensitivity of the P cells to stimulation is directly related to the preceding plasma glucose level,57it is possible that a lower average glucose level in physically active compared to sedentary individuals contributes to development of the P-cell adaptations. Additional factors which may contribute to the diminution in insulin secretion are the high catecholamine levels in exercising individuals. The mechanisms involved in development of training induced adaptations in pancreatic islets (and in other endocrine organs, e.g., the adrenal medulla), as well as characterization on the molecular level of these adaptations, are important areas for future research. Short lived effects of a single bout of exercise on sensitivity to stimulation of endocrine glands have to be separated from more permanent changes induced by regularly repeated exercise (physical training). Whole body insulin sensitivity is increased in trained subjects5$ as well as after a single bout of GALBO 391 exercise in untrained subjects.59The effect of acute exercise can at least partly be ascribed to an increase in glucose transport in skeletal muscle60 and increased transport has also been found in trained muscle in v i v ~Acute . ~ ~ exercise does not influence glucose transport in fat cells, whereas glucose transport is increased by physical t r a i n i r ~ g . ~The ' , ~ ~latter effect has been shown to be due to an increase in the number of insulin-displaceable glucose transporters after training.62Insulin binding to muscle has been reported to be either unchanged63 or slightly increased after acute excise and similar findings have been reported concerning insulin binding to muscleMand fat61cells after training. These findings confirm the general impression65 that changes in insulin receptor status cannot explain the improvement in insulin-mediated glucose uptake following acute exercise or physical training. The topic of exercise and insulin sensitivity is discussed at length in the chapter by Koivisto and associates in this issue. Important aims for future research are to clarify the exact stimuli responsible for exercise-induced adaptations in hormone-sensitive target cells and to describe in molecular terms the basis for these adaptations. 8. Glucagon In man, a decrease in plasma glucagon concentration is found during brief exercise.',26If exercise is prolonged, the glucagon concentration subsequently increases but does not exceed basal levels until more than one hour of mild to moderate intensity exercise.1,66However, in rats and sheep the glucagon concentration increases early in exercise. In these species stimulation of glucagon secretion by epinephrine explains, in part, the re~ponse.~' In rats, as well as in dogs, autonomic nerves also are involved. In man, however, the autonomic nervous system (including the adrenal medulla) is not of major importance for the exercise-induced increase in plasma glucagon concentration.1,16,35 It w ould appear that decreased glucose availability stimulates the glucagon-secreting cells during prolonged exercise in man.23,34Studies comparing the effect of exercise and insulin-induced hypoglycemia indicate that the sensitivity of the glucagonsecreting cells to a decrease in plasma glucose concentration is increased during exercise.l 7 r 3 O Factors, which might contribute to an increase in sensitivity during exercise include decreased pancreatic blood flow, diminished tissue concentration of insulin, and increased plasma concentrations of GH, cortisol, gastrin, and VIP. A protracted decrease in glucose availability may also induce a resetting of the stimulus-secretion coupling during prolonged exercise.57 Insulin availability over the period preceding exercise may influence glucagon concentrations during exercise. Thus, glucagon levels are higher in states of insulin deficiency such as fasting,26high fat-low carbohydrate diet, and poorly controlled diabetes. Insulin availability is plentiful in obesity. Unfortunately, the available studies comparing glucagon responses to exercise in obese and normal weight subjects are inconclusive since the two groups were not matched for age, sex, and exercise intensity.67Physical training diminishes the increase in glucagon concentrations seen in response to a given absolute or relative work load.68The change in response is detectable within a few weeks of vigorous endurance training. EXERCISE ENDOCRINOLOGY 392 C. Somatostatin (SRIF) and Pancreatic Polypeptide (PP) The concentrations of SRIF and PP in peripheral plasma increase gradually during prolonged mild exercise.47The exercise-induced increases are inhibited by p-adrenergic antogonists and enhanced by a-adrenergic blockade. The increase in SRIF is seen earlier in diabetics than in controls. The PP concentration increases with exercise intensity, and the response to exercise is diminished by autonomic neuropathy and physical training. In addition to P-adrenergic activity, vagal activity stimulates PP secretion. The PP response to insulin-induced hypoglycemia is higher in trained compared to untrained s~bjects,~' and this may reflect a higher vagal activity in the former group. D. Other GEP Hormones The concentrations in peripheral plasma of vasoactive intestinal polypeptide (VIP), peptide histidine isosoleucine amid (PHI), secretin, substance P, and gastrin all have been shown to increase during prolonged e ~ e r c i s e . ~The ~,~~,~~ responses of VIP, PHI, and secretin, but not substance P, are inhibited when oral glucose is administered during exercise.69Training does not influence these response^.^^ During brief maximum exercise no changes have been found in the plasma VIP concentrationz6. Similarly, during prolonged exercise levels of neuand rotensin and bombesin (GRP),69 gastric inhibitory polypeptide (GIP),47,66 gut glucagon have been shown to be unchanged. For most of the GEP hormones (with the obvious exceptions of insulin and glucagon), we do not know their origin during exercise nor do we know the stimuli regulating their release nor do we understand their role, if any, in metabolic responses to exercise. Interestingly, VIP and PHI are probably cosecreted from peptidergic nerves. Similarly, peptides may be cosecreted with traditional hormones and neurotransmitters, such as enkephalins with epinephrine, and The possible importance of such coseneuropeptide Y with n~repinephrine.~' cretion has not been taken into account in previous inhibitionheplacement experiments designed to elucidate the role of these hormones in e ~ e r c i s e .Future '~ studies must take such cosecretion into account, since important interactions are likely to exist between cosecreted hormone^.^' V. PARATHYROID HORMONE (PTH) A small increase in the plasma concentration of PTH has been found during exercise in man7*and in animals. The increase cannot be explained by changes in the ionized calcium concentration, but may be related to increased P-adrenergic activity. Not all studies have shown an increase in PTH levels during exercise in man.72 However, it has been proposed that during exercise an adrenergic enhancement of PTH secretion is counteracted by an increase in ionized calcium that results from metabolic acidosis." GALBO 393 VI. THE PITUITARY GLAND In response to exercise ADH is released (see preceding discussion), whereas the evidence for an increase in the levels of the other posterior pituitary hormone, oxytocin, is weak. Several anterior pituitary hormones are released during exercise: VII. GROWTH HORMONE (GH) GH hormone concentrations in plasma increase during exercise, reflecting an increase in secretion rate. The increase is seen within a few minutes after the onset of work and the delay is inversely related to work intensity. Increased GH release may be found after 30-60 min of exercise at a work load equivalent to only 10-15% of VO, max. Plasma concentrations of GH increase progressively with time during exercise of constant intensity.”