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J ULY 2015, N O 18

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Editorial Dear Reader It is my pleasure to introduce the ISOPTWPO. ISOPTWPO(International Space Flight & Operations - Personnel Recruitment, Training, Welfare, Protocol Programs Office) is part of ISA, which support research on Human Space Flight and its complications.

The International Space Agency (ISA) was founded by Mr. Rick Dobson, Jr., a U.S. Navy Veteran, and established as a non-profit corporation for the purpose of advancing Man’s visionary quest to journey to other planets and the stars.

ISOPTWPO will research on NASA’S Human Research Roadmap. It will also research on long duration spaceflight and publish special issues on one year mission at ISS and twin study.

Mr. Martin Cabaniss

Director: Mr. Martin Cabaniss ISOPTWPO – International Space Agency(ISA) http: // www. international-space-agency. us/ Email:martin.cabaniss@international-space-agency.us

IN THIS EDITION Page No. 3-6

Article Name Main Medical Results of Extended Flights on Space Station MIR in 1986-1990

7-14

Autonomic Regulation of Circulation and Cardiac Contractility during a 14-month Spaceflight

16-30

Astronaut’s Adaptation in Space

Special Issue ’Long-duration Spaceflight’

Medical Results of Extended Flights on Space Station MIR in 1986-1990 During 1986-1990, seven prime crews (PC) carried out missions on the Mir space station and an 8th prime crew has started its space work which will be finished in 1991. A total of 18 cosmonauts (including the 8th prime crew) have participated in extended missions on the Mir space station, one cosmonaut being launched twice. The primary medical goals for these extended space missions have been maintenance of good health status and performance of space crews and making medical investigations.

Cardiovascular System The most regular inflight changes have occurred in the latter part of electrocardiographic tracings (12 standard leads). These demonstrate a decrease of T-wave amplitude in most leads in all cosmonauts.

Analysis of hemodynamic parameters has shown a tendency for an increase in mean heart rates (HR) and a lack of change in stroke volume (SV), cardiac output (CO) and actual specific peripheral resistance (SPRa). Ultrasonic examinations of the physician cosmonaut made during months 7-8 inflight did not reveal changes in left ventricular volumes, SV or ejection fraction (EF).

Arterial pressure (AP) measurements showed that diastolic pressure (DBP) had a tendency to decrease (P < 0.18) and pulse pressure (PP) to increase(P < 0.07).

Abdominal ultrasonic examinations carried out.Both inflight (7 cosmonauts examined–4 at the end of 56 months, 3 at the end of 8-9 months) and postflight (16 cosmonauts) demonstrated: a moderate increase in the size of the liver, spleen, kidneys, pancreas, blood filling of the lungs, cross-sectional area of the large ventral vessels, and a clearer vascular pattern of liver; decreased acoustic density of the pancreas; signs of lateral renal pelvic enlargement with a decrease in renal parenchyma (decreased parenchymal-pelvic system area ratios).

These changes are considered to be echographic signs of venous engorgement. An increased gall bladder area and dilatation of the common bile duct also point to the development of bile congestion in the biliary tree.

In contrast to the preflight period graded physical exercise tests on a bicycle ergometer during flight (at a work load of 125 W and 175 W for 5 and 3min, respectively with a l min interval) resulted in insignificant rises of HR, a decrease of SV and CO (by 14.5 and 15.1%) decline in D BP by 6.8% and a PP increase of 13.5% (P < 0.01). These reactions point to the nature of adaptive inflight processes uncovered by exposure to graded exercise when findings are compared to the preflight period.

Postflight hemodynamic studies during graded step-wise exercise conducted by A. F. Zhernakov et al. demonstrated a more distinct increase in absolute values of HR, systolic AP and diastolic AP (in most cases); and smaller increment of SV and shortening of the left ventricular ejection period vs its corrected value for changes in HR. No HR and ECG changes of an ischemic type were found. Severity of hemodynamic changes did not depend on flight duration. When compared to pretest hemodynamic parameters, lower body negative pressure (LBNP) tests (at -25, -35, and -45 mmHg for 1, 3, and 5 min respectively) applied in flight led to decreases of SV (5.2%) and CO (8%) as well as an increase in SPRa (15.7%). Blood pressure did not change significantly.

Inflight relative and absolute increases in SPRa were considered to be reactions to prevent pronounced changes in SV, CO and BP. It should be noted that cardiovascular responses to postflight postural tests had no correlation with flight duration.

Vestibular Function and Sensory Interactions Statistical analysis of questionnaire data on inflight subjective reactions performed by L. N. Kornilova demonstrated that 75% of cosmonauts experienced spatial illusions and orientation disturbances. Inflight vestibular discomfort occurred in 12% of cosmonauts. Postflight vestibular evidence was present in 38% of cosmonauts when not tested and in 31% of subjects when executing active head movements.

Illusions were noted by 50% of cosmonauts. Examinations of vestibular function in microgravity revealed a significant transformation of spontaneous and visual-vestibular stimulation induced oculomotor reactions. On the 3rd day of flight oculographic measurements revealed development of a spontaneous vertical nystagmus (especially with eyes closed), disturbances of eye tracking motions, and a decreased threshold for optokinetic

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and vestibular nystagmus in the majority of 9 cosmonauts examined within the Salyut 7 and Mir space programs. Combined vestibulo-optokinetic stimulation induced a predominant vestibular nystagmus. On day 5 of flight the severity of changes decreased, but again recurred on days 116 and 164 of flight with this level of severity maintained up to days 7-8 after returning to Earth gravity.

Observed changes in spontaneous and induced oculomotor activity, particularly during the early stages of flight, can result in the development of inflight specific sensory reactions. Examination of 14 crewmembers after long-term stays aboard Salyut-7 and Mir space stations revealed the presence of postgravitational dysmetric and dysrhythmic nystagmus associated with the vertical (mainly a downward motion) and horizontal (shift to the right) electro-oculographic (EOG) leads both at rest and during executing active and passive movements.

Simultaneously in most cases the pattern of oculomotor reactions for different tests and the visual tracking reflex were changed. Vestibulo-oculomotor reactions returned to the norm in almost all cosmonauts within 2 weeks. It was noted that in 17% of cases disturbances of the vestibular function and the vestibulo-oculomotor interaction correlated well with hemodynamic changes (r = 0.85, P < 0.05). In 22% these disturbances were concerned with altered activity of the vestibular input proper and on other sensory systems interacting with it.

Both factors were of significance in 61% of cases.

Motor System Statokinetic measurements (on days 3, 5, 63 and 193 in flight) during graded force tests revealed significant changes in the precision of applied strength and rate of movement. Incidence of findings were greater (approx.

2 times more) in an "eyes closed" position. The postural-motor coordination test demonstrated distinct changes in the standard (for a 1g environment) pattern of muscle activity.

However, on the 193rd day of flight the coordination patterns of posture synergies and postural control demonstrated a trend to return to an Earth-based standard. This was most likely due to the regular use of countermeasures and is interpreted to indicate adaptability of the motor control system during prolonged space missions.

Postflight shifts were manifested as 4-8 changes in sensory inputs and spinal automatisms in the form of an increased sensitivity (a decline in threshold levels) to support (vibration effects on the feet) and stimulate muscle (graded T-reflex) and as interextremity synergy disturbances; a decrease in lateral stiffness of muscles and muscular strength velocity parameters; subatrophy and atrophy of antigravitational muscle groups; decrements of vertical posture stability; locomotor disorders; and changes in coordination precision parameters revealing a declined effectiveness of precision regulation.

The severity and duration of manifesting the above mentioned shifts in crewmembers after flights of various durations were different, but did not correlate with flight duration and had a marked dependence on the amount, intensity and profile of inflight exercise usage.

Bone Changes Bone studies carried out by V. S. Oganov and co-workers using dual-photon absorptiometry after a 11-12 month flight (2 cosmonauts tested) revealed a decreased mineral density (5.6%) for the tibial diaphysis in one cosmonaut; in the other cosmonaut the bone densities of lumbar vertebrae, femoral neck, and femoral diaphysis did not differ significantly from preflight levels.

After an 8 month flight medical examinations of the physician-cosmonaut demonstrated a significant elevation in mineral mass of the upper body (in the area of the skull 10.4%) and + 11.3% for the trunk with a tendency for a decrease in the lower body (pelvis -2.8% and lower extremities +11.3%). There was no evidence of significant alterations in the total skeletal mass . A substantial decrement of mineral density was measured in the mid-part of the femoral neck (4.9%), in Wardâ&#x20AC;&#x2122;s triangle (14.5%) and the greater trochanter 10.2%).

