9
Endocrinology

Introduction

The endocrine, nervous, and immune systems regulate the human response to spaceflight and the readjustment processes that follow landing. There is a multidirectional flow of information among these three systems, which together are responsible for maintaining homeostasis and reestablishing homeostasis if it is perturbed.1 2 3 4 5 6 Quite apart from the intrinsic scientific interest of the underlying mechanisms, a basic knowledge and understanding of the effects of spaceflight on the endocrine and neuroendocrine systems are essential to the rational development of countermeasures.

Aspects of endocrine influence on specific organ systems are addressed in several chapters of this report. This chapter stresses integrative homeostatic functions of the endocrine and neuroendocrine systems. The principal spaceflight responses with a significant endocrine contribution are fluid shifts, perturbation of the circadian rhythms, loss of red blood cell mass, possible changes in the immune system, loss of bone and muscle, and maintenance of energy balance. The last three are chronic responses, whereas fluid shifts occur only after entry into a microgravity environment and again after return to Earth. Whether perturbations of circadian rhythms and loss of red blood cell mass are short- or long-term problems is not known.

In the space station era, systems physiology research will shift from the investigation of the acute responses to spaceflight to the long-term effects.7 The former are associated with large, immediate changes in certain hormones. Thus, the change in blood volume, red cell mass, and the associated fluid shifts are acute responses to the novel environment, with appropriately large and immediate changes in hormone levels such as ADH (antidiuretic hormone, or vasopressin), aldosterone, and norepinephrine. What is needed is a focus on the problems of long-term spaceflight, specifically calcium loss from bone, muscle atrophy, energy balance, and the possible perturbation of circadian rhythms.

Many biological investigations involve endocrine measurements. Such measurements are often not the primary focus of the study but are necessary to identify the perturbation mechanism that is the actual



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--> 9 Endocrinology Introduction The endocrine, nervous, and immune systems regulate the human response to spaceflight and the readjustment processes that follow landing. There is a multidirectional flow of information among these three systems, which together are responsible for maintaining homeostasis and reestablishing homeostasis if it is perturbed.1 2 3 4 5 6 Quite apart from the intrinsic scientific interest of the underlying mechanisms, a basic knowledge and understanding of the effects of spaceflight on the endocrine and neuroendocrine systems are essential to the rational development of countermeasures. Aspects of endocrine influence on specific organ systems are addressed in several chapters of this report. This chapter stresses integrative homeostatic functions of the endocrine and neuroendocrine systems. The principal spaceflight responses with a significant endocrine contribution are fluid shifts, perturbation of the circadian rhythms, loss of red blood cell mass, possible changes in the immune system, loss of bone and muscle, and maintenance of energy balance. The last three are chronic responses, whereas fluid shifts occur only after entry into a microgravity environment and again after return to Earth. Whether perturbations of circadian rhythms and loss of red blood cell mass are short- or long-term problems is not known. In the space station era, systems physiology research will shift from the investigation of the acute responses to spaceflight to the long-term effects.7 The former are associated with large, immediate changes in certain hormones. Thus, the change in blood volume, red cell mass, and the associated fluid shifts are acute responses to the novel environment, with appropriately large and immediate changes in hormone levels such as ADH (antidiuretic hormone, or vasopressin), aldosterone, and norepinephrine. What is needed is a focus on the problems of long-term spaceflight, specifically calcium loss from bone, muscle atrophy, energy balance, and the possible perturbation of circadian rhythms. Many biological investigations involve endocrine measurements. Such measurements are often not the primary focus of the study but are necessary to identify the perturbation mechanism that is the actual

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--> subject of investigation. Studies of bone calcium losses are an example. In contrast with other systems such as fluid and electrolyte balance and circadian rhythms, and for some muscle experiments, endocrine measurements are the primary focus of the study. Thus many of the chapters in this report refer to making endocrine measurements. In the past, postflight measurements have been used to extrapolate back to the in-flight situation. Postflight hormone measurements are not an adequate substitute for in-flight measurements because they measure only the postflight situation. The half-life of most hormones in the plasma is too short—usually on the order of minutes or less—to have any bearing on any situation except the one that exists at the time the sample was collected. Current Status of Research Effects of Spaceflight on Humans The human body seems to have little difficulty in restoring and maintaining homeostasis in those systems that must respond rapidly—specifically, the resetting of the cardiovascular, vestibular, and hematopoietic systems, together with the regulation of fluid and electrolyte balance. The problems that arise are in systems that acclimate slowly to a new situation, particularly muscle, bone, and energy balance, and possibly the circadian timing system. Failure to maintain bone and muscle mass and regulate energy metabolism at 1 g are major health care problems. Our current knowledge of the effects of spaceflight on humans is based largely on the results obtained on Skylab years ago and on the more recent SLS-1 and SLS-2 (Space Life Sciences 1 and 2) shuttle missions. The experiments that were conducted and samples collected on these missions match those expected from high-quality ground studies. New information of comparably high quality is expected when the results become available from the 1996 Life and Microgravity Sciences and the 1998 Neurolab shuttle missions. Neurolab was the last of a series of space shuttle Spacelab missions with a complement of experiments in the life sciences. Entry into Earth orbit elicits a metabolic stress response.8 9 The metabolic response of the human body to a physiological stress consists of an orderly and tightly controlled series of reactions. These responses include activation of the hypothalamic-pituitary-adrenal (HPA) axis, increases in the whole-body protein turnover rate and acute phase protein synthesis, increased gluconeogenesis, substrate cycling, proinflammatory cytokine activity, basal energy expenditure, and loss of body protein.10 11 12 13 14 15 16 17 18 19 Collectively, these reactions limit the extent of the injury or stress, protect the rest of the organism against any further stresses by mobilizing host defense mechanisms, and initiate various processes aimed at restoring the organism's homeostatic balance. The process has been termed the metabolic stress or hypermetabolic response and is regulated by the combined effects of the central nervous system and neuroendocrine and immune systems. Hypothalamic-Pituitary-Adrenal Axis Most of these responses result from activation of the hypothalamic-pituitary-adrenal (HPA) axis.20 21 22 23 24 25 26 Secretion of the anterior pituitary hormones is regulated by the release of neurohormones from the hypothalamus, by both direct and indirect feedback from target tissue hormones, and by the immune system via cytokines. The secretion of the anterior pituitary hormones is regulated by the release of neurohormones from the hypothalamus and by the direct/indirect feedback from target tissue hormones and by the immune