~~~ GH secretion increases with increasing work load. Studies comparing continuous and intermittent exercise75 or work with differentload and frequency of movements74have shown that the GH response is more closely related to the peak intensity of exercise than to the total work output. Furthermore, the GH response is higher during arm than during leg exercise.76 The GH response to exercise may have some peculiar features. Some authors have described lower concentrations in plasma during maximal than during submaximal exercise, and the GH response may wane with time during prolonged or intermittent exercise. Furthermore, individual changes in plasma GH concentrations during exercise sometimes have a rather irregular time course. These findings may, to some extent, be explained by the fact that GH secretion is pulsatile and is subjected to negative feed back inhibition from circulating GH Illustrating the complex nature of the neuroendocrine control of GH secretion, the GH response to exercise can be inhibited by administration of SRIF, a-adrenergic receptor-blocking agents, serotoninergic receptor-blocking agents, dopaminergic receptor-blocking agents, and by cholinergic receptor-blocking agents; conversely, GH secretion can be enhanced by p-adrenergic receptorblocking agents. Blockade of opioid receptors with naloxone does not alter the GH response to exercise.36 During exercise, GH release is enhanced by a decrease in glucose availability, by hypoxia, and by a rise in body t e m p e r a t ~ r e , ~and - ~ *is inhibited by free fatty acids. The GH response to exercise is smaller in trained than in untrained subjects when compared at similar relative or absolute work loads. Poor physical fitness in the elderly and in women is probably, in part, responsible for the exaggerated GH response to exercise in these groups. Insulin availability in the time preceding exercise also appears to be of importance in determining the GH response to exercise. In accordance with this view, the GH response is exaggerated in hypoinsulinemic states such as fasting,26intake of a high carbohydrate-low fat diet, and in poorly controlled diab e t e ~Conversely, .~~ the GH response to exercise is reduced in states of peripheral hyperihsulinemia such as obesity, optimally treated diabetes,27and ingestion of a high carbohydrate diet. The lack of significant increase in GH concentration 394 EXERCISE ENDOCRINOLOGY in diabetics with autonomic neuropathy during a graded exercise test is probably not due to impaired peripheral sympathetic activity but possibly to lesions in neurons that trigger GH relea~e.~' At variance with the view that GH secretion during exercise is diminished by autonomic neuropathy, it has been reported that, in response to 25 min of bicycle exercise, GH concentrations increased more or to the same extent in diabetics with neuropathy compared to those without neurologic i n ~ o l v e m e n t . ~ ~ VIII. PROLACTIN (PRL) In humans of both sexes the concentrations of PRL in plasma increase progressively during heavy exercise,s0,81The peak concentration may be reached ~~ one , ~ study ~ PRL levels decreased during 30 min after the end of e x e r c i ~ e .In of mild exercise. However, it is known that PRL levels decrease spontaneously during the morning, making the reported decreases3 difficult to interpret. In women, exercise increases PRL levels in the follicular as well as in the luteal phase. Interestingly increased PRL levels have been found in women after a marathon but not during an intense 3 h water polo training session.80Although postmarathon levels were in the abnormal range, none of the runners complained of galactorrhea.*' In rats, no significant change in plasma PRL was found during prolonged running.@ The PRL response to exercise is enhanced when a diet rich in fat and low in carbohydrate is ingested.85A similar enhancement is observed during a 59 h fast, by an increase in body temperature,s6 and by blockade of opoidZ6or P-adrenergic receptor. Conversely, the exercise-induced stimulation of PRL secretion is inhibited by a-adrenergic blockade. Glucose availability during exercise is not an important determinant of the PRL response69and the increase in plasma PRL during insulin-induced hypoglycemia is similar in trained and untrained subjects.88In men, basal PRL levels are not changed during 20 days of strenuous running.81However, lower resting PRL levels have been reported in male distance Similarly, in female swimmers, resting PRL levels have been found to be decreased following strenuous compared to moderate intensity training programsm With submaximal exercise the PRL response has been found to be slightly lower in trained versus untrained males.69In some contrast to these findings a small increase in the TRH-stimulated PRL response has been reported to occur during training. It has been claimed that the PRL response to running at 80% of VOgmax is lower in amenorrheic compared to eumenorrheic women.% However, as judged from heart rates and plasma lactate levels, the relative work load may have been lower in the former than in the latter group. IX. ADRENOCORTICOTROPIC HORMONE (ACTH) AND ADRENAL GLUCOCORTICOIDS The concentration of ACTH in plasma increases with the intensity" and d ~ r a t i o n of ~ ~exercise. , ~ ~ During exercise of constant intensity an increase in ACTH is followed within 10 min by an increase in the secretion rate and plasma concentration of ~ o r t i s o 1ACTH . ~ ~as~well ~ ~as~cortisol ~ ~ ~levels ~ ~ may peak after GALBO 395 the end of e ~ e r c i s e . ~The ~ , ~increase ~ , ~ ~ in plasma ACTH also stimulates the production of aldosterone, but its effect is less important than the rise in angiotensin levels in response to the hyperreninemia (see preceding discussion). The lowest work load at which an increase in plasma cortisol level has been However, this does not mean that low intensity detected is 25% of VO,,. exercise (< 25% of VO,),,, does not stimulate cortisol secretion, because the clearance of cortisol is increased at low (as well as high) work loads. Thus, a stimulatory effect of exercise on cortisol secretion could be masked by an increase in the metabolic clearance rate. The relative, rather than the absolute work load, has been shown to be important for the plasma cortisol response to exercise and, at any given work intensity, the plasma cortisol level increases more during hypoxic exercise than under normoxic conditions. When studied at the same submaximal work loads, trained persons have been found to have a smaller rise in plasma cortisol than untrained persons. This may partly be due to a higher cortisol clearance in trained subjects. In one study, training increased the ACTH response to a given relative work load.91 The plasma cortisol concentration displays an intrinsic circadian periodicity. During the day the cortisol concentration decreases, but this decrease may be interrupted by secretory peaks related to meals or provoked by e x e r c i ~ e . ~ ~ , ~ ~ , ~ ~ A meal prior to subsequent exercise diminishes the cortisol response.95 Similarly, prior exercise blunts subsequent meal related peak^.