Postflight measurements using computer tomography of another cosmonaut (participated on a year long mission on the Mir station) revealed a decreased mineral density of spongy bone of lumbar vertebrae which did not exceed 10%.

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Special Issue ’Long-duration Spaceflight’

Endocrine and Metabolic System Postflight endocrine stress reactions measured by B. V. Morukov and V. B. Noskov demonstrated increased plasma concentrations of cortisol (excluding the year-long mission), insulin, thyroxin and catecholamines. In some cases an increase in blood cortisol occurred with an unchanged or decreased level of ACTH. After the 12 month flight there was a 10-fold increase in plasma ACTH concentration which was associated with an insignificant change in blood cortisol level. Studies of hormones regulating fluid-electrolyte metabolism in most cosmonauts revealed a 2-3-fold rise in plasma antidiuretic hormone (ADH) as well as renin and aldosterone at R + 1.

Following the year long mission renin and aldosterone concentrations increased only at R + 7 which pointed to the nature of the adaptation process to microgravity. In most cases the postflight blood levels of calcitropic hormones were characterized by increased and decreased levels of parathyroid hormone and calcitonin, respectively. Metabolic studies performed by B. V. Morukov and I. A. Popova revealed regular postflight changes.

Fluid-electrolyte studies revealed increased blood calcium levels and in most cases decreased blood potassium levels (in the 4th prime crew it decreased). Over several postflight days urine volume decreased as did renal excretion of sodium, chloride and osmotically active substances. Divalention excretion changed insignificantly. Measurements of osmo- and ion-regulating renal function using water and salt loading tests revealed a mismatch in the ion regulating system manifest as multidirectional changes for excretion of fluid and some ions.

Nitrogen metabolism was usually characterized by multidirec ional and insignificant changes in blood levels of total protein. In the case following a year long flight there was a decrease in plasma levels of α and γ-globulin fractions which assume a decline in biosynthetic-liver activity and/or simultaneous increase of atherosclerotic β-globulins.

In most cases postflight carbohydrate metabolism manifested a moderate hyperglycemia and was associated with an increased secretion of insulin and significant accumulation of underoxidized products of carbohydrate metabolism–lactate and pyruvate.

These data combined with changes in plasma lipid parameters point to a significant rise in anaerobic metabolic processes which at R + 7 still exceeded baseline values. Examinations carried out by K. V. Smirnov indicated that on the 69th day of flight of the physician-cosmonaut, as well as on days 321-322 in both cosmonauts, glucose utilization slowed down, as determined by a glucose tolerance test. Glucose tolerance curve findings returned to baseline levels over the 2-week period following flight in most cases, but this depended to some extent on flight duration.

Changes in lipid metabolism were characterized by both an increase and decrease in levels of basic lipid substrates—triglycerides and free fatty acids. The content of POL products in blood and erythrocyte membranes was increased at R + 7 following 5 and 7 month flights and frequently at R + 1 and R + 2 when flights were longer than 8 months.

Lipoperoxidation, as a rule, was not increased at R + 1 and R + 2 with flights longer than 200 days duration when cosmonauts did not show signs of vestibular disorders. In some cases an activation of POL occurred by R + 7. Thus, data obtained to date in man points to rather extensive and widespread metabolic changes after long-term exposures to microgravity.

Serum enzyme measurements did not demonstrate significant changes in levels of lactate dehydrogenase activity following flights lasting up to 8 months. Its levels did decrease after 11-12 month flights as did levels of malate dehydrogenase activity (MDG) and isocitratedehydrogenase. The fraction of cytoplasmic form of MDG increased due to a decrease in fraction of mitochondrial isoenzyme MDG-3 -a sign of a diminished intensity of the basic energy generating process at the cellular level and of changed permeability of membrane structures at the cellular and subcellular levels.

The observed postflight increase in serum creatinephosphokinase activity at the cost of its muscular frac-

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tion is probably the result of an increased gravitational load on the musculoskeletal system during the readaptation period following microgravity exposure. Specific postflight decrement of the hepatic isoenzyme component of alkaline phosphatase and an increase in its osseous isovnzyme component in a number of flights appears to indicate increased activity of bone cells in response to return to Earth gravity.

Blood Blood alterations during a long stay in microgravity typically include development of transient erythrocytopenia. In the flights of PC-3 and PC-4 there was a decrease in erythrocyte counts (in the physician- cosmonaut from 3.6 X 1012 /l to 3.8 X 1012 /l), anisocytosis and hypochromy. The hematocrit decreased by 4-14%.

Postflight studies several hours following landing performed by Legenkov et al. revealed a decrease in reticulocytes (from 32.8 X 109 /l to 21.4 X 109 /l), erythrocytes (average count decreased from 4.91 X 1012 /l to 4.68 X 1012 /l), hemoglobin concentration (decrease from 152 to 145 g/l) and hematocrit (decrease from 45 to 42%). Further declines occurred during the first 7 days following flight as body fluids were restored and symptoms of body hypohydration abated: erythrocyte counts fell to 4.1 X 1012 /l, hemoglobin concentration to 131 g/l and hematocrit to 38.5%. In this case there was the rapid onset of reticulocytosis and counts increased to 60.8 X 109 /l, i.e. an 85% increase.

Hemoglobin mass at R + 7 decreased from 738 to 589 g, i.e. fell 20% compared to preflight baseline values. The reticulocytosis associated with readaptation gradually normalized over the following 1.5-3 month postflight period. By this time there was practically complete restoration of all remaining "red blood" parameters.

The physician-cosmonaut displayed changes in erythrocyte shape during flight: target cells, ovalocytes, and spherocytes. Target cells were also found in other crewmembers of PC-3 (year-long flight) and PC-4. The target cells disappeared after a period following landing.

Immune System From experimental findings provided by I. V. Konstantinova, immune system changes demonstrated a decrease in activity of T-lymphocytes (PHA activity determined by synthesis rates in PHA cultures), suppression of T-lymphocytes in PHA cultures (diminished levels of [3 H]thymidine labelled cells), reduced functional activity of T-helpers (along with B-lymphocytes) participating in production of antibodies and implementing antigenantibody reactions on the killer surface. In some cosmonauts the actual number of T-helper cells diminished: cytofluorometric analysis of surface markers showed a decreased level of CD-4 positive cells.

Natural killer cell activity decreased as a rule over the first postflight week. In addition there was a significant decrease in the number of lymphocytes capable of recognizing target cells and producing with them strong conjugates for retention of lytic potency as natural killers. At the same time there was reduced lymphocyte production of interleukin-2 -a key factor responsible for immune system response, maintaining T-lymphocyte growth and enhancing antibody production. Synthesis of endogenous a- and g-interferons was reduced in some crewmembers.

Results obtained during medical investigations during manned space missions on the Mir space station have shown that man adapts well and can work efficiently for as long as a year.

Inflight and postflight studies demonstrated that body system changes were functional in nature and reversible. The observed patterns of readaptation (including a year-long flight) have been similar for all extended missions. In this case in point, after 326-366 days of flight, the changes were even less severe than those observed after shorter-term missions.

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Special Issue ’Long-duration Spaceflight’

Autonomic Regulation of Circulation and Cardiac Contractility during a 14-month Space ight The existing concepts of how the cardiovascular system adapts itself to a long-term space flight are based on the recognition of three adaptation stages - acute (first 10-15 days of flight), transitional or unstable (<3 months), and relatively stable (>3 months). That a stable stage sets in after several months in space has been confirmed by numerous flights of cosmonauts lasting 4 to 6 months. Variations of the basic cardiovascular parameters in these cosmonauts were within normal physiological limits with some interindividual differences.

However, three important practical questions that need to be addressed are (1) how stable is the established cardiovascular homeostasis , (2) what mechanisms sustain this homeostasis, and (3) what are the reserves of these mechanisms? The space flight of physician cosmonaut V.V. Polyakov, the longest to date (438 days), has yielded new data of direct relevance for providing answers to these questions.

The space flight of physician cosmonaut V.V. Polyakov. the longest to date (438 days), has yielded new data about human adaptation to long-term weightlessness. Autonomic regulation of circulation and cardiac contractility were evaluated in three experiments entitled Pulstrans, Night. and Holter.

In the Pulstrons experiment, which was conducted in daytime (usually before noon), electrocardiographic (ECG),ballistocardiographic (BCG), seismocardiographic (SCG), and some other parameters were recorded.

