6
Endocrinology and Nutrition

INTRODUCTION

Endocrinology is concerned with signaling between cells and tissues. Together with the nervous and immune systems, the endocrine system regulates the human response to spaceflight and the readjustment processes that follow landing. Quite apart from the intrinsic scientific interest of the underlying mechanisms, understanding the effects of spaceflight on the endocrine system is essential for the rational development of countermeasures.

The principal spaceflight responses that have a significant endocrine involvement are fluid shifts; perturbation of circadian rhythms; losses of red cell mass, bone, and muscle; and maintenance of energy balance. Endocrine and nutritional imbalances may also contribute to immune dysfunction, altered pharmacological responses, behavioral changes, and decreased resistance to radiation.

The Strategy report (NRC, 1998) identified three areas in endocrinology for investigation. The highest priority was assigned to obtaining a baseline in-flight human hormone profile. Lower-priority topics were refining and developing ground-based models and continuing the construction of a life sciences database that is accessible to the outside community. In the area of nutrition, the report focused on energy and protein requirements, with emphasis on the importance of maintaining energy balance in astronauts during spaceflight.

NASA’S CURRENT RESEARCH PROGRAM IN ENDOCRINOLOGY AND NUTRITION

This analysis is based primarily on the FY 1999 NASA Research Announcement (NRA) (98-HEDS-02), although any major program changes due to the approved projects resulting from the 1999 NRA solicitation (99-HEDS-03, funding starting October 1, 2000) have been identified. Also included in the analysis are projects from the National Space Biomedical Research Institute (NSBRI) that were active during FY 1999. Only three projects can be considered to be purely endocrine system research, although approximately sixteen other projects have significant endocrine components. This was about the same level of activity as the previous year. Two projects with significant endocrine involvement



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Review of NASA’s Biomedical Research Program 6 Endocrinology and Nutrition INTRODUCTION Endocrinology is concerned with signaling between cells and tissues. Together with the nervous and immune systems, the endocrine system regulates the human response to spaceflight and the readjustment processes that follow landing. Quite apart from the intrinsic scientific interest of the underlying mechanisms, understanding the effects of spaceflight on the endocrine system is essential for the rational development of countermeasures. The principal spaceflight responses that have a significant endocrine involvement are fluid shifts; perturbation of circadian rhythms; losses of red cell mass, bone, and muscle; and maintenance of energy balance. Endocrine and nutritional imbalances may also contribute to immune dysfunction, altered pharmacological responses, behavioral changes, and decreased resistance to radiation. The Strategy report (NRC, 1998) identified three areas in endocrinology for investigation. The highest priority was assigned to obtaining a baseline in-flight human hormone profile. Lower-priority topics were refining and developing ground-based models and continuing the construction of a life sciences database that is accessible to the outside community. In the area of nutrition, the report focused on energy and protein requirements, with emphasis on the importance of maintaining energy balance in astronauts during spaceflight. NASA’S CURRENT RESEARCH PROGRAM IN ENDOCRINOLOGY AND NUTRITION This analysis is based primarily on the FY 1999 NASA Research Announcement (NRA) (98-HEDS-02), although any major program changes due to the approved projects resulting from the 1999 NRA solicitation (99-HEDS-03, funding starting October 1, 2000) have been identified. Also included in the analysis are projects from the National Space Biomedical Research Institute (NSBRI) that were active during FY 1999. Only three projects can be considered to be purely endocrine system research, although approximately sixteen other projects have significant endocrine components. This was about the same level of activity as the previous year. Two projects with significant endocrine involvement