^',^^ During prolonged submaximal exercise in man increases in ACTH and cortisol levels coincide with a decrease in blood glucose concentration below 3.3 mmoUliter .17,96 Physical training delays the time at which this glucose concentration is reached and also delays the increase in ACTH and cortisol levels (Tabata, personal communication). Furthermore, the infusion of glucose during prolonged submaximal exercise in man inhibits the rise in plasma ACTH levels.% Shularly in running dogs, SIUF infusion exaggerates the decrease in plasma glucose and this is associated with an increase in the plasma cortisol level. When hypoglycemia is prevented with a concomitant glucose infusion,19 the plasma cortisol response is blocked. These results indicate that the blood glucose level plays an important modulating role on the cortisol response to exercise. Available evidence indicates that receptors in brain and liver mediate the effect of the plasma glucose concentration on the glucocorticoid response to exercise, and that this response is exaggerated in hypoinsulinemic states such as diabetes. An increase in body temperaturesE as well as psychological stress97also have been shown to augment the exercise-induced increase in plasma cortisol concentration. The cortisol response to exercise also is enhanced by blockade of P-adrenergi~~~ or ~ p i o i dreceptors. ~~ The physiological significance of the changes in plasma glucocorticoid concentration during exercise has not been determined. However, it may be proposed that during prolonged exercise an increase in glucocorticoids may enhance the stimulatory effect of other hormones on glucose production and lipoly~is.'~ Another possibility is that repeated increases in plasma cortisol with each exercise bout are involved in some enzymatic adaptations to training.I7 Interestingly, an increased number of glucocorticoid cytosolic receptors has been found in hearts from trained rats. 396 EXERCISE ENDOCRINOLOGY X. ENDOGENOUS OPIOID PEPTIDES These substances have drawn considerable attention in recent years because they have properties, including narcotic potency, similar to those of morphine. p-endorphin is derived from p-lipotropin which, in turn, is derived from the same precursor molecule as ACTH. The enkephalins are shorter peptides, which share a region of homology with p-endorphin but are derived from a distinct precursor. P-endorphin and enkephalins are found in several areas within the brain and are also found outside the brain, for instance, @-endorphinis cosecreted with ACTH from the anterior pituitary and enkephalins are cosecreted with catecholamines from the adrenal medulla. The evidence concerning the response of these hormones to exercise is still scarce. An increase in @-endorphinlevels have been documented during exercise% and the plasma concentration is directly related to the intensity98and duration99,'00 of exercise. The response is enhanced by increased body temperature during exercise.loo A rise in plasma met-enkephalin also has been found in response to prolonged, high intensity but not to less demanding exercise.%In exercising rats the opioid levels in different regions of the brain have been shown to change to varying extents and in different directions.@ Resting @-endorphinlevels in plasma have been claimed to increase during periods of strenuous training,89but in other studies, similar values were found in trained and untrained subjects.98~w~10' Training has also been reported to increase plasma p-endorphin levels during exercise of a given relative intensity9*,lm but this finding has not been observed by others.w The increase in plasma pendorphin during insulin-induced hypoglycemia is similar in trained and untrained subjects.88 Endogenous opioids have been proposed to account for the increase in pain threshold as well as for the acute reduction in anger, depression, and anxiety which may result from a single bout of exercise. However, the latter observations have been refuted by others. 102,103 Studies with nalaxone have suggested that the opioids may be involved in the regulation of hormonal responses to exercise.36During intense exercise, ventilation tends to be increased by naloxone, whereas other cardiopulmonary variables are not a f f e ~ t e d . ~ ~ , " ~ XI. TSH AND THYROID HORMONES In spite of much research, the influence of physical exercise on thyroid function is still obscure. In a number of investigations, including varied work protocols, including mild to strenuous exercise in both normal and diabetic subjects, no effect of exercise on the plasma concentration of thyroid-stimulating hormone (TSH) was found. In contrast, in other studies the TSH concentration has been found to increase progressively with work 10ad.l'~More recent studies have attempted to resolve this controversy, but again both increasedlo6 and decreased36TSH levels have been found in response to exercise. An exercise-induced increase in TSH levels might be expected to stimulate the thyroid gland. However, a delay is inherent in the stimulus-secretion coupling and an increase in the concentration in plasma of the thyroid hormone may not be expected until several hours after the increase in TSH. In accordance GALBO 397 with this, increased T, levels have been found 90 min after a 60 min bout of acute exercise'06 and at the end of a 60 km run.81 The evaluation of thyroid function from measurements of thyroid hormone concentrations in plasma is complicated for a number of other reasons. First, the extracellular hormone pool is large, making small changes in plasma hormone concentration difficult to detect. Second, changes in the hormone clearance during exercise (due to an increase in the concentration of free hormone resulting from a decrease in binding affinity to circulating proteins or to a tissue adaptation facilitating removal) could easily obscure away increased secretion of thyroid hormone. Third, exercise-induced changes in thyroid hormone concentrations in plasma may be entirely due to changes in the concentrations of binding proteins. However, the literature is clear that the plasma concentrations of the thyroid hormones, T, and T, (triiodothyronine), and of the inactive T4 metabolite, reverse T, (IT,), are essentially unchanged by a single bout of exercise. Controversy also exists concerning the effect of chronic physical training on circulating thyroid hormone levels. In some studies basallo6TSH levels have been found to be increased by physical training in man and an increased rate of T, secretion has been reported in man and horses following physical training compared to sedentary individuals. However, these findings have not been confirmed by others, and the T, secretion rate has been shown to be similar in trained rats and in weight-matched controls. Furthermore, in both groups the T, secretion rate was lower than in freely eating controls. Similarly, basal and TRH-stimulated plasma TSH concentrations have been shown to be similar in trained rats and in weight-matched controls, and in these groups lower than in freely eating controls. These differences were accompanied by opposite changes in peripheral tissue sensitivity to thyroid hormones. Available data on basal metabolic rate and on thyroid hormone-dependent mitochondria1 enzymes in the liver do not suggest that physical training changes the "thyroid status." XII. PITUITARY GONADOTROPINS (LH AND FSH) AND GONADAL HORMONES In male as well as in female rats the concentration of the luteinizing hormone (LH) in plasma has been found to decrease during