In the Night experiment,only the ballistocardiogram was recorded, but a special feature of this experiment is that the BCG records were obtained with a contactless method, using a sensor-accelerometer fixed to the sleeping bag of the cosmonaut. It is responding to all bodily oscillations during his sleep, not only those due to pulsatile micromovements of the body, but also those associated with respiration and motor activity. This method has several advantages,the most important of which are the following three: the cosmonaut’s sleep is not disturbed in any way; a large amount of data can be gathered without encroaching on the cosmonaut’s working time: and the possibility of studying slow-wave variations in physiologic parameters (ultradian rhythms) on the basis of recordings made under standard conditions over a prolonged period.

The Pulstrans and Night experiments were carried out in the framework of a Russian-Austrian research program. The Holter experiment (24-hour electrocardiographic monitoring) used a portable cardiorecorder (Spacelab, USA). The electrocardiographic data obtained were used to analyze heart rate variability (such analyses are currently performed for evaluating the autonomic regulation of circulation.

Heart rate variability was analyzed in standard segments of recording 5 min in duration each. In the processing of 24-hour recordings, 5-minute sections were also analyzed and the results were averaged for each hour, for each stage of the study, and for each 24- hour period. These analyses used a special set of programs(entitled Control) developed jointly with the Bavaria Kreischa Clinic (Germany) and Konto Company (Russia).

For the analysis of data from the Night experiment, a specialized set of programs was developed for identifying in and extracting from BCG recordings the data on heart rate, respiratory rate, and motor activity as well as on alterations in the BCG amplitude. The means of the parameters measured were calculated for each 30-second period and processed using spectral and cross-spectral analyses.

During the spectral analysis, the total power of the spectrum under study was calculated for frequency bands corresponding to the time interval of between 2 and 200 minutes. Spectral powers were also calculated for the following time intervals (in minutes): 2-3.5, 3.5-10, 10-35,35-60,60-120, and 120-200. Interactions between minute and hour waves were characterized by factor K. defined as the ratio of total powers in the frequency bands corresponding to the time intervals of 3.5-35 minutes and 60-120 minutes.

The cross-spectral analysis was used to disclose interrelations among the measured parameters and to identify the more closely correlated periodicities. During the l4-month space flight, the Pulstrans experiment was undertaken 10 times, the Night experiment 9 times, and the Halter experiment 7 times. These experiments were also conducted twice before the flight and also twice after it.

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Results Heart-rate variability and cardiac contractility in the Pulstrans experiment Figures 3 and 4 show temporal variations of the basic cardiologic parameters measured in the Pulstrans experiment in the course of the 14-month space flight.

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As can be seen in Fig. 3A, systolic and diastolic pressures during the flight were lower by 10-15 mm Hg than before it. The decreases were most marked on days 147-189 and 257 of the flight. The heart rate rose somewhat at first but reached the preflight level on days 200 and 340 of flight. The heart rate was at its maximum on day 250 of flight when it exceeded the preflight level by 10 beats/min. The SCG amplitude had increased by day 55 of flight, was markedly increased on day 250-257 (Table 1), and was highest near the end of the flight, on days 340 and 410.

Of note is the drastic increase of the SCG amplitude in the first few days after landing when it exceeded about 10-fold the preflight level. The BCG amplitude showed less marked increases and had three maxima - on

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days 189 ,257 and 410 of flight. Of much interest seems to be the considerable (nearly 1.5-fold) increase in the SCG/BCG ratio at the end of flight , although a much larger (nearly 20-fold) increase in this ratio was noted in the first few days after landing.

Heart-rate variability values (Table 1 and Fig. 3B, 3C) demonstrated phasic changes. The SD showed a tendency toward a reduction during the first 6 months, a marked increase in the next two months of flight (days 220-257) and a reduction near the end of straying for 14-months in weightlessness.

Worthy of note are also big changes in the ratio of spectral components (PNS and SNS) of the heart rate variability during months 7 and 8 of the flight. The power of respiratory waves fell sharply (indicating reduced activity of the parasympathetic component of regulation), whereas the power of LF waves with periods of 20-50 seconds showed a similarly large increase (indicating heightened activity of the sympathetic component).

The power of MF spectral component showed a decrease during first 5 months of flight with minima at day 147, but it increase till preflight level at days 250-257 and than fall sharply, especialy in postflight period.

The relative power of MF had other dynamics (Fig.3B).It minima is observed at days 250-257.

Diurnal variations in heart-rate variability values The data on alterations in mean 24-h values of heart rate variability parameters are indicative of at least two important features of circulation regulation during the 14-month flight(fig. 4): 1.The heart rate significantly decreased in the course of the flight, whereas the SD (standard deviation) increased; 2.The absolute power of the heart-rate’s variability high frequency (HF) component decreased, whereas that of its MF component increased.

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Mean 24-h values of the heart rate and SD were closest to their background (terrestrial) values on day 165 of flight, but spectral components differed considerably from their background values during that period.

Of interest is separate consideration of mean diurnal and nocturnal data. Of particular interest in this respect is the graphic representation of "morning-evening-night" relationships in the form of a so-called phase plane (Fig.5). Here, heart rate values are plotted on one axis while values of the absolute power of MF component are plotted on the other.

It can be seen that the "regulation area" (i.e. the area of the triangles formed by the "morning-evening" and "evening-night" vectors) during the preflight period is approximately the same as on day 165 of flight. The "regulation area" is greatly reduced and is characterized by a considerable elongation of the "evening-night" vector early during the flight (day 12) and at its end (day 391).

Moreover, the direction of the "morning-evening" vector changed by the end of flight. These data show that the circadian organization of the regulation of circulation changes in the course of a prolonged flight, which may be due to the inclusion of the hypothalamic-pituitary level in regulation processes.

Ultradian rhythms during the 14-month flight Ultradian rhythms reflect the activity of regulatory mechanisms, by which appropriate interactions among various systems of the human body are assured.

The relevant data obtained during Polyakov’s 14 month flight are presented in Fig. 6. It is the dynamics of factor K. Fig. 6 compares the mean values of factor K obtained in the Night experiments of V.V. Polyakov and of the four cosmonauts who were on a 6-month flight. It can be seem that factor K increased during the first 3 months of flight in all five cosmonauts, and that its values in the 6th-7th months of flight were close in all of them to those recorded preflight. A second increase in this factor was observed for V.V. Polyakov in the 8th-10th months of flight.

Particular attention was paid to analyzing waves in the hour range. The presence of distinct 90-minute

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cycles and their clearly defined structures reflect sleep of good quality. The 90-minute periodicities were evaluated by cross-spectral analysis. The baseline data used were the means of heart rate, respiratory rate, motor activity, BCG amplitude, and heart rate/respiratory rate ratio. The periodicities of each parameter pair that correlated better than others are shown in Table 2. The basic crosspectral period increased in the 2nd-3th months of flight and then returned to a normal value of 102 minutes in the 5th-6th months before showing a second increase to 227-240 minutes in the 9th-10th months.

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In the first 6 months of the 14 month flight, the dynamics of cardiovascular parameters in V.V.Polyakov was virtually the same as in the other cosmonauts. Thereafter, however, the following differences were noted for Polyakov: 1. A tendency of the heart rate to decrease, particularly in night time, to values below those recorded early during the flight; 2. Alterations in the amplitude and duration of superslow oscillations of physiologic parameters in the 7th-8th months, with a fall in the total power of the oscillations and a rise of their relative power in the interval of 3.5-35 minutes;

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3. The tendency of SCG and BCG amplitudes to substantially increase, particularly in the 8th-9th and 14th months of flight; 4. A considerable rise in daily average values of the absolute power of the heart rate’s variability MF component accompanied by a fall in its HF component.

The first 5-6 months of flight were, therefore, sufftcient only to stabilize physiologic functions, in particular functions of the circulatory system, at levels close to terrestrial ones. Stronger adaptational processes appear to develop later.

After the first 6 months of Polyakov’s sojourn in space: 1. Activation of a new, additional adaptive mechanism in the 8th-9th months of flight, as is evidenced by alterations in the periodicity and power of superslow wave oscillations (ultradian rhythms) reflecting the activity of the subcortical cardiovascular centers and of the higher levels of autonomic regulation; 2. Growth of cardiac contractility (both the SCG and BCG) accompanied by a decrease in heart rate during the last few months of flight; and 3. A considerable increase in the daily average values of absolute power of heart rate’s variability MF component, which reflects the activity of the vasomotor center.