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--> system. Of particular significance for the response to stress is the enhanced release of adrenocorticotropic hormone (ACTH) from the pituitary, which stimulates glucocorticoid release by the adrenal cortex. An increase in cortisol production is a good marker for a metabolic stress response. During the first day or two of spaceflight, there is increased cortisol secretion, protein turnover, acute phase protein synthesis, and activation of the proinflammatory cytokine IL-6.27 Protein breakdown is increased more than synthesis, and so the net effect is a loss of body protein. 28 29 The rise in protein turnover reflects the increased synthesis of proteins involved in host defenses. Thus, fibrinogen synthesis is increased even though there was no actual injury.30 All of these measurements indicate that entry into orbit is associated with a metabolic stress response, which is over after about 1 week in space. 31 There is currently little interpretable in-flight data on the endocrine system beyond the initial response period (less than 1 week), and obtaining reliable data has been difficult for the following reasons: (1) Observations from spaceflight experiments may have three components: mission specific, microgravity specific, and genetic. Mission-specific components include low dietary intakes, varying levels of activity, mission-specific elements of stress, and failure to allow the subjects to adapt their circadian rhythms to the mission. Attention should be paid to separating these effects and minimizing any interference from mission-specific components. (2) Conflicting experiments. Careful preflight planning can minimize the occurrence of this potential difficulty. (3) The endocrine changes associated with the chronic effects of spaceflight (bone calcium loss, muscle atrophy, and possible shifts in energy balance) are likely to be small and therefore difficult to detect except under very carefully controlled conditions. Nevertheless, the cumulative effects of small changes in endocrine response can result in the characteristic bone loss and muscle atrophy that are found. The absence of reliable endocrine measurements can preclude drawing conclusions about the in-flight mechanism. Collection of data of the quality needed to detect small changes has proven problematic for individual experiments because of the time and resources needed to collect a quality set of controlled endocrine measurements for an individual experiment. Without these data, an understanding of the human response and adaptation to spaceflight will be impossible. Integrating experiments encompassing the best of several different investigator groups into one program offer the best hope of obtaining quality data using limited in-flight resources. Even though the details of the mechanism are not known, spaceflight clearly induces multiple changes within the endocrine system. These can be characterized as changes in the interrelationship among hormones and alterations in the sensitivity of responding systems. Obtaining a baseline data set will be more complex than just obtaining a series of controlled blood and urine samples, because many hormones are released in a pulsatile manner; the frequency of the pulses, the quantity per pulse, and the total released over a 24-hour period are likely to be important factors in defining the endocrine responses to spaceflight. Defining what should constitute the baseline set of hormone measurements and when in-flight the measurements should be made should be left to a future group of experts in this field. Making these measurements properly once, so that the question does not have to be revisited, should be given very high priority. Measurements should be made both early and late in the mission. Serial blood sampling will be required, and the measurement period would probably extend over 2 to 5 days. Full use should be made of novel technologies now available for making precise measurements on small blood samples. Alterations in endocrine activity can be expressed at the level of the concentration of the circulating hormone, receptor activity, and the subsequent signal transduction. To date, only hormone concentrations have been measured during spaceflight. Although it is reasonable to assume that any spaceflight-induced

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--> alteration in the circulating level of a hormone has some physiological significance, the absence of an observable change may not always imply that the effect of the hormone in question is unaltered. There is always the real possibility that the response may be altered at the receptor or transduction stages. These issues require invasive studies and as a result can only be addressed in ground models. Models Most ground-based animal studies to date have been done on rats and monkeys. In contrast to the human situation where some in-flight data is available, there is little useful in-flight animal endocrine data available to compare against the data derived from ground-based models. There is data from some of the Russian Bion missions, but most of it (and earlier Soviet data) is difficult to interpret because there was no in-flight monitoring of the test animals. The animals are not recovered until several hours postflight, and the landing is rough and may cause alterations and even injury or damage. Postflight data primarily reflect the stresses involved in landing and recovery and cannot be extrapolated to the in-flight situation.32 Assessing the relevance of rodent studies for humans is difficult. The situation with humans may be different for a number of reasons: 33 34 (1) Humans do not vegetate in space,35 they make a conscientious effort to maintain health, and they exercise and are aware of the need to eat. (2) Space vehicles are designed to minimize changes from the normal lifestyle for astronauts, whereas the animals are often housed in confining conditions and their movement is often restricted. The environment may be quite stressful for reasons not related to spaceflight. Space life support systems are necessarily noisy, and the noise may disturb the rats. (3) Some flight studies use immature rats, because their smaller size allows fitting more rats into the cages. As a result, the body weight and muscle changes found include a "rate-of-growth" component. In contrast, human flight crew members are mature adults. (4) Psychological factors may be important, because emotions can influence the hormonal response (see Chapter 12). With these caveats, the rodent may be a better subject for endocrine studies designed to characterize the basic effects of microgravity, simply because more can be done with rodents than with humans. Any extrapolation of the results to humans must take the above factors into account. Although flight experiments should be the primary focus, there is a continuing need for ground-based studies with the appropriate models. Currently available models range from whole body (human bed rest, rodent hindlimb unloading, centrifugation) to tissue culture systems. 36 Ground-based studies are not subject to the numerous restrictions and variations of spaceflight investigations and therefore provide the opportunity to elucidate mechanisms at the cellular and molecular levels. However, care must be taken to ensure that the model studied is appropriate. Recommendations The following recommendations are listed in order of priority. Studies should obtain a baseline in-flight human hormone profile early and late in-flight. As a control, the measurement set should include preflight measurements on the same individual over an extended period of time. Studies should also continue to evaluate the relevance of ground-based models to spaceflight. Researchers should continue to construct the human component of the life sciences database so that the issue of human variability can be addressed by modern statistical techniques.