running, whereas that of the follicle stimulating hormone (FSH) does not ~ h a n g e . ~LH , ' ~levels ~ have also been reported to decrease in both men and women during marathon running,80,*08 but in these investigations the lack of homogeneity in the populations studied, the timing of blood sampling, and the lack of control of dietary intake may be criticized. Moreover, in a study of men performing moderate bicycle exercise LH and FSH levels increased, and the increase in LH was enhanced by the infusion of the opioid blocker n a l ~ x o n e Most . ~ ~ studies support the view that in man the concentrations of the gonadotropins LH and FSH, in plasma do not change during exercise.81,82*101,105 Since most studies have shown that plasma LH and FSH levels do not change during exercise, one would expect the secretion of the gonadal hormones also to remain constant. Nevertheless, the plasma concentrations of gonadal hormones have been found to increase in exercise, the increase being more pronounced the higher the work load.36,82,93,105 However, these changes (when 398 EXERCISE ENDOCRINOLOGY corrected for changes in plasma volume) are, in large part, due to decreased hepatic blood flow and decreased clearance of the hormones. In line with this, during exercise the percentage increases in the concentrations of the female gonadal hormones (estradiol and progesterone), in the follicular (preovulatory) and in the luteal (postovulatory) phase of the menstrual cycle, are similar. Furthermore, after training, the absolute as well as the percent increase in the concentrations of both hormones in response to a certain absolute work load is reduced compared to the pretraining response. In exercising men, an increase in the concentration of free testosterone occurs without any change in the percentage of testosterone bound to protein."' The increase in serum testosterone during prolonged heavy exercise gradually and after long-term exercise, the testosterone concentration has returned to or below pre-exercise levels.",'08 The decline probably reflects a reduced secretion rate and in man has variably been ascribed to decreased testicular blood flow, increased body temperature, diminished LH levels or elevated plasma prolactin or cortisol concentrations. However, inhibition of prolactin release by L-dopa has been found not to affect the testosterone response to moderate exercise.82In exercising rats, the decrease in plasma LH concentration appears to account for the decrease in plasma testosterone level since testosterone secretion can be restored to normal by stimulation with LH.'07 The physiologic significance of the small changes in the plasma concentrations of sex hormones which may be seen during exercise is unknown and does not appear to be related to exercise-related changes in either glucose or glycogen rnetab~lism.~~,"~ During daily prolonged exercise, the basal testosterone level has been shown to decrease in men,'l and lower t e s t ~ s t e r o n eand ~ ~ higher total estrogen levels have been found at rest in trained compared to untrained male subjects. Levels of serum LH, FSH, and sex hormone binding globulin were sirmlar in the groups.87 Fertility measures were not reported in these studies, but in a study in which daily exercise was performed over a five day period sperm production rates did not change. However, basal testosterone levels did not decrease in this study. In women training may cause menstrual irregularities, including delayed menarche, shortening of the luteal phase, anovulatory cycles, oligomenorrhea and amenorrhea."' Altered menstrual cycle function has been reported during all kinds of endurance training but the prevalence of amenorrhea seems to be much higher in runners compared to swimmers or cyclists."' Menstrual irregularties correlate positively with amount of t r a i n i ~ ~ g , ~ ~and , ~ ~are ' , ' particularly '~ seen in girls with late menarche and in girls who start training prior to menarche. It is important to note that training-induced menstrual dysfunction is reversible, and hormone levels and menstrual cycles return to normal when exercise is reduced or ~ t o p p e d . ' ~ In training women, plasma sex hormone concentrations vary from normallo' to levels reflecting hypothalamic hypogonadotropia (decreased levels of LH, FSH, estradiol, and p r ~ g e s t e r o n e ) ' ~ , ~and ~ , " ~correlate well with variations in the menstrual function, which also range from normal to amenorrhea. In accordance with ovarian hypoactivity, the weight of the ovaries as well as the activity of enzymes involved in ovarian hormone production have been shown GALBO 399 to be lower, and the cholesterol and ascorbic acid content of the ovaries higher in trained rats compared to controls. Athletes with menstrual dysfunction have a lower mean body weight and less fat than athletes with normal menstrual f u n ~ t i o n . ~ ' ~However, ,"~ the lower body mass probably do not cause the menstrual irreg~larities.~~,"~ It is also unlikely that the amenorrhea in athletes can be attributed to hyperandrogenism, hyperprolactinemia, or psychological s t r e s ~ . ~ ~ In , ~female ' , ~ ' ~ rats basal serum testosterone levels as well as androgenreceptor binding, are not influenced by training. In endurance-trained women with normal menstrual cycles there does not appear to be any problem in becoming pregnant. However, in women with menstrual and hormonal irregularities the ability to conceive may be reduced. In those who do become pregnant and continue to exercise up to the preconceptual levels, weight gain is less, delivery occurs earlier, and infants have lower birthweights but without increased morbidity."' XIII. THE POSTEXERCISE PERIOD At the beginning of the recovery period, the metabolic rate, although lower than during exercise, is still increased, glycogen stores in the exercised muscles are depleted, excess heat has been stored, and the fluid volume is diminished and redistributed. Accordingly, there is a need for fuel mobilization, fuel redistribution, cardiovascular adaptation, and conservation of water and electrolytes. However, the need is less than during exercise. It should be remembered that the derangement in the body metabolism and composition after exercise is determined by the preceding muscular activity (e.g., with respect to intensity, duration, and environment), and that complete return to the pre-exercise state requires rest as well as intake of nutrients and fluid. After short-term, heavy exercise, derangement of homeostasis is not profound and normalization of plasma hormone levels occurs rather quickly.'16 Immediately after this type of exercise, there may even be a rebound increase in plasma insulin levels above basal levels, reflecting a sudden diminution of alpha-adrenergic inhibition of the pancreatic p-cells. After prolonged exhaustive exercise, the derangement of homeostasis is marked and plasma hormone concentrations only return slowly towards basal v a l ~ e s . ~ ~The , ' ' ~slow hormonal recovery reflects the rate with which the stimuli underlying the hormonal changes are normalized, but may also reflect that a change in the sensitivity of hormonal secretion to stimulation has developed during exercise. Thus, after a single bout of prolonged exercise, the insulin concentration in plasma remains low for a long time, and this kind of exercise also results in a reduced insulin response to glucose. XIV. UNIFYING SCHEME FOR THE CONTROL OF THE HORMONAL RESPONSE TO EXERCISE The time course of hormonal changes during