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Review of NASA’s Biomedical Research Program were approved from the 1999 NRA solicitation. To estimate the expenditure on endocrine research, the fraction of a project that is endocrine related has been multiplied by the total dollar amount of the grant. The total expenditure in FY 1999 on endocrine-related themes was about $1.225 million (~3.4 percent of total NASA expenditures). About half ($650,000) of the funds were used to support studies of the endocrine aspects of circadian rhythm dysfunction (three projects). The total expenditure in FY 1999 was unchanged from 1998, although there was a decrease in the number of projects funded (21 versus 16). Table 6.1 summarizes the funding and project distributions between subdisciplines and between the NRA and NSBRI programs for FY 1999. The Strategy report (NRC, 1998) identified circadian rhythm dysfunction as being a high-priority area for investigation. Two circadian rhythm studies were included as part of the Bion program in 1998 but were discontinued in FY 1999 ($100,000). The current program encompasses three ground-based human studies. The total expenditure on the endocrine aspects of circadian rhythm and sleep studies ($650,000) was unchanged from FY 1998. (For additional discussion of circadian rhythms and the relevance of their study to NASA, see Chapter 9.) Expenditure on the endocrine component of other programs with endocrine involvement was about $575,000 in FY 1999 (13 projects). No currently funded projects relate to the highest-priority objective, obtaining a baseline in-flight human hormone profile. The Integrated Testing Regimen (ITR) does not meet this requirement. The lack of activity is a consequence of the current lull in flight opportunities. The second objective, the refinement and development of ground-based models, is more nebulous because model development is not a specifically stated objective of any project. For the most part, endocrine measurements are secondary objectives. The endocrine components of currently funded studies are directed toward elucidating underlying mechanisms, as recommended in the Strategy report. The greatest number of interdisciplinary projects with an endocrine component in FY 1999 were in the areas of bone (five studies), muscle (five studies), sleep and circadian rhythm (three studies), and TABLE 6.1 Summary of FY 1999 Funding for Subdisciplines for Endocrinology, Nutrition, and Related Fields   NRA   NSBRI   Subdiscipline Total ($ thousands) No. of Projects Total ($ thousands) No. of Projects Endocrinology 1,225 9 600 5 Sleep 650 3 0 0 Bone 300 3 150 2 Muscle 25 1 450 3 Cardivascular 50 2 0 0 Fluid/electrolyte 200 1 0 0 Nutrition 325 3 0 0 Gender 200 1 0 0 Thermoregulation 200 1 0 0 Pharmacology 150 2 0 0 Total 2,100 16 600 5 NOTE: For most of the projects listed under endocrinology, endocrinology is only a part of the project. To estimate the expenditure on the endocrine aspects, the total sum expended on the project has been multiplied by the estimated percentage of endocrine involvement.

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Review of NASA’s Biomedical Research Program cardiovascular (two studies). Where appropriate, investigators include endocrine measurements in their studies. Although questions related to potential gender-specific effects of spaceflight have received some public interest, there is little research in this area. Two studies concerned with gender effects were carried out in FY 1998, a ground-based study of orthostatic intolerance at Johnson Space Center (JSC) and a student fellowship to study the response to exercise. In FY 1999, only the former was continued. There were also two ground-based studies on the cardiovascular aspects of thermoregulation in 1998 of which only one was continued into FY 1999. The NRA and NSBRI programs for the two years for which detailed information is available involve little research in nutrition, and nutrition was the smallest of the research disciplines identified by NASA as a program area. Expenditure on nutrition was about $430,000 in 1998 and $325,000 in 1999. In 1998 there were five projects—vitamin D, assessment of body composition, gastrointestinal function, and two projects on renal stone formation. In 1999, two of the nutrition projects were discontinued. Related studies involve water balance (discontinued in 1999) and thermoregulation. However, there appears to be a trend in the FY 2000 NRA grants toward increasing activity in nutrition research in response to the recommendations in the Strategy report. Three projects have nutrition as their primary focus (two dealing with protein-energy balance and one with vitamin E), and three other projects have significant nutrition involvement. The JSC metabolism section has a clinical program to provide astronauts with balanced and acceptable diets. The program does not seem to have research components, although members of this group are involved in NASA- or NSBRI-funded research in other disciplines. The endocrine component of the current NRA and NSBRI research programs is small. This is consistent with the Strategy report conclusions and appropriate given the lack of flight opportunities. Absence of flight opportunities precludes any work being done on the highest-priority objective, obtaining a baseline in-flight human hormone profile. The nutrition program remains small but, as recommended in the Strategy report, does appear to be receiving more attention. PROGRAMMATIC BALANCE Balance of Subdiscipline Areas Given the current lack of flight opportunities, the small size of the direct investment in endocrinology at present is consistent with the Strategy report. The Strategy report identified endocrine measurements as important components of other disciplines (e.g., bone, muscle, circadian rhythms), and this is reflected in the distribution of endocrine measurements within the program. However, within the endocrinology discipline there may be an overemphasis on circadian rhythm studies (see Chapter 9). There is currently no activity related to acquiring a comprehensive hormonal profile of humans adapted to spaceflight, the principal recommendation of the Strategy report. The issue of gender is important and does not appear to be addressed adequately. Prior studies have shown decisively that there are gender effects. A previous NASA-funded bed rest study showed that cortisol was elevated in males, but not females, during one week of bed rest (Vernikos et al., 1993). Except for the study on orthostatic hypotension, gender has not been a consideration in other studies where it might be relevant, for example, studies of bone loss. Including projects approved from the 1999 NRA solicitation (funding to start in FY 2000), ongoing investigations include studies of calcium metabolism (one study), vitamins D (one study) and E (one study) metabolism, renal stone formation (two studies), body composition by bioimpedance (one study),