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--> Energy Metabolism And Balance Energy expenditure for comparable ground-based activity is reduced in space for both humans and monkeys.37 38 39 The principal hormone regulating energy metabolism is thyroxine (T3). Urine gives a time-averaged value, and in-flight urine analyses on the SLS-1 and SLS-2 crew showed a consistent decrease of about 40 percent in the urinary excretion of T3. Astronauts are anabolic during the postflight period; as expected for an anabolic state, there has been a consistent finding of increased plasma T3 concentrations.40 41 42 43 Likewise, most but not all thyroid-stimulating-hormone (TSH) measurements were increased postflight.44 45 46 47 The complicating role of nutrition tends to confound the interpretation of human experiments involving endocrine studies. Most hormones that are of interest are sensitive to nutritional intake and status. There may be a problem in maintaining energy balance during spaceflight in missions where there is a high level of physical activity. Two in-flight energy balance studies have been done,48 49 50 the first on Skylab using a combination of dietary intake and body composition measurements,51 and the second on the Life and Microgravity Sciences (LMS) shuttle mission using the doubly labeled water method.52 In both cases, astronauts were in negative energy balance. On the long-term Skylab mission, the deficit was about 3 kcal kg-1 day-1, with the deficit being greatest during the first month and tapering off toward the end of the mission (Table 9.1).53 On the 16-day LMS mission, the average energy deficit for the four payload crew members was ˜10 kcal kg-1 day-1.54 The deficit on the LMS mission was due to a shortfall in energy intake (24 kcal kg-1 day-1) rather than an increase in energy expenditure (34 kcal kg-1 day-1).55 The negative energy balance and consequent greater N (protein) losses found in astronauts on the Skylab and LMS missions are a mission-specific response rather than a general response to spaceflight. Both missions had a heavy exercise component, whereas SLS-1 and SLS-2 did not. This raises some questions: (1) Is it possible to maintain energy balance with a substantial exercise regimen? On the ground, some exercise studies have reported a cachectic effect from intensive exercise.56 57 58 (2) What contribution does negative energy balance make to muscle protein loss? As on the ground, if energy TABLE 9.1 Comparison of Energy Intake, Expenditure, and N Balance for First 12 Days of Spaceflight Vehicle Energy intake (kcal kg-1 day-1) N balance (mg N × kg-1 day-1) Energy balance (kcal kg-1 day-1) Skylaba-c 37 ± 1 (9) -19 ± 6 (9) -3 Shuttle, SLS-1, SLS-2d 30 ± 2 (11) 16 ± 3 (11) ~0 Shuttle, LMSe 24 ± 2 (4)   -10 a The energy balance value for Skylab is averaged over the duration of the Skylab missions (28 to 84 days). b Rambaut, P.C., Leach, C.S., and Leonard, J.I. 1977. Observations in energy balance in man during spaceflight. Am. J. Physiol. 233:R208-R212. c Leonard, J.I., Leach, C.S., and Rambaut, P.C. 1983. Quantitation of tissue loss during prolonged spaceflight. Am. J. Clin. Nutr. 38:667-679. d Stein, T.P., Leskiw, M.J., and Schluter, M.D. 1996. Diet and nitrogen metabolism during spaceflight on the shuttle. J. Appl. Physiol. 81:82-92. e Stein, T.P., Schluter, M.D., Leskiw, M.J., Gretebeck, R.J., Lane, H.W., and Hoyt, R.W. 1998. 1 year report of the LMS Shuttle mission. NASA, Washington, D.C.

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--> intake is inadequate, exercise will probably exacerbate the loss of body protein during spaceflight.59 60 61 (3) Does a negative energy balance also affect bone homeostasis? (4) Is there a dietary problem? Dietary intake on the recent LMS mission in 1996 (24 kcal kg-1 day -1) was remarkably low, although exercise levels were much greater on this mission than on SLS-1 and SLS-2. The poor dietary intake raises questions as to whether enough time was allocated for eating on this busy mission, whether there were "taste" problems with diet, or whether something more serious occurs when there is a heavy exercise schedule. Construction and maintenance of the International Space Station will require many hours of extravehicular activity (EVA) where energy costs are high (200+ kcal/hr).62 On missions with a heavy exercise component, there is apparently a problem in maintaining energy balance. Clearly, an inadequate energy intake will lead to a starvation response, and the hormonal associations with that response may well mask any microgravity-induced changes. Attention needs to be paid to diet; for the data to have any validity, they must be collected under conditions where subjects are in or at least near to energy balance. Beyond its importance for interpretation of scientific data, it is essential for crew health that astronauts be in approximate energy balance. Ensuring that this is the case for all astronauts should be given a very high priority, since prolonged periods of negative energy balance create serious health concerns. Apart from the loss of muscle and decreased physical performance,63 64 there is progressively increasing susceptibility to infection.65 66 67 Decreased immunocompetence during spaceflight has been reported.68 69 70 Would healing is also compromised, which may be a problem if injury ever occurs during spaceflight.71 72 73 Recommendations Ensure adequate dietary input during spaceflight. Energy intake must meet needs, and physiological measurements must be made on subjects that are in approximate energy balance so that measurements are not confounded by an undernutrition response. Furthermore, a chronic negative energy balance is detrimental to overall health. The relationship between the amount of exercise and the protein and energy balance in-flight needs to be investigated. Of lesser priority is the need to address the question of the quality and acceptability of in-flight diets. Reproduction The success of reproduction is highly dependent upon a diverse set of hormonal changes. A single aberration in either males or females can result in the inability to reproduce. The ultimate sign of acclimation to a new environment is the ability to reproduce the species. Alterations of the reproductive hormones during spaceflight are poorly understood. As yet, there is no information about the effects of exposure to spaceflight on the endocrine profile of females. In males, a reduction in testosterone levels has been reported during flight and postflight in both rats74 75 76 and humans.77 The reduction in testosterone in rats during spaceflight is not associated with changes in spermatogenesis in relatively short flights,78 and the ability of humans to reproduce following spaceflight does not appear to be an issue. However, the ability of mammals to reproduce during spaceflight has yet to be evaluated. The rearing of multiple generations in space and a clear understanding of the changes in hormones important in maturation and reproduction will be essential to the acclimation to spaceflight and the success of colonization of remote planets. (For additional discussion of developmental biology, see Chapter 3.)