exercise and in the postexercise period indicates that the regulation of the autonomic neuroendocrine response to exercise has a fast nervous component and a slow "infernal milieu" 400 EXERCISE ENDOCRINOLOGY component. The response may be regulated as follows: at the onset of exercise, impulses from motor centers in the brain, as well as from working muscles, elicit a work load-dependent increase in sympathoadrenal activity and in release of some pituitary hormones (GH, ACTH, PRL, possibly TSH). These changes, in turn, are responsible for modulation of secretion of subordinate endocrine cells: sympathoadrenal activity depresses insulin secretion, stimulates the reninangiotensin-ADH system, and enhances the secretion of pancreatic polypeptide, glucagon, and possibly PTH, gastrin, and other hormones as well. ACTH stimulates adrenal cortical secretion. In man the secretion of the gonadotropins is not influenced by acute exercise and increased concentrations of gonadal hormones are due to decreased clearance. The state of the organism prior to exercise is an important measure of the magnitude of the hormonal response. Thus, physical training diminishes the response of many hormones since their secretion, to a large extent, depends upon the relative rather than on the absolute work intensity. In contrast, the concentrations of other hormones are higher during exercise in several conditions in which insulin availability is lower than normal. If exercise is continued, the hormonal changes may be gradually intensified by impulses from receptors sensing changes in internal milieu, (e.g., in glucose concentrations, temperature, and intravascular volume). A decrease in plasma glucose concentration is probably the most important signal coupling fuel mobilization to substrate need. In principle, the depicted control of the hormonal response to exercise is similar to that of respiration and circulation, including feed-for~ard''~ as well as feed-back components. Interestingly, hormonal responses very similar to those that occur during exercise are seen in other kinds of stress (e.g., psychological stress, hyper- and hypothermia, hypoxia, hypoglycemia, trauma, burn injury, sepsis, hemorrhage, and surgery). In accordance with the advanced hypothesis for the control of the hormonal response to exercise, in psychological stress the stimuli eliciting hormonal changes arise primarily within the brain. Furthermore, neuroendocrine activity in the brain can be influenced by stimulation of muscle recept01-s~~. The meaningfulness of the hormonal changes is not obvious in all of the above-mentioned stress conditions. Although the hormonal response, when elicited by exercise, at first sight appears expedient, it should not be taken for granted that the hormonal changes are accurately adjusted to the needs of the body. Our knowledge regarding the hormonal responses to exercise is far from complete. Much information is still lacking concerning those factors that regulate the changes in hormone secretion and clearance, and of the feed-back control mechanisms. Furthermore, although "new" putative hormones and neurotransmitters are being continuously discovered, their precise role in the adaptive changes that occur during exercise remains to be elucidated. Probably, the most fascinating area of future research lies in the definition and neurochemical characterization of the CNS regulatory pathways involved in the feedforward control of hormonal and, in turn, metabolic responses to exercise. Studies of the control of respiration and circulation in exercise'17 and of the neurochemical basis for the CNS regulation of the autonomic nervous system'ls may serve as models for such research. CALBO 401 XV. ACCURACY OF FUEL MOBILIZATION IN EXERCISE Contractile activity per se directly elicits breakdown of intramuscular glycogen and triglyceride. The mobilization of intramuscular fuel is subjected to feed-forward regulation and this may not be accurately adjusted to the fuel needs of the organism. Thus, glycogen breakdown and lactate production in stimulated perfused muscle are increased, if pre-exercise glycogen levels are s~pranormal.~~’ During stimulation, glucose uptake is impaired in muscle with supranormal glycogen concentration compared to muscle with a normal glycogen content but the difference is smaller than the difference in glycogen depletion.”’ It appears that mobilization of intramuscular fuel is not mainly called on when delivery of exogenous fuel is insufficient. Similarly, other experiments have shown that combustion of intramuscular fuels may increase with exercise intensity while muscular uptake of glucose and free fatty acids (FFA) decreases in spite of increased delivery of these blood-borne metabolites. The hormonal response to exercise is essentially nondiscriminatory, promoting mobilization of both glycogen and triglyceride from extra- as well as intramuscular stores. This hormone-mediated fuel mobilization is superimposed on mobilization of intramuscular stores by contractile activity per se. As previously discussed, the hormonal response to exercise is, to a significant extent, regulated by feed-forward mechanisms that are intimately related to motor activity rather than to substrate need. Furthermore, the hormonal changes elicited by exercise are critical to the regulation of the circulation, body temperature, volume, and osmolality of body fluids, in addition to metabolism. Thus feedback from nonmetabolic error signals will influence the response of hormones that have important roles in regulating the metabolic adaptations to exercise. For instance, increased sympathoadrenal activity elicited by a decrease in the intravascular volume will inhibit insulin secretion. Similarly, the finding of higher intramuscular glucose-6-phosphate and lactate concentrations during intense exercise performed at cool versus normal temperatures12’ probably reflects an “inappropriate” enhancement of glycogenolysis mediated by epinephrine that is released in response to stimulation of cold receptors. In accordance with the view that mobilization of extramuscular fuel may be regulated in a ”feed-forward” fashion rather than by ”feed-back’ mechanisms, it has been shown in running rats that hepatic glycogen is mobilized and glucose ”forced” upon the exercising muscles at a time when they are rich in endogenous fuel.121Furthermore, when rats are studied at the same exercise intensity, oxygen uptake, and muscular glycogen concentration, hepatic glucose production is higher when liver glycogen stores have previously been increased by fructose than in experiments in which hepatic glycogen has been depleted before exercise.lZ2 During exercise of a fixed intensity, the state of the organism immediately prior to the onset of physical activity (e.g., with respect to nutrition,123degree of training, plasma hormone concentrations, and level of physical activity) influences the exercise-induced hormonal changes, the fuel depots (e.g., in terms of size, ,hormone receptors, enzymatic capacity, sensitivity to stimulation) and the capacity of recruited muscle fibers for metabolism of the different substrates. Extra- and intramuscular fuels are burned in competition with each other, and 402 EXERCISE ENDOCRINOLOGY the final choice of fuel depends on availability of substrates and on the capacity of the metabolizing, energy-yielding enzymatic pathways. Some feed-back inhibition is exerted by the mobilized fuels on the initial enzymatic steps involved in mobilization of glycogen and triglyceride