The above-mentioned increases, toward the end of the flight, of vasomotor wave amplitudes in the MF range well agree with the growth of cardiac contractility (SCG and BCG amplitude). If an increase in vascular tone in the upper part of the body does not result in elevated arterial pressure but occurs when the arterial pressure is somewhat lowered, this may be interpreted as a consequence of augmented filling with blood of the vascular bed because of an increase either in the stroke volume or in the volume blood flow rate.

Since the circulating blood volume is known to be reduced and the stroke volume not to increase during a prolonged spaceflight, the only way in which the volume blood flow rate can be increased may be a rise in the rate of blood ejection into large vessels, which will require additional energy expenditure. That such a compensatory mechanism operates is suggested by the increased amplitudes of seismo and ballistocardiograms in the second half of the 14 month flight.

On the other hand, we can see the activation of the vasomotor center which is responsible for maintaining adequate vascular tone. This appears to be a second mechanism by which arterial pressure is sustained.

This mechanism is associated with elevated activity of subcortical sympathetic centers which appear to be in turn activated by higher levels of regulation.

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Astronaut's Adaptation in Space

As of June 2013, the demographics of the international astronaut and cosmonaut population indicated that a total of 534 humans have flown in space - 477 men and 57 women (approximately 11% of the total).

A total of 129 NASA astronauts have flown to the International Space Station (space station), comprising 103 men and 26 women (approximately 20% of the total). Female NASA space station astronauts are on average 2 years younger than male astronauts.

While there were no significant differences in the percentage of male (76%) and female space station astronauts(69%) who were married, a significantly greater percentage of male astronauts had a least one child (67%versus 38%) and overall, men had more children than women.

From a professional perspective, female NASA space station astronauts have almost twice as many doctoratelevel degrees as their male counterparts (50% versus 28%); conversely male NASA space station astronauts had more military experience (73% versus 39%). Sex and gender differences as well as these social determinants could impact adaptation to spaceflight.

Results and Key Findings Cardiovascular Long-duration spaceflight may result in eccentric cardiac atrophy and impair cardiac compliance, leading to a prominent reduction in upright stroke volume and orthostatic tolerance in astronauts upon returning to the Earth.

Female astronauts are more susceptible to orthostatic intolerance after spaceflight than male astronauts.

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It has been proposed that low vascular resistance responses, a strong dependence on volume status, and/or a smaller stroke volume secondary to a smaller and less compliant left ventricle may be the underlying mechanisms.

After spaceflight, a greater reduction in plasma volume was reported in female astronauts. The change in lower extremity vein capacitance resulting from a loss of external fluid forces in the dehydrated extracellular compartment was proposed to be another potential mechanism associated with reentry orthostasis.

This condition appears accentuated in women due to their inherent lower center of gravity and proportionately larger mass in the lower extremities.In both male and female astronauts, systemic peak oxygen uptake was well maintained during 9 to 14 days of spaceflight but was significantly reduced immediately on return to Earth, most likely because of reduced intravascular blood volume, stroke volume, and cardiac output.

Visual Impairment Intracranial Pressure Syndrome The VIIP syndrome, first identified in 2005, is currently NASAâ&#x20AC;&#x2122;s leading spaceflight-related health risk.The syndrome manifests with changes to ocular structures such as optic disc edema, choroidal folds, cotton wool spots, globe flattening, and distended optic nerve sheaths (ONSD), and with changes to visual function such as hyperopic shifts, scotomas, and enlarged blind spots. In a few of the cases, post-flight lumbar puncture demonstrated elevated cerebrospinal fluid pressure reflecting increased intracranial pressure (ICP). Some of the observed signs and symptoms persist for months to years after flight, although the implications for long-term health are yet unknown.

The leading pathophysiologic hypotheses for the VIIP development include microgravity-induced cephalad fluid shifts along with loss of gravity-assisted drainage of venous blood from the brain,leading to cephalic congestion and increased ICP. Although not all crewmembers have manifested overt signs or symptoms of the VIIP syndrome, it is assumed that all astronauts exposed to microgravity have some degree of ICP elevation in-flight.

The concern surrounding VIIP stems from the fact that prolonged elevations of ICP can cause long-term loss of visual acuity and peripheral visual fields, and could be related to mild cognitive impairment seen in the analog terrestrial population of idiopathic intracranial hypertension (IIH).

Similar changes to eye structure and function were also observed in short-duration flyers, with lesser severity and a shorter timeframe to resolution.The closest terrestrial analog to VIIP is the syndrome of IIH, which is more prevalent in young, overweight women, although the reason for this sex difference is still unclear.

In contrast, VIIP is slightlymore predominant in males. Out of 41 International Space Station crew members to date, 25 underwent VIIP-specific medical evaluations, including extensive vision testing, refraction, tonometry, pupillary reflexes, extraocular muscle balance, biomicroscopy, fundoscopy, ocular coherence tomography, ocular ultrasound, and magnetic resonance imaging (MRI) of the eyes, orbits, and brain.

The 25 evaluated crewmembers include 17 males (68%) and 8 females (32%). Five of the 8 evaluated females (62.5%) manifested evidence of the VIIP syndrome, compared with 14 of the evaluated 17 males (82.3%). This difference was not statistically significant ( p = 0.09). However, female crew members presented with milder signs and symptoms (mild globe flattening, mild optic disc protrusion on MRI or ultrasound, minor changes in refraction), compared with male crew members (who in general had more marked globe flattening, overt optic disc edema, marked ONSD, larger changes in refraction, etc.). There are insufficient data to evaluate for sex differences among short-duration crew members.

The sex differences observed in VIIP severity may be related to higher vascular compliance in women,which may be protective. A younger age is also associated with higher vascular compliance and the female crew members who manifested VIIP are younger (mean age 44.25 years) than their male counterparts (48.57 years, p = 0.039). High acceleration jet pilot training (65% of men vs. 25% of women, p = 0.024) may lead to lower vascular compliance and higher VIIP susceptibility.

Immunologic Spaceflight takes place in an extreme environment where multiple variables have the potential to alter immune

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responses. These variables include microgravity, physiological stress, radiation, isolation, and circadian misalignment. Prolonged exposure to a spaceflight environment with limited clinical care capability - for example, deep space exploration-class missions - may increase crew risk for adverse health events such as infectious disease, hypersensitivities, autoimmunity, and malignancy.

It has been shown that spaceflight and spaceflight analogue culture conditions globally alter gene expression, virulence, and/or virulence-related phenotypes of obligate and opportunistic bacterial pathogens.

While preflight countermeasures (such as NASA’s Health Stabilization Program) have decreased the incidence of infectious disease during spaceflight missions, a significant number of incidences have been well documented that range from minor infections to potentially incapacitating or life threatening conditions, including a debilitating dental infection and an incapacitating urinary tract infection In addition, spaceflight has been shown to reactivate latent viral infections in astronauts. These observations indicate that the crew may be exposed to obligate and opportunistic pathogens. This risk is expected to increase with longer mission durations and increased use of regenerative life support systems. While evaluations of microbial ecology aboard the Mir and International Space Station suggest a predominance of common environmental and commensal flora, clear pathogen transmission routes have been identified, including opportunistic pathogens carriage and in-flight exchange of intestinal microbial flora by the crew.

Evaluation of spaceflight food prior to shipment for in-flight consumption indicates that most foods do not contain medically significant organisms, but pathogens like Salmonella have been detected and have disqualified that production lot.

It is noteworthy that spaceflight culture has shown significant increases in the virulence of Salmonella, which is a pathogen that has been previously recovered from crew refuse.

Radiation affects numerous immune system parameters, thought to be primarily due to its cell-killing effects in hematopoietic/immune system cells. As radiation effects represent a major hazard for space travel, sex differences in sensitivity to radiation effects are an important consideration for future missions because they will result in considerably higher radiation doses than those received by astronauts participating in the relatively short missions of the past.

It is reported that women are more susceptible to radiation induced cancer than men; both cancer incidence and mortality rates are 50% higher for women. While radiation-induced breast cancer contributes to this increased risk for women, there is also an increased risk for other major types of radiationinduced cancer in women compared with men. The mechanism(s) involved in sex-specific, radiation-induced cancer incidence and mortality rates are not known, although numerous differences exist for sex-specific changes related to radiation-induced carcinogenesis.

Neurosensory Systems The brain exhibits extensive sex differences in gross anatomy, differentiation and development of neurons, neurochemical pathways, and responses to stress or other environmental cues. Also, many central nervous system-related disorders show sex differences in their incidence and nature, including, but not limited to Alzheimer’s disease, post-traumatic stress disorder, anxiety disorders, schizophrenia, stroke, multiple sclerosis, autism, addiction, fibromyalgia, attention deficit disorder, irritable bowel syndrome, Tourette’s syndrome, and eating disorders.