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--> Fluid and Electrolyte Balance Upon entry into orbit, the body loses water, and water also shifts from the lower to the upper body. The cephalic fluid shifts result in facial edema,79 80 decreased leg volume,81 and decreased plasma volume.82 It is believed that these changes are effected to reduce a postulated increase in intrathoracic blood volume by the Gauer-Henry response,83 (the inhibition of ADH secretion by an increase in arterial pressure). Leach's SLS-1 and SLS-2 experiment showed that if the Gauer-Henry mechanism is operative, it is over within the first day in orbit.84 Most of the initial reduction in body mass is from a loss of water. Electrolytes are lost, and there are some changes in blood hormone concentrations and hormones excreted in the urine. Changes in fluid-electrolyte metabolism and kidney function are secondary to the hypohydration status, which stimulates the hormonal systems responsible for fluid-electrolyte homeostasis. The principal hormone changes are summarized below. All of the in-flight fluid and electrolyte data are from human studies. Hormonal Systems and Changes Anti-Diuretic Hormone On the ground, a reduction in plasma volume and an increase in blood osmolality are the main physiologic stimulants of antidiuretic hormone (ADH) secretion. The osmolality increases that occur with spaceflight do not seem to be large enough to cause consistent increases in ADH secretion during flight.85 Thus, overall urinary ADH decreased during both the long-term Skylab86 and Salyut-7 missions.87 On a later Salyut flight, a transient increase of <100 percent was found.88 Smith suggested that this increase may result from the combination of exercise and the high ambient temperature and CO2 levels aboard.89 During the first day on the shuttle, ADH levels increased in both plasma and urine.90 91 On SLS-1 and SLS-2, ADH returned to baseline by the end of the first day in space and remained unchanged for the rest of the mission.92 Aldosterone The renin-angiotensin-aldosterone system is also involved in the regulation of fluid and electrolyte balance. Most studies of aldosterone have been done on urine, and consistent increases in aldosterone levels have been reported.93 94 On Skylab, urinary aldosterone levels were elevated for the entire flight.95 Similar findings were made on Mir during the 25-day Mir-Aragatz flight96 and at the end of the 8-month Salyut-7/Soyuz-T mission.97 Overall plasma aldosterone was elevated during the first month on Skylab and then returned to baseline for the remaining 2 months in space.98 99 The results from shuttle experiments are conflicting, with increases in aldosterone levels being reported on some missions100 but (except for the first day in orbit) not on SLS-1 and SLS-2.101 The postflight data on plasma aldosterone levels are conflicting. Plasma aldosterone levels were increased after Skylab,102 shuttle missions,103 104 105 a Russian short-term mission,106 and some of the long-duration Russian flights.107 108 But after other long-term Soviet Salyut missions, plasma aldosterone levels were lower than preflight.109 In contrast, urinary aldosterone has consistently been elevated in the immediate postflight period.110 111 112 113 114 This increase has been ascribed to the need to retain sodium postflight. 115 The lack of significant changes during the SLS-1 and SLS-2 missions may have been because crew members were encouraged to maintain fluid intake. This result suggests that the aldosterone changes are intake related and are no longer of any great interest.

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--> Angiotensin Angiotensin concentrations are usually assessed indirectly by measuring renin activity. Plasma renin activity of Skylab crew members decreased for the first 2 days in space and the increased.116 117 During the first month on Skylab, plasma renin levels were elevated most of the time.118 Similarly, on SLS-1 and SLS-2, plasma renin levels were elevated on some but not all days.119 With increasing in-flight time on Skylab, the fluctuations stabilized after the first month, with angiotensin 1 levels being consistently elevated.120 Levels were also elevated during the eighth month of the Soviet Salyut-7 mission. 121 As with ADH, the fluctuations are within the normal range and appear to have little physiological significance. Atrial Natrurietic Factor Atrial natrurietic factor (ANF) has been measured in both urine and plasma. Urinary ANF was reduced at most sampling times during the first 8 days of two early shuttle flights, although there were "spikes" where the in-flight values were above the mean.122 The decrease occurs as early as 5 hours in-flight, probably as a result of the decrease in central venous pressure.123 On the more recent SLS-1 and SLS-2 missions, where sample collection was more controlled, a constant decrease in ANF was found with a trend increasing toward the preflight value by the end of the mission.124 Catecholamines On Earth, catecholamines have widespread effects on systems ranging from blood pressure to substrate metabolism. Most studies found no consistent change in epinephrine with spaceflight.125 126 A Russian report from the long-duration Salyut-7 mission found increases in catecholamine levels toward the end of the mission, but these did not appear to be physiologically significant.127 Norepinephrine is decreased, although the significance of this is not clear.128 129 130 131 It is likely that much more will be known about the neuroendocrine system as a result of the 1998 Neurolab mission. Summary Comments Hundreds of humans have flown in space with no apparently serious consequences from the fluid shifts. The observed variations in hormonal response can be attributed to differences between missions and other mission-related factors such as dietary salt content and water consumption. 132 The SLS-1 and SLS-2 data provided the best values to date, and they showed little change in endocrine status. It is not likely that more studies will help us learn much more about the endocrine control of fluid balance. From an endocrine standpoint, the fluid shifts are unlikely to be of much importance for long-term missions, since there have been no reports of clinical consequences from the readjustment of fluid balance. Further study of the renal-endocrine relationships in microgravity is unlikely to contribute significantly to the study of disturbances in fluid and electrolyte equilibrium on Earth Models Bed rest, particularly with 6° head-down tilt, has been the model of choice for investigating fluid shifts. Because the model is so convenient and reproduces the symptoms of spaceflight reasonably well, there has been little interest in other models.

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--> Recommendation Although not of high priority, further studies on the endocrine changes associated with the fluid shifts in microgravity may be a useful adjunct to studies of the fluid shifts that occur on return to Earth. Hematology In-flight Observations Spaceflight anemia characterized by decreased red blood cell (RBC) mass has been noted since the early days of human spaceflight.133 134 Typically, there is a 1 percent daily loss of RBC mass, resulting in as much as a 10 percent decrease in total blood volume. Erythropoietin, the hormone responsible for stimulating RBC production, decreases in-flight.135 Along with the decreased reticulocytes136 and the absence of any evidence of hemolysis in-flight, this suggests that the observed anemia results from decreased RBC production rather than increased RBC destruction. Comprehensive experiments by Alfrey et al. conducted aboard SLS-1 and SLS-2 provided an understanding of the mechanisms underlying spaceflight anemia.137 138 These studies also provided new information on the role of erythropoietin in both the production and maturation of RBCs. Preflight and in-flight isotopic labeling studies were performed on six astronauts. In these studies, plasma volume (PV) decreased approximately 17 percent on the first day of flight, and although it increased slightly by 8 to 14 days in orbit, it remained significantly below preflight levels. Plasma volumes returned to normal by about 1 week after flight. Both RBC count and hemoglobin increased in-flight, as would be expected with the marked decrease in plasma volume. Serum erythropoietin showed substantial variability, but a statistically and physiologically significant decrease was detected early in-flight, and a significant rise occurred postflight. Serum iron levels in spaceflight and on Earth did not differ, but in-flight incorporation of 59Fe was 66 percent of preflight levels when measured after 22 hours in orbit. Although RBC production decreased in-flight, the survival rate of labeled RBCs was not changed by spaceflight.139 140 Spaceflight anemia appears to be a self-limiting and appropriate response to fluid shifts associated with microgravity. Space motion sickness induces decreases in fluid intake. This, along with increased regional perfusion with increased vascular permeability, causes shifts of fluid from plasma out of the intravascular compartment. The relative increases in RBC mass and hemoglobin concentration cause decreased erythropoietin production, which persists until RBC mass normalizes to a level appropriate for the persistently reduced in-flight plasma volume. Over time, the plasma volume and hemoglobin concentration are normal; however, when plasma volume increases postflight, an anemia is seen, because the reduced RBC mass is now distributed in a "normal" plasma volume. Increased erythropoietin levels quickly return RBC mass to normal within 1 to 2 weeks of return to gravity. Perhaps the most surprising result from this study was the extent to which RBC production decreased with the decrease in erythropoietin. It had been generally thought that erythropoietin regulates the number of blast-forming erythroid units, which determine the number of proerythroblasts and therefore the number of RBCs produced.141 Koury and Bondurant noted that there appears to be a substantial excess of blast-forming erythroid units and that erythropoietin is required for their survival. 142 Thus, in their model, erythropoietin actually regulates apoptosis in the bone marrow. The data from SLS-1 and SLS-2 are entirely consistent with this hypothesis and provide some of the best experimental support available for understanding the role that erythropoietin plays in RBC formation. The Koury and Bondurant study143 was important for the space program. It was one of the first