stores. However, this is not sufficient to allow an accurate adjustment of fuel mobilization to energy demand. During exercise, fuel may be mobilized in excess of the body's needs. Such fuels may be restored as evidenced by the accumulation of triglyceride in liver124and the incorporation of infused radiolabelled glucose in muscular glycogen.125 It might be argued that excess mobilization is necessary to allow optimal fuel delivery to the working muscles. However, during prolonged exercise the concentration of FFA in plasma and the supply of FFA to a working muscle group may increase without an accompanying decrease in whole body RQ or local muscle RQ,'6,123 indicating that FFA mobilization may proceed beyond the point at which mobilization limits combustion. However, some reservation about this interpretation, should be considered. Exhaustion may take place at a time when triglyceride stores are plentiful, yet may be delayed by exogenous administration of FFA. Clearly, much more information is needed concerning the balance between feed-forward versus feed-back control of metabolism during exercise. Nonetheless, presently available evidence would suggest that feedforward control is an important regulatory mechanism that, in certain circumstances, may be maladaptive to the exercising organism. References 1. Galbo H, Holst JJ, Christensen NJ, et al: Glucagon and plasma catecholamines during beta-receptor blockade in exercising man. J Appl Physiol 40:855-863, 1976. 2. Tesch PA, Kaiser P: Effect of beta-adrenergic blockade on maximal oxygen uptake in trained males. Acfu Physiol Scand 112:351-352, 1981. 3. Scheen A, Lemaire P: Abaissement du seuil &hyperventilation par perfusion intraveineuse dadrenaline lors d'un exercice triangulaire. Arch Int Physiol Biochim 91~187-196,1983. 4. Hughson RL, Smyth GA: Slower adaptation of VO, to steady state of submaximal exercise with beta-blockade. Eur 1Appl Physiol 52:107-110, 1983. 5. Violante B, Buccheri G, Brusasco V: Effects of beta-adrenoceptor blockade on exercise performance and respiratory response in healthy, physically untrained humans. BY 1Clin Phurmacol 18:811-815, 1984. 6. Warren JB, Jennings SJ, Clark TJH: Effect of adrenergic and vagal blockade on the normal human airway response to exercise. Clin Sci 66:79-85, 1984. 7. Davidson L, Vandongen R, Beilin LJ, et a1 Free and sulfate-conjugated catecholamines during exercise in man. J Clin Endocrinol Metub 58:415418, 1984. 8. Favier R, Pequignot JM, Desplanches D, et al: Catecholamines and metabolic responses to submaximal exercise in untrained men and women. Eur J Appl Physiol 50:393404, 1983. 9. BCliveau L, Trudeau F, Peronnet F, et al: Dynamics of circulating catecholamines during mild exercise in dog. Clin Physiol5(Suppl4): A27, 1985. 10. Peronnet F, Nadeau R, de Champlain J, et al: Plasma catecholamines and response to exerase in 6hydroq-dopamine-treated dogs. Can J Physiol Phrmucol60:1219-1224, 198213. 11. Sonne B, Galbo H, Christensen NJ:Sympathoadrenal and metabolic responses to graded exercise in rats. Int 1Sports Med 2:212-215, 1981. 12. Sonne B, Mikines KJ, Richter EA, et al: Role of liver nerves and adrenal medulla in glucose turnover in running rats. 1Appl Physiol (in press). GALBO 403 13. Christensen NJ, Galbo H: Sympathetic nervous activity during exercise. Ann Rev Physiol 45339-153, 1983. 14. Galbo H: Catecholamines and muscular exercise: Assessment of sympathoadrenal activity, in International Series Sport Sciences Vol. 11B, Biochemistry of Exercise lVB, Poortmans J, Niset G (eds): Baltimore, University Park Press, 1981, pp. 5-19. 15. Kjaer M, Christensen NJ, Sonne B, et al: The effect of exercise on epinephrine turnover in trained and untrained men. J Appl Physiol 1985 (in press). 16. Galbo H, Holst JJ, Christensen NJ: Glucagon and plasma catecholamine responses to graded and prolonged exercise in man. J A p p l Physiol 38:70-76, 1975. 17. Galbo H: Hormonal and Metabolic Adaptation to Exercise. Stuttgart-New York, Georg Thieme Verlag, 1983. 18. Lewis SF, Snell PG, Taylor WF et al: Role of muscle mass and mode of contraction in circulatory responses to exercise. J App1 Physiol 58:146-151, 1985. 19. Wassermann DH, Lickley H, Lavina A, et al: Interactions between glucagon and other counterregulatory hormones during normoglyccmic and hypoglycemic exercise in dogs. Clin Invest 74:1404-1413, 1984. 20. Escourrou P, Johnson DG, Rowell LB: Hypoxemia increases plasma catecholamine concentrations in exercising humans. J AppZ Physiol57:1507-1511, 1984. 21. Rowell LB, Blackmon JR, Kenny MA, et al: Splanchnic vasomotor and metabolic adjustments to hypoxia and exercise in humans. Am J Physiol247:H251-H258, 1984. 22. Galbo H, Houston ME, Christensen NJ, et al: The effect of water temperature on the hormonal response to prolonged swimming. Acta Physiol Scand 105:326-337, 1979. 23. Galbo H, Holst JJ, Christensen NJ: The effect of different diets and of insulin on the hormonal response to prolonged exercise. Acta Physiol Scand 107:19-32, 1979. 24. Kolowski S, Brzezinska Z , Nazar K, et al: Carbohydrate availability for the brain and muscles as a factor modifying sympathetic activity during exercise in dogs, in Biochemistry of Exercise, IV-B, Poortmans J, Niset G (eds): Baltimore, University Park Press, 1981, pp 54-62. 25. Kozlowski S, Nazar K, Brzezinska Z, et al: Mechanisms of sympathetic activation during prolonged physical exercise in dogs. The role of hepatic glucoreceptors. Pfliigers Arch 399:63-67, 1983. 26. Galbo H, Christensen NJ, J-Mikines K, et al: The effect of fasting on the hormonal response to graded exercise. Clin Endocrinol Metab 52:1106-1112, 1981. 27. Tamborlane WV, Sherwin RS, Koivisto V, et al: Normalization of the growth hormone and catecholamine response to exercise in juvenile-onset diabetic subjects treated with a portable insulin infusion pump. Diabetes 28:785-788, 1979. 28. Svedenhag J, Henriksson J, Juhlin-Dannfelt A: Beta-adrenergic blockade and training in human subjects: Effects on muscle metabolic capacity. Am J PhysioZ 247:E305-E311, 1984. 29. Svedenhag J, Wallin BG, Sundlof G, et al: Skeletal muscle sympathetic activity at rest in trained and untrained subjects. Acta Physiol Scand 120:499-504, 1984. 30. K j m , M. Mikines KJ, Christensen NJ, et al: Glucose turnover and hormonal changes during insulin-induced hypoglycemia in trained humans. J Appl Physiol 5721-27, 1984. 31. Kjzr M, Farrell P, Christensen NJ, et al: Responsiveness of adrenal medullary secretion to exercise in trained and untrained humans. Clin Physiol 5(Suppl4), A54, 1985. 32. Sowers JR, Rubenstein LZ, Stern N: Plasma norepinephrine responses to posture and isometric exercise increase with age in the absence of obesity. J Gerontology 38~315-317, 1983. 33. Dimsdale JE, Hartley LH, Ruskin J, et al: Effect of beta blockade on plasma catecholamine levels during psychological and exercise stress. Am J Cardiol 54:182-185, 1984. 34. Galbo H, Christensen, NJ Holst JJ: Glucose-induced decrease in glucagon and epinephrine responses to exercise in mm, J Appl Physiol42:525-530, 1977. 404 EXERCISE ENDOCRINOLOGY 35. Galbo H, Christensen NJ, Holst JJ: Catecholamines and pancreatic hormones during blockade in exercising man. Acta Physiol Scand 10k428-437, 1977. 36. Grossman A, Bouloux P, Price P, et al: The role of opioid peptides in the hormonal responses to acute exercise in man. Clin Sci 67:483491, 1984. 37. Fagard R, Cattaert A, Lijnen P, et a1 Responses of the systemic circulation and of the renin-angiotensin-aldosterone system to ketanserin at rest and exercise in normal man. Clin Sci 66:17-25, 1984. 