Memory processing Studies consistently indicate a preferential involvement of the left amygdala in memory for emotional material (generally visual images) in women, but a preferential involvement of the right amygdala in memory for the same material in males. This laterality, "women left, men right," mirrors what is seen at rest, indicating that the response to emotional stimulation stems from a baseline that is already differentially "tilted" between the sexes.

Neuronal cell death

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Neuronal cell death pathways differ between men and women. Female neurons more often die through classical, caspase-dependent apoptosis, while male cells die more often through caspase-independent, apoptosis initiating factor-mediated cell death. This finding could potentially be important in developing treatment for neurodegenerative disorders or injuries following stroke.

Opioid receptor binding Several brain regions show significantly different levels of opioid receptor binding in men versus women, including the amygdala and thalamus. These differences can lead to sex differences in response to pain analgesics.

Vision processing Men have significantly greater sensitivity for fine detail and for rapidly moving stimuli, while women exhibit better color discrimination, in part because many males suffer from color blindness, an X-chromosome related genetically inherited disorder.

Somatosensation Relatively little information is available on sex differences associated with tactile sensation, but some differences are known. On average, women are more sensitive than men, over the entire body, to touch and pressure.

Women appear to be more sensitive to temperature differences while men score better than females on a variety of haptic tasks (object or position recognition involving touch and proprioception).

Reporting of pain and pain sensation is rife with many biases (social, gender, ethnicity, culture, etc.), but on average, women do appear to show a greater sensitivity to pain than men- probably due to biological mechanisms, as well as psychological and psychosocial factors.

Vestibular system The vestibular system is notoriously difficult to assess. Relevant research includes anatomy, central physiology, and functions affected by vestibular input including postural responses, spatial orientation, responses to intense motion stimuli, and the occurrence of disease.

Gross anatomy Women have fewer total myelinated axons in the vestibular nerve than men, which may help explain the female bias (that has been verified via epidemiological studies) of developing many vestibular disorders, such as vertigo. In men, the otoliths, utricle, saccule, and superior semicircular canals are significantly larger than in women.

Vestibular nucleus and hormones In rats, some evidence suggests that the estrus (menstrual) cycle may influence the medial vestibular nucleus synaptic transmission and plasticity, with the levels of circulating 17β estradiol being the main factor in these differences.

Spatial task performance Sex differences have been found in circular vection (orientation within a spinning environment), field dependence (perceiving orientation based only on visual cues), perception of veridical vertical with body tilt (correctly identifying the true vertical to the ground when the body is tilted), and perception of the morphological horizon. These differences have been partially assigned to biological differences in the vestibular system, including the difference in otolith size, but some evidence suggests that cognitive training regarding attention to cues can decrease these sex differences.

Motion sickness-laboratory testing A commonly held belief is that females are more susceptible to motion sickness than males. Both social and research design have probably contributed to this bias.

Research conducted in the NASA Johnson Space Center’s Neurosciences Laboratory has subjected over 200 subjects to a variety of motion sickness tests (coriolis sickness susceptibility [CSSI], sudden stop, off-vertical rotation, parabolic flight, etc.).

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No difference was found in susceptibility between men and women nor did testing during any phase of the menstrual cycle for females have an effect. Responses to particular tests were variable. For example, some individuals became nauseous during a CSSI test but not during the off-vertical axis rotation test.

Motion sickness: spaceflight The incidence of motion sickness obtained from post-flight debriefs of long-duration International Space Station, or "space station," (32 male, 10 female) and short-duration Space Shuttle (564 male, 100 female) astronauts show that, on average, female crewmembers that flew on both the space station and shuttle reported both space motion sickness and entry motion sickness (EMS) symptoms more frequently than male crewmembers (these data were mined from the NASA Lifetime Surveillance of Astronaut Health [LSAH] database). The one exception is that men who were crew members on the space station reported a higher incidence of EMS than women after returning from a long-duration spaceflight.

Postural ataxia: spaceflight On average, female crewmembers who flew on both the space station and space shuttle reported post-flight vestibular instability symptoms (feeling abnormally heavy, clumsiness, vertigo, persisting sensation after-effects, or having difficulty walking a straight line) more frequently than male crewmembers (these data were also mined from the LSAH database). All responses were subjective and were reported to a flight surgeon as part of a standard post-flight medical debrief. The debrief did not always specify the symptoms. In a study of computerized dynamic posturography before and after long-duration bed rest, analyses of sensory organization test scores suggest no differences between men and women.

Hearing/auditory function Numerous epidemiological studies have been conducted to compare differences in hearing sensitivity among men and women, confirming that hearing sensitivity declines with age, even in populations screened for a history of noise exposure. These studies have also shown that hearing sensitivity (when reported by conventional pure-tone audiometry) declines faster in men than in women at most ages and in most frequencies tested.

The most recent National Health and Nutrition Examination Survey revealed that the odds of such hearing loss were 5.5-fold higher in men than in women. Even when studies carefully screen for ear disease and noise exposures, however, hearing levels and longitudinal patterns of hearing change are highly variable. This variability has been attributed to smoking, genetic factors, and cardiovascular risks. Hearing sensitivity is particularly vulnerable to hazardous noise exposures (e.g., in industrial, military, and recreational environments), but sex differences in age-associated hearing loss occur even among populations with relatively low-noise occupations and with no evidence of noise-induced hearing loss.

In addition to pure-tone audiometry, distortion product otoacoustic emissions (DPOAEs) have also been used to assess peripheral hearing status. DPOAEs are believed to reveal subtle cochlear changes that may be overlooked by audiometry.

Studies show that aging males experience greater decreases in DPOAEs amplitudes compared to aging females. This decrease in DPOAEs is often proportional to the degree of hearing loss. NASA conducts a unique hearing-monitoring program, in which crewmembers undergo audiometric testing at least once per year during their active astronaut career (and even more frequently when assigned to space missions). Later, when participating in NASA’s LSAH program, former astronauts may continue to have their hearing tested for the rest of their lives. This database offers the opportunity to compare longitudinal differences in hearing sensitivity seen in male and female astronauts over asmuch as a 5-decade span of life (Fig. 1).

When comparing high-frequency hearing sensitivity, the LSAH database’s female population has better hearing thresholds than men at every epoch of life, starting in their mid-30s, approximately the age when most astronauts begin their careers. Female astronauts show no significant differences in hearing thresholds between ears except in those older than 55 (though the sample size for this population is rather small at that age), when the left ear thresholds are slightly better than those in the right ear.

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Male astronauts show greater hearing loss in the left ear than in the right ear at every age; this finding is consistent with many demographic studies, particularly those in which right-handed subjects have shot shoulder-fired weapons (exposing the left ear to most of the blast wave from the weapon’s muzzle). The vocational and avocational activities of many astronauts, military and nonmilitary, often include such firearms.

An important finding from this database (unpublished data) is that although males and females show the expected age-related differences in hearing loss, spaceflight does not seem to affect men and women differently.

Musculoskeletal Men and women differ in many aspects of the musculoskeletal system, with men generally having greater muscle and bone mass. It is well established that the human musculoskeletal response to unloading is highly variable among individuals, with 10-fold differences in response among participants often observed.

As an example, after 30 days of unilateral lower limb suspension, individual responses ranged from a 2.5% to a nearly 20% decline in plantarflexor cross-sectional area compared with before the suspension.

Similarly, with actual spaceflight the loss of cancellous bone in the distal tibia after 6 months aboard Mir ranged from 2% to 24%; such changes range from a negligible loss to deficits equal to those observed after spinal cord injury. Understanding the factors that contribute to such large variability is an important step toward both selecting and protecting the first astronauts who undertake very long (2-3 year) exploration missions.

Time Course and Magnitude of Response: Muscle There is considerable individual variability with respect to loss of muscle size and function as a result of unloading. The precise extent to which sex differences contribute to this is unknown. There is limited evidence in the literature that sex differences related to muscle atrophy might exist.

In the first 2 weeks of unloading, minimal sex differences are apparent in whole muscle atrophy (2%4%) in side-by-side comparisons. If unloading extends beyond 2 weeks, women may experience greater reductions in whole muscle volume and fiber area, particularly in fast-type 2 fibers. Slow-type 1 fibers in both men and women exhibit preferential atrophy with unloading.