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--> instances in which a systematic scientific approach to a spaceflight-induced change not only resulted in an explanation of why the observed change occurred, but also it added to our knowledge of how red blood cell volume is controlled. It was the first study to show that the control of the red blood cell mass resides in part outside the bone marrow. Models The rat has been used as a general model for studying erythropoiesis in both ground-based and in-flight studies.144 However, from the limited data available to date (from SLS-1 and SLS-2), it appears that there may be important differences between rat and human erythropoiesis. In both cases, spaceflight affects the bone marrow progenitor cells; but in rats, there appears to be no effect on peripheral erythroid parameters. The reason for this discrepancy is not understood. Recommendations Further hematology research is not of the highest priority. As a result of the SLS-1 and SLS-2 studies, the hematological changes must be regarded as one of the best-understood physiological changes that occur during spaceflight. Where the opportunity is available, it would be useful to refine the details of these processes, particularly that of sequestration in bone. Investigations of how erythropoiesis is regulated by hyper- and hypogravity should be continued with human and rodent models. Endocrine Aspects of Muscle Loss A decrease in muscle mass has been a consistent finding in humans and animals after short- and long-term missions. As expected, the decrease is found principally in muscles with antigravity functions in the back and the legs. It is likely that spaceflight induces muscle loss through remodeling, with the adaptation and the retention of functions needed for the new status. If there is an energy deficit, the remodeling response will also include a simple starvation-type muscle loss component. The anatomical, physiological, and biochemical changes in muscle are discussed in detail in Chapter 7. This section focuses on the nutritional and endocrine involvement. As yet there are no fully effective measures for preventing the muscle atrophy associated with spaceflight. Exercise provides some protection, but whether some sort of exercise program alone will suffice or if other approaches need to be considered is not known. It is clear that current exercise procedures are not wholly effective, for the problem persists. Further development of in-flight measures requires that the nature of the atrophy be defined at a biochemical level in humans, and this requires a detailed knowledge of the endocrine changes. As described in detail in Chapter 7, much is now known about the molecular and cellular aspects of responses of rodent muscles to unloading. Muscle atrophy and remodeling involve changes in the synthesis and breakdown of muscle proteins. These two processes are regulated primarily by hormones; however, at 1 g there are many pathways by which changes in human muscle protein content can be carried out. Pathways that have been proposed as relevant to the spaceflight situation include a bed rest/atrophy response,145 146 an energy deficit,147 148 149 a metabolic stress response,150 151 altered activity of the HPA axis,152 153 154 tension-induced remodeling,155 156 and altered neuroendocrine signals.157 Each of these proceeds via different mechanisms, and there are different ground-based models for each. For atrophy, there is bed rest and hindlimb suspension; for an energy deficit, starvation; for altered HPA axis

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--> function, hindlimb suspension with manipulation of the HPA axis hormones; for remodeling, applying tension to muscle cells in tissue culture and possibly also hindlimb suspension; and for the neuroendocrine hypotheses, denervation. Good progress is being made in tracing the mechanisms of the various models to the molecular level in ground-based studies (Chapter 7). However, the relationships between in-flight data and data obtained from ground-based models, and between data on animal systems (particularly in-flight rodent experiments) and on humans in space, are not known. The principal hormones and hormone systems that have been implicated to date in humans are insulin, hormones of the HPA axis, and prostaglandins, as well as the hormones that regulate energy metabolism (T3) previously discussed. Hormones Involved Insulin Insulin is an important factor in the regulation of muscle protein synthesis and breakdown, and insulin activity and resistance are therefore likely to be closely associated with muscle protein loss. 158 Many ground-based studies have shown a correlation between insulin levels, insulin resistance, and decreased nitrogen balance.159 160 161 162 Insulin data are difficult to interpret in the absence of parallel dietary data. The Skylab data are conflicting. After an initial drop in insulin levels, there was a trend toward an increase, followed by a very sharp drop and then a spike between the third and fourth weeks in-flight.163 For the remaining two months of the mission, plasma insulin levels were less than preflight levels. A study on a single subject suggested that glucose tolerance might be impaired during spaceflight, implying the development of insulin resistance. 164 On SLS-1 and SLS-2, insulin secretion increased with time in orbit, even though dietary intake was significantly less than preflight. 165 Other in-flight studies have demonstrated both insulin resistance together with variable increased insulin activity and increased insulin secretion during spaceflight. There is a good correlation between the increased insulin secretion and the protein loss.166 Progressively increasing insulin secretion and decreased nitrogen retention are consistent with the development of insulin resistance and with a role for the insulin resistance in the etiology of the poorer nitrogen balance found toward the end of the mission.167 Postflight measurements by the Skylab investigators and Soviet scientists showed that postflight plasma insulin levels were increased, an increase that persisted for as long as 2 weeks after landing.168 169 This increase was probably associated with an increase in dietary intake and so was part of an anabolic response. Adrenocorticotropic Hormone The Skylab investigators found that plasma adrenocorticotropic hormone (ACTH) levels were depressed early and late in-flight, while growth hormone (GH) levels were elevated early in-flight and then declined toward the end of the mission relative to preflight baseline.170 171 On the early shuttle missions, there was an initial increase followed by a return to the preflight value of plasma ACTH.172 The one subject studied by Gauquelin on MIR showed an increase in ACTH level.173 Under the more carefully controlled conditions of the SLS-1 and SLS-2 missions, ACTH levels were unchanged during the 2 weeks of the mission and increased on landing which is in agreement with prior findings.174