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Review of NASA’s Biomedical Research Program gastrointestinal function (one study), and protein-energy balance (two studies). All of these projects address areas identified in the report as being of high priority; four astronauts are now known to have developed renal stones. It would appear that the recommendations of the Strategy report have been followed, the number of studies in nutrition has been increased, and the recent NRA (September 1999 for FY 2000) continues to list nutrition as a priority area. Overall, the program is balanced and the distribution of projects between the various subdisciplines reflects the recommendations of the Strategy report. Specifically the trend for an increase in nutrition is consistent with the Strategy report. Baseline studies of the in-flight human endocrine profile will not be feasible until flight opportunities become available. Gender effects, although not a specific recommendation in the Strategy report, should receive more emphasis. Balance of Ground and Flight Investigations The small research program in endocrinology is predominantly ground based because of a lack of flight opportunities. Two of the three strategy recommendations require flight experiments, namely, determination of the in-flight human endocrine profile and further refinement of ground-based models. The 1998 circadian rhythm projects were well balanced between flight- and ground-based studies and between human and nonhuman studies, principally because of Neurolab projects. The Neurolab projects were completed in FY 1998, so there was minimal activity in the flight program for sleep and circadian rhythms in FY 1999 although one project was approved for FY 2000. One particularly important project was the first double-blind, first-in-flight clinical trial of a countermeasure utilizing melatonin, a potential countermeasure to regulate circadian rhythm. The experiment was flown on the Neurolab mission and completed in FY 1998. A follow-up study was approved for funding in FY 2000. Astronaut nutrition has to be studied during spaceflight; so with the paucity of flight opportunities, the balance within the small program is reasonable. One of the four FY 2000 NRA awards with a significant nutrition component was a flight experiment. Gastrointestinal function is related to nutrition. The two studies in this area are concerned primarily with pharmacokinetics, an important and underrepresented topic. Three additional studies in pharmacokinetics were approved for FY 2000, of which one was a flight experiment. This shift toward flight experiments is the results of some nutrition and pharmacological studies becoming feasible during the early phases of International Space Station (ISS) activity. Future endocrine experiments are mostly ground based. However in accord with the high priority given to nutrition studies by the Strategy report, some of the funded nutrition projects are flight experiments and have been selected for consideration for early flight opportunities. Emphasis Given to Fundamental Mechanisms Endocrine studies play a supporting role in many areas. The ground-based work has the appropriate emphasis on mechanistic studies. Gone are the descriptive projects of uncontrolled phenomena and the random measurements of random plasma hormones from random samples. The nutrition studies recommended in the Strategy report are directed toward the maintenance of nutritional adequacy. The foci of the endocrine and nutrition programs are appropriate and in concordance with the recommendations of the Strategy report.