There is limited evidence that women experience greater loss of strength in the first 30 days of bed rest, but this sex difference in rate of loss may be reversed with long duration unloading ( > 4 months). Women

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demonstrate greater impairment in neural activation of muscle after short-term unloading; future studies should determine if this leads to greater fatigue susceptibility in women in the first 2 weeks of unloading. There is one study suggesting that recovery of strength after unloading may be slower for women than men. Taken together these data suggest that the time course of unloading-induced muscle loss may be sex specific.

For both men and women, whole muscle and single muscle fiber atrophy does not fully account for the strength and power loss; the reduction in the force and cross-sectional area of type 1 fibers appears to be very similar in both genders. A significant gap in knowledge is whether sex differences in strength loss/neural activation translate to differences in functional performance (e.g., mission-related tasks).

Time Course and Magnitude of Response: Bone Sex differences in bone mineral density (BMD) are well documented; since bone mass scales to body mass, men on average have a larger skeletal mass. There is little evidence, however, on whether there is a sex difference in rates of bone loss with unloading or in the rate or magnitude of recovery therefrom.

While the effects of bed rest on BMD and/or bone metabolism have been examined separately in men and in women, there have been no human studies that have been statistically powered to make direct sex comparisons.

In one 17-week bed rest study that included both men (n = 13) and women (n = 5) at one of 10 sites measured (calcaneus), bone loss was markedly less in women than men. However, the dual energy x-ray absorptiometry-assessed total hip BMD for women in a 60-day bed rest study revealed a substantial loss at that site, whereas men in a similar study did not have a decrease in total hip bone mineral content.

Volumetric BMD and bone geometry of tibial cancellous and cortical compartments have been evaluated after prolonged bed rest using peripheral quantitative computed tomography (pQCT) in men and highresolution pQCT in women.

The small gender differences observed in the bone loss rates at those tibial sites are within the reported precision for these pQCT variables. Side-by-side investigations using rodent hindlimb unloading (a commonly used surrogate for microgravity) reveal greater cancellous bone loss in skeletally mature female mice and a distinct effect of starting values (mice with greater bone volume at the start lost less bone). However, in mature rats few differences between genders are apparent.

There is little definitive evidence showing sex-specific differences in the rate of bone loss. Certainly, some of the individual differences may be related to sex-specific hormonal factors. As is the case with muscle, the individual variability within gender in response to unloading is large and should be better understood.

Negative Energy Balance Some bed rest studies have restricted energy intake and allowed weight loss by design or allowed subjects to consume food at their discretion, so as to not coerce intake. The 60-day Womenâ&#x20AC;&#x2122;s International Simulation for Space Exploration study was one of these studies, and as a result, these female subjects did lose body weight (lean tissue more than fat) during bed rest at a rate of 0.06 kg/day.

In a similar 90-day study with male subjects conducted earlier at the same institution, men also lost weight at 0.04 kg/day (calculated from the published average weight loss). Due to the many differences in study design, it cannot be concluded with any certainty if this slight difference in rate of weight loss between men and women is of any significance. While "weightlessness" is a key aspect of space travel, an unexpected analog comes in the form of studies related to weight loss. Though there is a fair amount of literature on weight loss and effects on bone similar to space-related research, few studies have examined the effects of negative energy balance on bone with regard to gender, and those that have attempted are plagued bymany confounding factors (age, body size, diet- and/or exercise-induced weight loss, rate of weight loss, etc.), making drawing conclusions difficult.

Joint Injury Sex-based differences have been identified in the incidence of osteoarthritis (OA), with OA of the knee, in particular, significantly more common in women. Sex-based risk factors explaining this include the loss of

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estrogen’s anabolic effect on cartilage after menopause, a higher incidence of predisposing knee injuries-such as anterior cruciate ligament tears-in women, and increased joint laxity.

There is clear evidence from animal studies that regular mechanical loading is essential to cartilage health. In humans, 6 or more weeks of non-weight-bearing can produce changes in magnetic resonance imaging images of knee cartilage that resemble OA. However, sex-based differences in the response to joint unloading have not been elucidated. Because articular cartilage health is impacted by the quality of the underlying bone as well as the strength of muscles around the joint, assessment of the potential risk for articular cartilage injury imposed by unloading needs to include evaluation of all three tissues: bone, muscle, and cartilage.

There is some evidence to suggest that osteopenia of subchondral bone underlying articular cartilage contributes to cartilage degeneration. Conversely, damaged cartilage releases receptor activator of nuclear factor kappa-B ligand (RANKL) and other inflammatory components, which can lead to the loss of adjacent bone.

Since muscles serve to stabilize and dampen forces across joints, loss of muscle mass and strength after a prolonged unloading can contribute to joint injury risk and early degenerative joint changes, especially in the knee.

However, sex-based differences in the relative impact of bone and muscle loss on joint health have not been defined. Specific interventions to increase loadbearing or strengthening activities in space will be indicated. They may also identify the need for progressive strengthening and joint loading upon arrival on a planetary surface after extended microgravity exposure, after return from space or after prolonged period of non-weight-bearing on Earth.

Musculoskeletal injuries have been reported in-flight at a rate of 0.021 per flight day for men and 0.015 per flight day for women; hand injuries are the most common, with abrasions and small lacerations the most common manifestations.

There are few data on the recovery of the musculoskeletal system following spaceflight and even less data on sex differences in recovery rates. Generally, international space station crew have substantial recovery of muscle strength within a month following flight. The time course of recovery of bone mineral density has been evaluated but not specifically for sex differences. In general, half-lives for recovery of bone mineral density are ≈150-200 days depending on site.

Reproductive Radiation dose to crew is mission-specific and dependent on multiple factors such as mission destination and duration, vehicle and habitat design, and solar conditions. Typical ISS exposures for a 6-month mission in low-Earth orbit are on the order of 54 to 108 mSv with exposure levels varying with solar activity and ISS altitude. Exposures during interplanetary travel required to reach Mars and on the Mars surface are far greater, with annual exposures spanning 210 to 1,070 mSV and 80 to 330msV, respectively. Relative to other organ systems, the gonads are highly sensitive to radiation exposure. In men and women, temporary infertility is associated with high-dose, acute radiation exposure-for men, 150 mSv acute x-rays , and for women, 650 to 1500 mSvV acute x-rays or gamma rays to the ovaries.

Cancer risk assessment requires evaluation of organ doses (measured in Sv) from dosimetry and physical considerations, which are combined with age and gender-dependent risk coefficients to project mission risk. Women have a higher incidence of radiation-induced cancers, largely driven by lung, thyroid, breast, and ovarian cancers, and therefore reach maximal safe days in space earlier than men.

There are presently insufficient numbers of humans exposed to space-characteristic radiation to accurately assess differential effects on men and women. NASA studies have examined cancer risk in animals following exposure to space radiation (protons and high-linear energy transfer (LET) radiation); however, little attention has been paid to sex differences.

During the space shuttle era, most exposures were up to ≈ 2 weeks in duration. In contrast, ISS mis-

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sions are extending durations of exposure to 6-12 months. This change is significant with regard to the physiology of sperm production by the testis in the male and the estrous cycle in the ovary in the female.

Longer duration missions, spanning multiple reproductive cycles in both men and women, raise a significant knowledge gap concerning the impact of long-term spaceflight on reproductive health.

There are a number of reproductive health concerns for men and women in space potentially related to microgravity and/or stress (including sleep disruption). Spermatogenesis in men may be impaired beyond effects of radiation exposure.

A 120-day Russian bed rest study found that sperm collected after 50-60 days and 100 days exhibited a reduction in live spermatozoa showing active mobility and an increase in the percentage of morphologically/structurally altered spermatozoa. Basic research studies of male rats exposed to 6 weeks of simulated microgravity have reported severe testicular and epididymal degeneration including massive testicular apoptosis 6 months later.

These effects have been postulated to occur due to (a)Chronic testicular hyperthermia, (b) Invasion of inflammatory cells, and/or (c) Catastrophic apoptosis, leading to aspermatogenic dysfunction.

There has been no post-spaceflight research involving humans on this topic.

Reproductive changes during or post flight have not been systematically studied in female astronauts. In female adult mice that were cycling at launch (Space Transportation System [STS]-131, STS-133, and STS135), spaceflight induced cessation of cycling, loss of corpora lutea, and significantly reduced estrogen receptor mRNA levels in the uterus (HM Holets, University of Kansas Medical Center, unpublished data).

Comparable evaluations in women are lacking. Systematic data regarding reproductive history in men and women astronauts is lacking. Although many male astronauts have produced children following spaceflight, information on conceptions and birth outcomes upon returning from space are not available. The incidence of infertility following prolonged spaceflights in men and women and the incidence of pregnancy complications in women are not known.