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--> Circadian Rhythms Circadian rhythms serve to coordinate the physiology and behavior of an animal so that they are in synchrony with environmental needs. There are daily, monthly, and even annual rhythms, with out-of-phase circadian rhythms leading to chronic fatigue and impaired performance on the ground.215 216 There is some evidence that spaceflight affects circadian rhythms.217 218 219 220 221 This is potentially of serious concern because it could lead to avoidable "human" errors (see Chapter 12). The monkey has proven to be a useful model for studying circadian rhythms, but the future of this program is currently uncertain. Fuller et al. studied the effects of the spaceflight environment on circadian rhythms of male rhesus monkeys flown on the Russian Bion missions. 222 During flight, the animals were maintained on a 24-hour (light [16-hr]-dark [8-hr]) cycle. This enabled the animals to maintain normal heart rate cycling and motor activity, even though actual heart rate was decreased, presumably because of the lower rate of energy expenditure.223 224 In contrast, several studies have now documented delays in the phasing of body temperature rhythms in monkeys and rats.225 226 227 This discrepancy probably reflects the presence of more than one pacemaker in the body.228 Perturbed circadian rhythms are not unique to monkeys; the free-running activity rhythm of beetles was decreased,229 as was spore formation in the fungus Neurospora crassa.230 Circadian rhythms are important and should be assigned a high priority. Quite apart from performance and psychosocial effects (which are discussed in Chapter 12), there may be other unrecognized effects of out-of-phase circadian rhythms—for example, the perturbation of growth-hormone secretion that occurs when sleep patterns are disrupted. Although there are several ways of determining circadian rhythms, including temperature monitoring, plasma metabolite levels, and the diurnal variation of the secretion of various hormones, there are few useful human data from flight experiments. The spaceflight-induced changes in human circadian rhythms need to be determined and countermeasures developed if warranted. There is good evidence from ground-based studies that countermeasures using a combination of light therapy and melatonin treatment are effective in resetting the human biological clock.231 Recommendations The study of circadian rhythms is a high-priority area for research. In order of priority, the recommendations are as follows: The effect of spaceflight on human circadian rhythms needs to be determined. If significant degradation of performance is found, and it can be attributed to the disturbed circadian rhythm, the use of countermeasures (including the use of a combination of light and melatonin) should be explored. Gender An important issue about which little is known is whether there are gender differences in the human response to spaceflight. The differences in body composition, particularly the degree of musculature and bone mass, could affect the response of women astronauts to spaceflight. Stress and strenuous exercise can induce amenorrhea, which (like menopause) has been shown to cause bone loss. Furthermore, on Earth the incidence of osteoporosis is much higher in women because women have less bone mass to start with. Women may therefore be at higher risk following microgravity-induced bone loss.

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--> There is reason to suspect that differences will be found in systems other than the obvious ones of bone and muscle. In a ground-based study,232 Vernikos and colleagues showed that male and female subjects showed marked differences in endocrine responses to 7 days of 6° head-down bed rest. All of these changes are regulated by various aspects of the endocrine system. Therefore, as part of its program to include women on missions, NASA should monitor the data to investigate whether there are significant gender differences in the human response to spaceflight. Should evidence of differences become apparent, a high priority must be given to investigating their significance. Recommendation NASA should continue to examine data from in-flight and ground-based model experiments, for gender differences in the response to microgravity. References 1. Bellomo, R. 1992. The cytokine network in the critically ill. Anaesth. Intensive Care 20: 288-302. 2. Besedovsky, H.O., and DelRey, A. 1982. Immune-neuroendocrine circuits: Integrative role of cytokines. Front. Neuroendocrinol. 13: 61-94. 3. Nistico, G., and De Sarro, G. 1991. Is interleukin-2 a neuromodulator in the brain? Trends Neurosci. 14: 146-150. 4. Madden, K.S., and Felten, D. 1995. Experimental basis for neural immune reaction. Physiol. Rev. 75: 77-106. 5. Hughes-Fulford, M. 1993. Review of the biological effects of weightlessness on the human endocrine system. Receptor 3(3): 145-154. 6. Berg, H.E., and Tesch, P.A. 1996. Changes in muscle function in response to 10 days of lower limb unloading in humans. Acta Physiol. Scand. 157: 63-70. 7. Space Science Board, National Research Council. 1987. A strategy for Space Biology and Medical Sciences for the 1980s and 1990s. National Academy Press, Washington, D.C. 8. Stein, T.P., Leskiw, M.J., and Schluter, M.D. 1993. The effect of spaceflight on human protein metabolism. Am. J. Physiol. 264: E824-E828. 9. Stein, T.P., Leskiw, M.J., and Schluter, M.D. 1996. Diet and nitrogen metabolism during spaceflight on the shuttle. J. Appl. Physiol. 81: 82-92. 10. Cerra, F.B. 1987. Hypermetabolism, organ failure and metabolic support. Surgery 101: 1-14. 11. Lowry, S.F. 1992. Modulating the metabolic response to infection. Proc. Nutr. Soc. 51: 267-277. 12. Kern, K.A., and Norton, J.A. 1988. Cancer cachexia. J. Parenter. Enteral. Nutr. 12: 286-298. 13. Weissman, C. 1990. The metabolic response to stress: An overview and an update. Anesthesiology 73: 308-327. 14. Stein, T.P., Leskiw, M.J., Oram-Smith, J.C., Wallace, H.W., and Blakemore, W.S. 1977. Changes in protein synthesis after trauma: Importance of nutrition. Am. J. Physiol. 233: 348-355. 15. Gore, D.G., Jahoor, F., Wolfe, R.R., and Herndon, D.N. 1993. Acute response of human muscle protein to catabolic hormones. Ann. Surg. 218: 679-684. 16. Lowry, S.F. 1992. Modulating the metabolic response to infection. Proc. Nutr. Soc. 51: 267-277. 17. Kern, K.A., and Norton, J.A. 1988. Cancer cachexia. J. Parenter. Enteral Nutr. 12: 286-298. 18. Naito, Y., Tamai, S., Shingu, K., Shindo, K., Matsui, T., Segawa, H., Nakai, Y., and Mori, K. 1992. Responses of plasma adrenocorticotrophic hormone, cortisol and cytokines during and after upper abdominal surgery. Anesthesiology 77: 426-431. 19. Besedovsky, H.O., and DelRey, A. 1982. Immune-neuroendocrine circuits: Integrative role of cytokines. Front. Neuroendocrinol. 13: 61-94. 20. Besedovsky, H.O., and DelRey, A. 1982. Immune-neuroendocrine circuits: Integrative role of cytokines. Front. Neuroendocrinol. 13: 61-94. 21. Naito, Y., Tamai, S., Shingu, K., Shindo, K., Matsui, T., Segawa, H., Nakai, Y., and Mori, K. 1992. Responses of plasma adrenocorticotrophic hormone, cortisol and cytokines during and after upper abdominal surgery. Anesthesiology 77: 426-431. 22. Weissman, C. 1990. The metabolic response to stress: An overview and an update. Anesthesiology 73: 308-327.