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Review of NASA’s Biomedical Research Program Utilization and Validation of Ground and Animal Models The Strategy report repeatedly stressed the importance of validating and refining ground-based models. Current ground-based models can reproduce most of the symptoms of spaceflight, but there is not necessarily a commonality of mechanism. There is a critical unmet need for ongoing evaluation and refinement of existing models through comparison with flight data and endocrinological measurements, including a comprehensive in-flight human hormone profile. When ground and flight studies have been compared, the results have sometimes been surprising. For example, a flight study on the Life and Microgravity Spacelab shuttle mission by Wronski et al. (1998) attempted to address the effects of glucocorticoids on rat bones during spaceflight, since there was ample ground-based data to suggest that glucocorticoids had a major role in bone loss. No effect of spaceflight or of cortisol on bone growth was found. Analysis of this unexpected finding showed that changes in bone in rats induced by spaceflight were influenced by (1) the way the animals were housed, (2) the age of the animal, (3) the particular strain (genetic background) of the rat used in the study, and (4) flight duration. Group housing inhibited bone formation, whereas single housing did not. Instead of being simple, the rat model turns out to be complex! The majority of ongoing studies use ground-based models. Even though the Strategy report identified validation of ground-based models as a high-priority area, there is little activity aimed at validation or research to develop new models. DEVELOPMENT AND VALIDATION OF COUNTERMEASURES One of the bed rest countermeasure studies, the use of alendronate to reduce bone calcium loss, involves a series of measurements to evaluate any endocrine perturbations induced by the drug. The study involves a close interaction between university investigators (NRA funded), the NSBRI, and the JSC countermeasures task group. Endocrine measurements are also minor components of two other studies, which address the efficacy of resistive exercise in reducing bed rest-induced muscle atrophy. All of these studies have been well planned and are being done in general clinical research centers, where diet is controlled and the number of subjects is adequate for statistical analysis. Apart from the validation of ground-based models, some countermeasures, particularly those involving drugs or hormonal manipulation, might have some long-term effects on other systems. For example, a potential scenario of secondary impact is the possibility of female astronauts being placed on oral contraceptives for regulation of the menstrual cycle. This may lower estrogen levels and promote bone loss in an already vulnerable population. There does not appear to be any consideration of such side effects in either the 1998 or the 1999 program, although it does appear to have been identified as a high-priority area for investigation in the FY 2000 NRA solicitation. Investigation of treatment interactions should be part of every countermeasure study. In the area of nutrition, four studies are targeted at countermeasures. Two relate to countermeasures against in-flight renal stone formation with the objective of developing a dietary intake (fluid and electrolytes) and urine electrolyte excretion profile to predict the probability of renal stone formation. A third study is focused on vitamin E as an antioxidant, and the fourth on protein-energy balance. All of these studies are appropriate. There is a need to minimize the risk of renal stone formation. Oxidative damage has been implicated as a factor in chronic ground-based disease states such as cancer and atherosclerosis, so a study of the use of vitamin E as an antioxidant is relevant. The energy balance study is targeted at elucidating the mechanisms of the inability to maintain energy balance in flight. Endocrine involvement in the countermeasures program is mostly consistent with the Strategy report. Two areas that require further emphasis are treatment interactions and gender effects.

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Review of NASA’s Biomedical Research Program The nutrition program is focused almost exclusively on countermeasures, and this is in concordance with the Strategy report. EPIDEMIOLOGY AND MONITORING The Strategy report assigned a high priority to obtaining an in-flight hormone profile. The database on the astronaut corps collected and maintained by the Space Medicine Program at JSC contains a substantial amount of endocrine data. The NASA list does not appear to match the likely requirements for the in-flight hormone profile. Having an external panel of experts would be helpful in deciding which hormones should be measured. NASA should ensure that the database being compiled by medical operations at JSC is congruent with the Strategy report recommendation for determining the in-flight human hormone profile. SUPPORT OF ADVANCED TECHNOLOGIES For the most part, new methodologies—particularly sensitive micromethods—are not being used in individual research programs. At the First Biennial Life Sciences Investigators’ Workshop, NASA (Ames) presented an exhibit of some advanced technologies, including the use of miniature time-of-flight mass spectrometers. At present, the endocrine programs do not appear to be taking full advantage of the advanced technologies that have been developed to make endocrine measurements for medical studies on patients. SUMMARY Given the current lack of flight opportunities, the small endocrine program is reasonable. Two of the three recommendations in the Strategy report require flight data that currently cannot be obtained. The Strategy report identified determination of the in-flight endocrine profile as the highest priority for endocrine research. In the absence of flight opportunities, this goal is at present unattainable. However, no plan has been developed for obtaining a set of core data on the human endocrine response to living in low Earth orbit. Knowledge and understanding of endocrine changes with flight are essential for the refinement of ground-based models. In other studies, endocrine measurements are being made where appropriate. Although in the past the nutrition program was inadequate, during the last two years NASA,1 the NSBRI, and this committee (Strategy report) have independently identified nutrition-energy balance as a very high priority area for future studies. NASA appears to have responded to the Strategy report by giving increased emphasis to research in nutrition. Inadequate attention is being paid to gender issues and treatment interactions. REFERENCES National Research Council (NRC), Space Studies Board. 1998. A Strategy for Research in Space Biology and Medicine in the New Century. Washington, D.C.: National Academy Press. Vernikos, J., M.F. Dallman, L.C. Keil, D. O’Hara, and V.A. Convertino. 1993. Gender differences in endocrine responses to posture and 7 days of 6-degrees head-down bed rest. Am. J. Physiol. (Endo. and Metab.) 265:E153-61. Wronski, T.J., M. Li, Y. Shen, S.C. Miller, B.M. Bowman, P. Kostenuik, and B.P. Halloran. 1998. Lack of effect of spaceflight on bone mass and bone formation in group-housed rats. J. Appl. Physiol. 85:279-85. 1   As indicated in NASA’s Critical Path Research Plan presentation (including EDOMP results presented at that time) at the Committee on Space Biology and Medicine meeting, March 3-5, 1999, Houston, Texas.