In female astronauts who have delayed pregnancy, it will be difficult to parse out the effects of space travel (microgravity, radiation exposure) from natural effects of aging. Female astronauts who experience hypertensive pregnancy disorders may require additional monitoring for cardiovascular disease, because on Earth these disorders are associated with increased risk of future adverse cardiovascular events such as stroke and myocardial infarction.

Physiological Systems Central to Reproductive Function Endocrine system The hypothalamic-pituitary-gonadal (HPG)and hypothalamic- pituitary-adrenal (HPA) axes cross-communicate through neuronal signaling and hormonal negative feedback. Several hypothalamic neurotransmitters are known to be altered by real or simulated microgravity or severe changes in gravity, namely histamine (increases), serotonin (decreases), oxytocin (decreases), norepinephrine (decreases), and to a lesser magnitude, glutamate (decreases).

These neurochemical disparities may be a direct result of the significant change in the gravitational environment on neuronal signaling or an indirect effect via the hormonal response from the downstream hormonal axes. Alterations in HPG and HPA axes functioning have been reported following spaceflight. Most evaluations focused on the reduced levels of circulating testosterone in men that appear to rebound after return to Earth.

This has been recapitulated in short and long-duration spaceflight and long duration head-down bed rest studies. A recent report indicated no decrement in serum total, free, and bioavailable testosterone during either long-duration spaceflight or bed rest, but a significant decrease on landing day for the longduration flights and after short-duration spaceflight. The HPA axis, which exhibits both a circadian rhythm and enhanced

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output of circulating glucocorticoids (i.e., cortisol) in response to stressors, exhibits increased activation during spaceflight, simulated microgravity, and during long-duration stress studies. However, like the gonadal hormones, circulating concentrations of these hormones quickly recover upon return to Earth.

With respect to women, estrogen and gonadal function in space and in simulated microgravity (bed rest) are grossly understudied. Oxytocin, a hormone that acts to attenuate the HPA axis and dampen stress responses in women, exhibits long lasting reductions following spaceflight.

Similarly, oral contraceptives (OCs) decrease the release of oxytocin but do not increase stress responsiveness, as OCs reduce cortisol release in response to stressor exposure as well. OC use is not mandatory during spaceflight; however, flight surgeons have recommended 30-35mcg OCs to female astronauts to provide (a) better suppression of the ovary (less chance for cysts and breakthrough bleeding, depending upon OC formulation) and (b) reduced risk of bone loss.

Circulating levels of testosterone, dihydroepiandrosterone, corticosteroid-binding globulin, prolactin, and sex hormone-binding globin are affected by OCs and are involved in stress responses and the regulation of both the HPG and HPAaxes.Unfortunately,with ever-changing formulations, periodic reevaluation of oral contraceptive cost-benefit is also required.

Genitourinary system While reproductive functions have not been a direct concern during space travel, diseases of organs of the reproductive system have adversely affected flight duration.

For example, a serious case of prostatitis in a cosmonaut occurred in 1985 that impacted the length of the mission.

Little is known about sexual activity in space, and infrequent ejaculation resulting in accumulation of prostate secretions can support bacterial growth.

Hence, the risk of prostatitis may well need to be addressed again during prolonged exploratory travel.Renal and urinary tract problems are a recurrent issue with space travel. Microgravity and privacy concerns can lead to infrequent and incomplete bladder emptying, increasing the risks for urinary tract infections.

In addition, medications for motion sickness reduce bladder emptying. Formation of stones becomes more likely when hydration is compromised, and microgravity increases the amount of calcium excreted in the urine. Inadequately treated stones and urinary tract infections could eventually impair renal function.

On Earth, urinary tract stones are more common in Caucasian men, but struvite stones are more common in women. Urinary tract infections are more common in women and prostatitis occurs only in men. The long-held belief that the urinary tract is sterile is being called into question with emerging work on the urinary microbiome.

There are no data regarding sex differences in spontaneous or unprovoked urinary retention in the age range of the astronauts. However, data regarding provoked urinary retention after surgery, with nearly equal numbers of men and women of similar age to the astronauts, do not show a sex difference.

Cumulative experiences in space travel suggest there is no sex difference in the incidence of urinary tract stones during space travel or after returning to Earth, however women have experienced a higher incidence of urinary tract infections in space thanmen. Possible explanations for this sex difference include predisposition from womenâ&#x20AC;&#x2122;s urethral anatomy, adjustment to voiding in microgravity, a higher incidence of urinary retention, and a higher incidence of catheterization.

Interactions of Reproduction with Other Aspects of Health Estrogen receptor signaling Ground-based studies have identified age-related alterations in estrogen receptor (ER) signaling in many major organ systems. Several of these organ systems have shown changes in experimental animals during spaceflight. Altered ER signaling in these estrogen-regulated systems, shown in Figure 1 are also known to accelerate certain aging processes.The spaceflight-induced decline in multiple physiological systems may

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involve a common mechanism in dysregulation of reproductive steroid receptor-dependent signaling pathways.

Bone and cardiovascular health There are sex differences in response to stressors that affect the reproductive axis, and these can have long-term consequences for bone and cardiovascular health. Although contraceptive use is common among female astronauts, those that suppress ovarian function for extended periods [e.g., Depo-Provera or other contraceptives containing depot medroxyprogesterone acetate (DMPA), and Noristerat, Norigest, Doryxas, or others containing norethisterone enantate(NET-EN)] have been shown to adversely affect womenâ&#x20AC;&#x2122;s bone density on Earth.

Thus, if used in space, certain OC formulations may compound bone loss resulting from microgravity in female astronauts. This raises the question of whether total estrogen exposure would be reduced for female astronauts using those contraceptives on long-duration missions that, in turn, could impact bone health, muscle strength, and cardiovascular risks.

Thus, in women, increased risk for cardiovascular disease may be both directly and indirectly related to disruption of ovarian function, perhaps through binding of the adrenal cortical hormones to progesterone receptors and membrane surface receptors that also bind estrogen.

Brain-behavior relationships Sleep Flight-induced changes in gonadal hormone release may be the source of a nonreproductive functional outcome, namely altered sleep patterns. Sleep-wake cycles are also disrupted in Earth-based, long-duration microgravity simulations. Sleep quality is affected by some stressor exposures and is correlated with circulating

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testosterone and estradiol levels.Conversely, sleep deprivation disrupts normal gonadal hormone secretion and increases glucocorticoid release, thus potentially causing a positive feedback loop. Gonadal hormones affect the activities of brain monoamines, acetylcholine, and orexin, all neurotransmitters involved in maintaining wakeful state, sleep state, or transitions between sleep states.

Reproduction and rearing In adult animals flown in space, fertilization difficulties could potentially occur due to disruption of hypothalamic neurochemistry important for proceptivity and receptivity components of copulation. Several hypothalamic transmitters are affected by physical factors involved during spaceflight.

Oxytocin is both responsive to HPG axis functioning and attenuates HPA axis activation during stressor exposure in women. Hypothalamic oxytocin is also critically involved in female sexual receptivity. Unlike many other hormones, hypothalamic oxytocin remains reduced at 18 weeks following spaceflight in rodents. This effect may be more significant in women, as OCs reduce circulating oxytocin levels.

Given the influence of spaceflight and OC use on oxytocin release, further research is necessary to determine whether this combination could have long-term effects on reproductive health.

Enduring changes in oxytocin following spaceflight might be critical in postpartum behaviors, as oxytocin is implicated in social bonding. Thus, the implications of longduration spaceflight for the viability of the immediate offspring as well as the subsequent generation of offspring are an unknown, possibly ever-lasting effect within the families of those chosen to participate in such missions.

Sex and Gender Considerations in Astronaut Reproductive Health As compared with male astronauts, female astronauts delay reproduction (Table 1), which may be based, in part, on gender role requirements. Further, the biological processes that ensure successful reproduction are impacted by aging, a factor that can lead to infertility and pregnancy complications in those who delay childbearing. Thus, childbearing and childrearing events that occur along a continuum are examples where the variables of sex and gender collide.

Table 2 shows that in this astronaut cohort, the age of first mission and percent married is significantly different between men and women. Table 2 shows that male astronauts have a higher average number of children than female astronauts, and even with the low numbers of female astronauts, this finding was statistically significant. An important hypothesis to consider is that the gender component impacts this finding

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Because women are more likely to function as primary caregivers for their children and to take a hiatus fromtheir career due to this parental role, we could speculate that some women choose to delay reproduction due to the extensive time required for preparation and training for space travel, which may be discordant with societal roles and responsibilities of parenting.