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--> 23. Turnbull A.V., and Rivier, C. 1995. Regulation of the HPA axis by cytokines. Brain Behav. Immunol. 9: 253-275. 24. Besedovsky, H.O., and DelRey, A. 1982. Immune-neuroendocrine circuits: Integrative role of cytokines. Front. Neuroendocrinol. 13: 61-94. 25. Dunn, A.J. 1993. Infection as a stressor: A cytokine-mediated activation of the hypothalamo-pituitary-adrenal axis? Ciba Found. Symp. 172: 226-239. 26. Spangelo, B.L., Judd, A.M., MacCleod, R.M., Goodman, D.W., and Isakson, P.C. 1990. Endotoxin-induced release of interleukin-6 from rat medial basal hypothalami. Endocrinology 127: 1779-1785. 27. Stein, T.P., and Schluter, M.D. 1994. Excretion of IL6 by astronauts during spaceflight. Am. J. Physiol. 266: E448-E454. 28. Gore, D.G., Jahoor, F., Wolfe, R.R., and Herndon, D.N. 1993. Acute response of human muscle protein to catabolic hormones. Ann. Surg. 218: 679-684. 29. Stein, T.P., Leskiw, M.J., Oram-Smith, J.C., Wallace, H.W., and Blakemore, W.S. 1977. Changes in protein synthesis after trauma: Importance of nutrition. Am. J. Physiol. 233: 348-355. 30. Stein, T.P., Leskiw, M.J., and Schluter, M.D. 1996. Diet and nitrogen metabolism during spaceflight on the shuttle. J. Appl. Physiol. 81: 82-92. 31. Stein, T.P., Leskiw, M.J., and Schluter, M.D. 1996. Diet and nitrogen metabolism during spaceflight on the shuttle. J. Appl. Physiol. 81: 82-92. 32. Riley, D.A., Ellis, S., Slocum, G.R., Sedlak, F.R., Bain, J.L., Krippendorf, B.B., Lehman, C.T., Macias, M.Y., Thompson, J.L., Vijayan, K., and De Bruin, J.A. 1996. In-flight and postflight changes in skeletal muscles of SLS-1 and SLS-2 spaceflown rats. J. Appl. Physiol. 81: 133-144. 33. Dietlein, L.F. 1977. Skylab: A beginning. Pp. 408-418 in Biomedical Results from Skylab (R.S. Johnston and L.F. Dietlein, eds.). NASA SP-377. National Aeronautics and Space Administration, Washington, D.C. 34. Kinney, J.M., and Elwyn, D.H. 1983. Protein metabolism and injury. Ann. Rev. Nutr. 3: 433-466. 35. Riley, D.A., Ellis, S., Slocum, G.R., Sedlak, F.R., Bain, J.L., Krippendorf, B.B., Lehman, C.T., Macias, M.Y., Thompson, J.L., Vijayan, K., and De Bruin, J.A. 1996. In-flight and postflight changes in skeletal muscles of SLS-1 and SLS-2 spaceflown rats. J. Appl. Physiol. 81: 133-144. 36. Tipton, C.M. 1996. Animal models and their importance to human physiological responses in microgravity. Med. Sci. Sports Exercise. 28: S94-S100. 37. Stein, T.P., Dotsenko, M.A., Korolkov, V.I., Griffin, D.W., and Fuller, C.A. 1996. Measurement of energy expenditure in rhesus monkeys during spaceflight using doubly labeled water 2H218O). J. Appl. Physiol. 81: 201-207. 38. Stein, T.P., Leskiw, M.J., and Schluter, M.D. 1996. Diet and nitrogen metabolism during spaceflight on the shuttle. J. Appl. Physiol. 81: 82-92. 39. Stein, T.P., Schluter, M.D., Leskiw, M.J., Gretebeck, R.J., Lane, H.W., and Hoyt, R.W. 1998. 1 year report of the LMS Shuttle mission. National Aeronautics and Space Administration, Washington, D.C. 40. Huntoon, C.L., Cintron, N.M., and Whitson, P.A. 1994. Endocrine and biochemical functions. Pp. 334-351 in Space Medicine and Physiology, 3rd ed. (A.E. Nicogossian, C.L. Huntoon, and S.L. Pool, eds.). Lea and Febiger, Philadelphia. 41. Kalita, N.F., and Tigranian, R.A. 1986. Endocrine status of cosmonauts following long-term space missions. Space Biol. Aerosp. Med. 20(4): 84-86. 42. Popova, I.A., Vetrova, E.G., and Ruatamyan, L.A. 1991. Evaluation of energy metabolism in cosmonauts. Physiologist 34: S98-S99. 43. Grigoriev, A.I., Noskov, V.B., Atkov, O.Y., Afonin, B.V., Sukjanov, Y.V., Lebedev, V.I., and Boiko, T.A. 1991. Fluidelecrolyte homeostasis and hormonal regulation in a 237 day spaceflight. Space Biol. Aerosp. Med. 25: 15-18. 44. Huntoon, C.L., Cintron, N.M., and Whitson, P.A. 1994. Endocrine and biochemical functions. Pp. 334-351 in Space Medicine and Physiology, 3rd ed. (A.E. Nicogossian, C.L. Huntoon, and S.L. Pool, eds.). Lea and Febiger, Philadelphia. 45. Kalita, N.F., and Tigranian, R.A. 1986. Endocrine status of cosmonauts following long-term space missions. Space Biol. Aerosp. Med. 20(4): 84-86. 46. Popova, I.A., Vetrova, E.G., and Ruatamyan, L.A. 1991. Evaluation of energy metabolism in cosmonauts. Physiologist 34: S98-S99. 47. Gauquelin, G., Maillet A., Allevard, A.M., Vorobiev D., Grigoriev, A.I., and Gharib, C. 1990. Volume regulating hormones, fluid and electrolyte modifications during the Aragatz mission (Mir station). Pp. 603-608 in Proceedings of the Fourth European Symposium on Life Sciences Research in Space, Trieste, Italy, May 28-June 1, 1990. ESA-SP-307. European Space Agency, Paris. 48. Rambaut, P.C., Leach, C.S., and Leonard, J.I. 1977. Observations on energy balance in man during spaceflight. Am. J. Physiol. 233: R208-R212.