38. Watson RDS, Eriksson BM, Hamilton CA, et al: Effects of chronic beta-adrenoceptor antagonism on plasma catecholamines and blood pressure in hypertension. J. Cardiovasc Pharrnacol 2:725-738, 1980. 39. Richter EA, Galbo H, Sonne B, et al: Adrenal medullary control of muscular and hepatic glycogenolysis and of pancreatic hormonal secretion in exercising rats. Acta Physiol Scand 108:235-242, 1980. 40. Hilsted J, Galbo H, Christensen NJ:Impaired responses of catecholamines, growth hormone, and cortisol to graded exercise in diabetic autonomic neuropathy. Diabetes 29~257-262, 1980. 41. Nielsen JR, Gram LF, Fabricius J, et al: Sympathetic hyperreactivity in offspring of essential hypertensive patients. Life Sci 34:2551-2558, 1984. 42. Ehsani AA, Heath GW, Martin WH, 111, et al: Effects of intense exercise training on plasma catecholamines in coronary patients. J Appl Physiol 57:154-159, 1984. 43. Wade CE: Response, regulation, and actions of vasopressin during exercise: A review. Med Sci Sports Exercise 16:506-511, 1984. 44. Gleim GW, Zabetakis PM, DePasquale EE, et al: Plasma osmolality, volume, and renin activity at the “anaerobic threshold.” J Appl Physiol56:57-63, 1984. 45. Bouissou P, Guezennec C, Pesquies PC: Renin-angiotensin-aldosterone system during prolonged exercise. Clin Physiol 5(Suppl4): A100, 1985. 46. Fyhrquist F, Dessypris A, Immonen I: Marathon run: Effects on plasma renin activity, renin substrate, angiotensin converting enzyme, and cortisol. Horm Metabol Res 15:96-99, 1983. 47. Hilsted J, Galbo H, Sonne B, et al: Gastroenteropancreatic hormonal changes during exercise. Am J Physiol 239:G136-G140, 1980. 48. Richter EA, Sonne B, Christensen NJ, et al: Role of epinephrine for muscular glycogenolysis and pancreatic hormonal secretion in running rats. Am J Physiol 240:E526-E532, 1981. 49. Blom PCS, Hsstmark AT, Flaten 0, et al: Modification by exercise of the plasma gastric inhibitory polypeptide response to glucose ingestion. Acta Physiol Scand (in press). 50. Krzentowski G, Pirnay F, Luyckx AS, et al: Metabolic adaptations in post-exercise recovery. Clin Physiol 2:277-288, 1982. 51. James DE, Burleigh KM, Kraegen EW, et al: Effect of acute exercise and prolonged training on insulin response to intravenous glucose in vivo in rat. Appl Physiol 5511660-1664, 1983. 52. Bjomtorp P: Effects of exercise on plasma insulin and glucose tolerance, in; Obesity: Pathogenesis and treatment, Enzi G, Crepaldi G, Pozza G, Renold AE (eds). London New York, Academic Press, 1981, pp 197-205. 53. kotkiewski M, Bjorntorp P, Holm G, et al: Effects of physical training on insulin, connecting peptide (C-peptide), gastric inhibitory polypeptide (GIP) and pancreatic polypeptide (PP) levels in obese subjects. Int J Obesity 8393-199, 1984. 54. Richard D, LeBlanc J: Pancreatic insulin response in relation to exercise training. Can J PhysioI Pharmacol 61:1194-1197, 1983. 55. Galbo H, Hedeskov CJ, Capito K, et al: The effect of physical training on insulin secretion of rat pancreatic islets. Acta Physiol Scand 111:75-79, 1981. 56. Zawalich W, Maturo S, Felig P: Influence of physical training on insulin release and glucose utilization by islet cells and liver glucokinase activity in the rat. Am I Physiol 243:E464-E469, 1982. GALBO 405 57. Ward WK, Halter JB, Beard JC, et al: Adaptation of B and A cell function during prolonged glucose infusion in human subjects. Am J Physiol 246:E405-E411, 1984. 58. James DE, Burleigh KM, Kraegen EW, et al: Effects of exercise training on in vivo insulin action in individual tissues of the rat. Clin Physiol 5(suppl4): A64, 1985. 59. Mikines KJ, Sonne B, Farrell PA, et al: Insulin sensitivity and responsiveness after acute exercise in man, Clin Physiol 5(suppl 4):A67, 1985. 60. Ploug T, Galbo H, Richter EA: Contraction induced glucose transport in rat skeletal niuscle: Additive effect of insulin and monoexponential, glycogen independent reversal in slow and fast twitch red fibers. Clin Physiol S(supp1 4):A68, 1985. 61. Vinten J, Galbo H: Effect of physical training on transport and metabolism of glucose in adipocytes. Am 1Physiol 244:E129-E134, 1983. 62. Vinten J, Nsrgaard Petersen L, et al: Effect of physical training on glucose transporters in fat cell fractions. Biochern Siophys Acta (in press). 63. Zorano A, Balon TW, Garetto LP, et al: Muscle alpha-aminoisobutyric acid transport after exercise: enhanced stimulation by insulin Am J Physiol 246:E575-E580, 1985. 64. Tan MH, Bonen A, Clune PA: Physical training enhanced insulin binding in skeletal muscles but not in liver. Clin Physiol 5(suppl4):A31, 1985. 65. Shepherd RE, Noble EG, Klug GA, et al: Lipolysis and CAMP accumulation in adipocytes in response to physical training. 1Appl Physiol 50:143-148, 1981. 66. Bell PM, Henry RW, Buchanan KD, et al: The effect of starvation on the gastroentero-pancreatic hormonal and metabolic responses to exercise (GEP hormones starvation and exercise). Diabetes Metab 10:194-198, 1984. 67. Trovati M, Lorenzati R, Cassader M, et al: Metabolic effects of short-term treadmill exercise in moderately obese subjects, in Obesity: Pathogenesis and Treatment, Enzi G, Crepaldi G, Pozza G , Renold AE (eds): London-New York, Acadmic Press, 1981, pp 289-296. 68. Galbo H, Richter EA, Holst JJ, et al: Diminished hormonl responses to exercise in trained rats. J Appl Physiol 43:953-958, 1977. 69. Galbo H, Hermansen L, Fahrenkrug J, et a1 The effect of training and glucose ingestion on responses of some GEP hormones to exercise. Clin Physiol S(supp1 4):A45, 1985. 70. Ekblad E, Edvinsson L, Wahlestedt C, et al: Neuropeptide Y co-exists and COoperates with noradrenaline in perivascular nerve fibers. Peptides 8:225-235, 1984. 71. Joborn H, Ljunghall S, Lithell H, et al: Effects of long-term (5 hours-7 days) exercise on mineral homeostasis. Clin Physiol 5(suppl 4):A183, 1985. 72. Ljunghall S, Joborn H, Benson L, et al: Effects of physical exercise on serum calcium and parathyroid hormone. Eur J CIin Invest 14:469473, 1984. 73. Schnabel A, Kindermann W, Steinkraus V, et a1 Metabolic and hormonal responses to exhaustive supramaximal running with and without beta-adrenergic blockade. Eur J Appl Physiol 52214-218, 1984. 74. Vanhelder WP, Randomski MW, Goode RC. Growth hormone responses during intermittent weight lifting exercise in men. Eur J Appl Physiol 53:31-34, 1984 75. Vanhelder WP, Goode RC, Radomski MW: Effect of anaerobic exercise of equal duration and work expenditure on plasma growth hormone levels. Eur JAppl Physiol 52:255-257, 1984 76. Kozlowski S, Chwalbinska-Moneta J, Vigas M, et al: Greater serum GH response to arm than to leg exercise performed at equivalent oxygen uptake. Eur J Appl Physiol 52:131-135, 1983. 77. Hagen TC, Lawrence AM, Kirsteins L: Autoregulation of growth hormone secretion in normal subjects. Metabolism 21:603-610, 1972. 78. Christensen SE, Jsrgensen OL, Maller N, et al: Characterization of growth hormone release in response to external heating. Comparison to exercise induced release. Acta Endocrinologica 107295-301, 1984. 79. Sundkvist G, AlmCr L-0, Lilja B, et al: Growth hormone and endothelial function during exercise in diabetics with and without retinopathy. Acta Med Scand 215:55-61, 1984. 406 EXERCISE ENDOCRINOLOGY 80. Hale RW, Kosasa T, Krieger J, et al: A marathon: The immediate effect on female runners' luteinizing hormone, follicle-stimulating hormone, prolactin, testosterone, and cortisol levels. A m J Obsfet Gynecol 146:550-554, 1983. 