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--> 49. Leonard, J.I., Leach, C.S., and Rambaut, P.C. 1983. Quantitation of tissue loss during prolonged spaceflight. Am. J. Clin. Nutr. 38: 667-679. 50. Stein, T.P., Schluter, M.D., Leskiw, M.J., Gretebeck, R.J., Lane, H.W., and Hoyt, R.W. 1998. 1 year report of the LMS Shuttle mission. National Aeronautics and Space Administration, Washington, D.C. 51. Rambaut, P.C., Leach, C.S., and Leonard, J.I. 1977. Observations in energy balance in man during spaceflight. Am. J. 52. Leonard, J.I., Leach, C.S., and Rambaut, P.C. 1983. Quantitation of tissue loss during prolonged spaceflight. Am. J. Clin. Nutr. 38: 667-679. 53. Rambaut, P.C., Leach, C.S., and Leonard, J.I. 1977. Observations on energy balance in man during spaceflight. Am. J. Physiol. 233: R208-R212. 54. Stein, T.P., Schluter, M.D., Leskiw, M.J., Gretebeck, R.J., Lane, H.W., and Hoyt, R.W. 1998. 1 year report of the LMS Shuttle mission. National Aeronautics and Space Administration, Washington, D.C. 55. Stein, T.P., Schluter, M.D., Leskiw, M.J., Gretebeck, R.J., Lane, H.W., and Hoyt, R.W. 1998. 1 year report of the LMS Shuttle mission. National Aeronautics and Space Administration, Washington, D.C. 56. Kissileff, H.R., Pi-Sunyer, F.X., Segal, K., Meltzer, S., and Foelsch, P.A. 1990. Acute effects of exercise on food intake in obese and nonobese women. Am. J. Clin. Nutr. 52: 240-245. 57. King, N.A., Burley, V.J., and Blundell, J.E. 1994. Exercise-induced suppression of appetite: Effects on food intake and implications for energy balance. Eur. J. Clin. Nutr. 48: 715-724. 58. King, N.A., Lluch, A., Stubbs, R.J., and Blundell, J.E. 1997. High dose exercise does not increase hunger or energy intake in free living males. Eur. J. Clin. Nutr. 51: 478-83. 59. Friedl, K.E., Moore, R.J., Martinez-Lopez, L.J., Vogel, J.A., Askew, E.W., Marchitelli, L.J., Hoyt, R.W., and Gordon, G.C. 1994. Lower limit of body fat in healthy active men. J. Appl. Physiol. 77: 933-940. 60. Iyengar, A., and Rao, B.S. 1979. Effect of varying energy and protein intake on nitrogen balance in adults engaged in heavy manual labor. Br. J. Nutr. 41: 19-25. 61. Ku, Z., and Thomason, D.B. 1994. Soleus muscle nascent polypeptidechain elongation slows protein synthesis rate during non-weight bearing activity . Am. J. Physiol. 267: C115-C126. 62. Powell, M.R., Horrigan, D.R., Waligora, J.M., and Norfleet, W.T. 1994. Extravehicular activities. Pp 128-140 in Space Medicine and Physiology, 3rd ed. (A.E. Nicogossian, C.L. Huntoon, and S.L. Pool eds.). Lea and Febiger, Philadelphia. 63. Berg, H.E., Dudley, G.A., Haggmark, M.E., Ohlsen, K., and Tesch, P.A. 1992. Effects of lower limb unloading on skeletal muscle mass and function in humans. J. Appl. Physiol. 70: 1882-1885. 64. Convertino, V.A. 1990. Physiological adaptations to weightlessness: Effects on exercise and work performance. Exercise Sport Sci. Rev. 18: 119-166. 65. Askenazi, J.A., Weissman, C., Rosenbaum, S.A., Elwyn, D.H., and Kinney, J.M. 1982. Nutrition and the respiratory system. Crit. Care Med. 10: 163-187. 66. Chandra, R.K. 1990. McCollum award lecture. Nutrition and immunity: Lessons from the past and new insights into the future. Am. J. Clin. Nutr. 53: 1087-1101. 67. Keusch, G.T., and Farthing, M.J.G. 1986. Nutrition and infection. Ann. Rev. Nutr. 6: 131-154. 68. Hughes-Fulford, M. 1993. Review of the biological effects of weightlessness on the human endocrine system. Receptor 3(3): 145-154. 69. Gmunder, F.K., Konstantinova, I., Cogoli, A., Lesnyak, A., Bogulov, W., and Grachov, A.W. 1994. Cellular immunity in cosmonauts during long duration spaceflight on board the orbital MIR station. Aviat. Space Environ. Med. 65: 419-423. 70. Hughes-Fulford, M.H. 1991. Altered cell function in microgravity. Exp. Gerontol. 26: 247-256. 71. Kinney, J.M., and Elwyn, D.H. 1983. Protein metabolism and injury. Ann. Rev. Nutr. 3: 433-466. 72. Stein, T.P., and Gaprindachvili, T. 1994. Spaceflight and protein metabolism, with special reference to man. Am. J. Clin. Nutr. 80: 806S-819S. 73. Young, V.R., and Marchini, J.S. 1990. Mechanisms and nutritional significance of metabolic responses to altered intakes of protein and amino acids with reference to nutritional adaptation in humans. Am. J. Clin. Nutr. 51: 270-289. 74. Plakhuta-Plakutina, G.I. 1977. State of spermatogenesis in rats flown aboard the biosatellite Cosmos-690. Aviat. Space Environ. Med. 48: 12-15. 75. Serova, L.V. 1989. Effect of weightlessness on the reproductive system of mammals. Kosm. Biol. Aviakosmicheskaya Med. 23: 11-16.

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