81. Schurmeyer T, Jung K, Nieschlag E: The effect of an 1100 km run on testicular, adrenal and thyroid hormones. lnt ] Andrology 7:276-282, 1984. 82. Jezova-Repcekovd, D, Vigas M, Mikulaj L, et a1 Plasma testosterone during bicycle ergometer exercise without and after L-dopa treatment. Endocrinologia Experimentalis 16:3-8, 1982. 83. Johansson G, Uusitupa M, Harkonen M, et al: Hormonal effects of beta-receptor blockade during exercise. Acta Endocrinologica 104:lO-14, 1983. 84. Blake MJ, Stein EA, Vomachka AJ: Effects of exercise training on brain opioid peptides and serum LH in female rats. Peptides 5:953-958, 1984. 85. Johannessen A, Hagen C, Galbo H: PRL, GH, TSH, T, and T4 responses to exercise after fat and carbohydrate enriched diet. J Clin Endocrinol Mefab 52:56-61, 1981. 86. Brisson GR, Ledoux M, Pellerin-Massicotte J, et al: Blood Prolactin response to exercise in adult male athletes: Thermic stress more than osmolar stress. Clin Physiol 5(suppl 4):A93, 1984. 87. Wheeler GD, Wall SR, Belcastro AN, et al: Reduced serum testosterone and prolactin levels in male distance runners. ] A M A 252:514-516, 1984. 88. Milkines KJ, Kjier M, Hagen C, et al: The effect of training on responses of betaendorphin and other pituitary hormones to insulin-induced hypoglycemia. Eur J Appl Physiol (in press, 1985). 89. Russell JB, Mitchell, DE, Musey PI, et al: The role of beta-endorphins and catechol estrogens on the hypothalmic-pituitary axis in female athletes. Fertil Steril42:690-695, 1984. 90. Loucks AB, Horvath SM: Exercise-induced stress responses of amenorrheic and eumenorrheic runners. J Clin Endocrinol Metab 59:1109-1120, 1984. 91. Farrell PA: Adrenocorticotropic hormone and exercise, in Exercise Endocrinology. Fotherby K, Pal SB (eds): Berlin-New York, Walter de Gruyter & Co, 1985, pp 139-156. 92. Brandenberger G, Follenius M, Muzet A: Interactions between spontaneous and provoked cortisol secretory episodes in man. ] Clin Endocrinol Metab 59:406411, 1984. 93. Allenberg K, Holmquist N, Johnsen SG, et al: Effect of exercise and testosterone on the active form of glycogen synthase in human skeletal muscle, in Biochemistry of exercise, Knuttgen HG, Vogel JA, Poortmans J (eds): Champaign, Illinois, Human Kinetics Publishers, Inc., 1983, pp 625-630. 94. Jezov6 D, Vigas M, Klimes I, et al: Adenopituitary hormone response to exercise combined with propranolol infusion in man. Endocrinologia Experimentalis 1791-97, 1983. 95. Brandenberger G, Follenius M, Hietter B: Feedback from meal-related peaks determines diurnal changes in cortisol response to exercise. ] Clin Endocrinol Metab 54:592-596, 1982. 96. Tabata 1, Atomi Y, Miyashita M: Blood glucose concentration dependent ACTH and cortisol reponses to prolonged exercise. Clin Physiol 4:299-307, 1984. 97. Davis HA, Gass GC, Bassett JR: Serum cortisol response to incremental work in experienced and naive subjects. Psychosom Med 43:127-132, 1981. 98. Bach F, Kjier M, Farrell P, et al: Beta endorphin response to supramaximal treadmill exercise in trained and untrained males. Clin Physiol 5(suppl 4):A92, 1985. 99. Howlett TA, Tomlin S, Ngahfoong L, et al: Release of beta endorphin and metenkephalin during exercise in normal women: Response to training. Br Med ] 288~1950-1952, 1984. 100. Kelso TB, Herbert WG, Gwazdauskas FC, et al: Exercise-thermoregulatory stress and increased plasma beta-endorphinbeta-lipotropin in humans. ]. Appl Physiol 57444-449, 1984. GALBO 407 101. Bullen BA, Skrinar GS, Beitins IZ, et al: Endurance training effects on plasma hormonal responsiveness and sex hormone excretion. (J Appl Physiol 56:1453-1463, 1984. 102. Farrell PA, Gates WK, Morgan WP, et al: Plasma leucine enkephalin-like radioreceptor activity and tension-anxiety before and after competitive running, in, International Series Sport Sciences, Vol. 13, Knuttgen HG, Vogel JA, Poortmans J (eds): Champaign, Illinois, Human Kinetics Publ. Inc, 1983, p p 637-644. 103. Markoff RA, Ryan P, Young T: Endorphins and mood changes in long-distance running. Med Sci Sports Exercise 14:ll-15, 1982. 104. Surbey GD, Andrew GM, Cervenko FW, et al: Effects of naloxone on exercise performance. J Appl Physiol 57:674-679, 1984. 105. Galbo H, Hummer L, Petersen IB, et al: Thyroid and testicular hormone responses to graded and prolonged exercise in man. Eur J Appl Physiol 36:lOl-106, 1977. 106. Krotkiewski M, Sjostrom L, Sullivan L, et al: The effect of acute and chronic exercise on thyroid hormones in obesity. Acta Med Scand 216:269-275, 1984. 107. Guezennec CY, Ferre P, Serrurier B, et al: Effects of prolonged physical exercise and fasting upon plasma testosterone level in rats. Eur J Appl Physiol 49:159-168, 1982. 108. Kuusi T, Kostiainen E, Vartiainen E, et al: Acute effects of marathon running on levels of serum lipoproteins and androgenic hormones in healthy males. Metabolism 331527-531, 1984. 109. Webb MA, Wallace JP, Hamill C, et al: Serum testosterone concentration during two hours of moderate intensity treadmill running in trained men and women. Endocr Res 10:27-38, 1984. 110. Guezennec CY, Ferre P, Serrurier B, et al: Metabolic effects of testosterone during prolonged physical exercise and fasting. Eur J Appl Physiol 52:300-304, 1984. 111. Stager JM, Robertshaw D, Miescher E: Delayed menarche in swimmers in relation to age at onset on training and athletic performance. Med Sci Sports Exerc 16:550-555, 1984. 112. Sanborn CF, Martin BJ, Wagner WW Jr: Is athletic amenorrhea specific to runners? A m Obstet Gynecol 143:859-861, 1982. 113. Fisher EC, Nelson ME, Evans WJ, et al: Bone density, gonadotropic and estrogenic hormone levels in amenorrheic and eumenorrheic athletes. Clin Physiol 5(suppl 4):A163, 1985. 114. Carlberg KA, Buckman MT, Peake GT, et al: Body composition of oligo/amenorrheic athletes. Med Sci Sports Exercise 15:215-217, 1983. 115. Clapp JF, 111, Dickstein S: Endurance exercise and pregnancy outcome. Med Sci Sports Exercise 16:556-562, 1984. 116. Galbo H, Gollnick PD: Hormonal changes during and after exercise. Med Sport Sci 17:97-110, 1984. 117. Eldridge FL, Millhorn DE, Waldrop TG: Exercise hyperpnea and locomotion: Parallel activation from the hypothalamus. Science 211:844-846, 1981. 118. Brown MR, Fisher LA: Brain peptide regulation of adrenal epinephrine secretion. Am 1Physiol 247:E41-E46, 1984. 119. Richter EA, Galbo H: Rate of glycogen breakdown and lactate release in contracting, isolated skeletal muscle is dependent upon glycogen concentration. Clin Physiol 5(suppl 4):A82, 1985. 120. Blomstrand E, Bergh U, Essh-Gustavsson B, et al: Influence of low muscle temperature on muscle metabolism during intense dynamic exercise. Acta Physiol Scund 120~229-236, 1984. 121. Sonne B, Galbo H: Carbohydrate metabolism during and after exercise in rats. Studies with radioglucose. J Appl PhysioE (in press). 122. Sonne B, Galbo H: Regulation of hepatic glucose production in exercise. An alternative view. Clin Physiol 5(suppl 4):A57, 1985. 408 EXERCISE ENDOCRINOLOGY 123. Miller WC, Bryce GR, Conlee RK: Adaptations to a high-fat diet that increase exercise endurance in male rats. J AppI Physiol: Xespir Environ Exercise Physiol56:78-83, 1984. 124. GBrski J, Nowacka M, Namiot Z, et al: Accumulation of triglycerides in the liver during exercise. Clin Physiol 5(suppl 4):A71, 1985. 125. Sonne B, Galbo H: Carbohydrate metabolism in fructose fed and food restricted rats. J AppI Physiol (in press). 126. Galbo K: The hormonal response to exercise. Proceedings of the Nutrition Society 44~257-265, 1985. 127. Galbo H: Autonomic neuroendocrine responses to exercise. Srand 7 Sports Med, (in press).