Behavioral Sex, Gender, and Behavioral Health on Earth Anxiety disorders A variety of evidence indicates that anxiety disorders are about twice as prevalent in women as in men on Earth. Several differences in anxiety symptom presentation related to sex have been reported. Women have greater symptom severity of generalized anxiety disorder and more functional impairment. Women also have greater severity of social anxiety disorder, a greater number of social anxiety-related fears, and are more likely than men to have a generalized type of the disorder. Women with panic disorder have more frequent panic attacks, higher levels of phobic avoidance, and more functional impairment than men. Differences between men and women in the course of anxiety disorders have also been reported. Women have a more chronic course of generalized anxiety disorder compared to men, a later age of onset, and a more chronic and recurrent course of panic disorder. Women are more susceptible to developing post traumatic stress disorder in response to trauma. Differences in comorbidity with anxiety disorders have also been described.

In addition, there are differences in medication use and response between men and women. Women with generalized anxiety disorder are more likely to be prescribed medications for treatment, especially benzodiazepines. Women with post traumatic stress disorder respond better than men to sertraline.

Depressive disorders including premenstrual disorders As is true for anxiety disorders, major depressive disorder is about twice as common in women than in men on Earth.In addition to prevalence rate differences, gender differences have been noted in symptoms, course, comorbidity, and treatment response. Women are more likely than men to present with atypical depressive symptoms, such as increased appetite and weight gain, as well as more anxiety and somatic symptoms, whereas men are more likely to present with neurovegetative symptoms, such as insomnia and weight loss. While suicide attempts are more common in women, the rate of completed suicide is higher in men. Differences in comorbidity have also been noted, with depressed women having more anxiety and eating disorders and depressed men having more alcohol and substance abuse problems.

Women are also more likely to have a greater chronic and recurrent course of illness. Women are more sensitive than men to developing an episode of depression following stressful life events; moreover, the type of stressful life event trigger is different, with women more prone to becoming depressed in response to stressors

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involving family or interpersonal relationships and men in response to stressors involving work or financial issues.

Differences in antidepressant treatment response by women and men have been reported. Women respond better to selective serotonin reuptake inhibitors than men. Differences related to menopausal status have also been noted, with postmenopausal women responding more poorly to selective serotonin reuptake inhibitors than premenopausal women, and premenopausal women responding poorly to tricyclic antidepressants.

Premenstrual disorders (PMD) are prototypical female specific disorders that include premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), and premenstrual exacerbation (PME) of ongoing affective disorders such as dysthymia and major and minor depression. While the prevalence of PMS ranges from 10-85% of women depending on the criteria used, PMDD occurs in up to 5% of women, but the prevalence of PME is not as well characterized. Selective serotonin reuptake inhibitors are the gold-standard treatment for PMDD, taken daily throughout the menstrual cycle or during the luteal phase only. Intermittent dosing is popular as it reduces medication exposure and risk of side effects. Oral contraceptive pills are effective in reducing many of the physical symptoms of PMS/PMDD but are typically less reliable for the treatment of mood symptoms, making women with PMDD considerably more symptomatic in some cases.

Finally, supplements such as calcium (1,200 mg/d) may help to relieve some of the physical and emotional symptoms of PMS/PMDD. The evidence base of moderate exercise for improving mood and physical symptoms of PMDs is limited.

Relevance of clinical disorders to space and analog environments There is no evidence to date that astronauts experience the same risk for depression and anxiety disorders as their counterparts in the general population. Because all astronaut candidates undergo a process of psychological screening and selection, the likelihood of differences in mood disorders attributed to sex may be reduced, although the authors are unaware of research conducted among astronauts to support this assumption. With respect to the question of how space travel may impact PMDs or vice versa, one must consider the effects of hyper and hypo-gravity on ovarian function. Much of the literature on this topic has focused on non human mammals; relatively little is known about the impact of longterm exposure to gravitational changes and radiation on ovarian function and gamete development in humans.

Alterations in ovarian hormone production could lead to changes in mood in women, like those with PMDs, who are sensitive to ovarian hormone fluctuations. PMDs can worsen with age, and there is clear evidence that PMDs increase the risk of a major depressive episode in women during the menopause transition, which occurs in the age range of women currently transiting to and from and living on the ISS. In addition, it is possible that the separation from family and other important relationships inherent in long-duration spaceflight may make women more susceptible to the stress of isolation and perhaps even to depression, but it is possible they also may be more likely to be interpersonally supportive of others who miss family and friends. Men, on the other hand, may tend to express psychosocial isolation through anger, noncooperation, and conflict. These sex and gender differences in aspects of behavioral health on Earth provide the rationale for more investigation of sex and gender differences in behavioral health reactions in spaceflight and space analog environments.

Behavioral Health in Spaceflight and Analog Environments There are limited data on sex and gender based differences in behavioral health in space or in other isolated and confined extreme environments. Studies of sex and gender differences in behavioral health in Antarctica have produced mixed results.

In one study, winter-over female personnel reported a significantly larger number of depressive symptoms than males, although there were no sex-related differences in mood disorder diagnoses. However, another study reported no significant difference between men and women with respect to depressive symptoms in summer or winter.

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A third study found no difference in depressive symptoms after adjustment for coping resources and strategies. The major shortcoming of these studies is that the female and male participants were not demographically similar to astronauts, thereby limiting the ability to generalize study results.

Personality and behavioral health There are few studies of astronaut personality characteristics; published reports cover material collected close to two decades ago. The most striking finding comparing personality traits of 12 female and 51 male applicants assessed between 1989 and 1994 and selected into the astronaut corps was the overall similarity between sexes. Women scored higher than men on expressivity and achievement strivings, although these differences were only marginally significant. Men scored significantly higher on competitiveness. Findings on the same cohort indicated that astronauts who were rated the most effective displayed characteristics, termed the "right stuff," as high in positive expressivity and instrumentality and low on negative instrumentality.

Astronauts with higher levels of expressive traits were rated higher by their peers on group living (interpersonal and team) performance,although this factor was not related to flight assignments. A peer-rated performance and competence factor was closely associated with flight assignments of mission specialists. The several studies that assessed personality characteristics of women and men in polar work groups or expedition teams also have not found differences.

Men and women in Antarctic groups scored lower on neuroticism and higher on positive personality traits than normative gender groups, and were not significantly different from each other. In an all-women expedition team, personality traits indicative of low stress reactivity, and higher scores on positive compared to negative emotionality factors, were similar to findings with an all-men expedition team.

Adjustment aboard the ISS Results from the Journals Flight Experiment on the ISS suggest slight differences between men and women in terms of net positivity/negativity, as reflected in entries assigned to the "Adjustment" category by content analysis of confidential journals. Net positivity/negativity was calculated by subtracting the proportion of negative entries from the proportion of positive entries to obtain a single metric that can be tracked over time.

Men exhibited greater positivity than women overall and particularly during the first and fourth quarters of ISS expeditions, and the relevant entries of women fluctuated less than those of their male comrades in this metric.

Emotional stability was found to be among the characteristics of successful adaptation and esteemed leadership in previous studies of isolated and confined personnel, suggesting that the difference, if actual, reflects successful adaptation by women to the conditions aboard the ISS. The small number of female participants and the large difference in the number of entries do not permit a definitive answer to any questions concerning differential adjustment and performance.

Sex, gender, and stress In examining sex and gender differences related to stress and stress reactivity on Earth, women generally show both heightened stress sensitivity and an increased presentation of stress-related affective disorders. The stress response is essential for maintenance of homeostasis, but increased response to stress or persistence of stress reactions can lead to disease or inappropriate behaviors, including an elevation in risk factors for depression and anxiety. Further, increased passive behavioral responses to stress are associated with the occurrence of depressive symptoms.54 Differences between men and women exist in the hypothalamic-pituitary-adrenal axis stress response where women display a greater physiological stress response than men as demonstrated by higher cortisol levels following a variety of stressors.

In addition to the hypothalamic-pituitary-adrenal axis, women are more sensitive to the effects of elevated adrenaline during stress activation as part of the autonomic nervous system stress response. In these studies, the magnitude of sex-related differences was influenced by individual life experiences and fluctuations in reproductive hormone levels in women. As evidence of such effects, functional magnetic resonance imaging (fMRI) analyses in women have shown fluctuations across the menstrual cycle in response to emotional stress-provoking stimuli in the orbitofrontal cortex, a brain region important in affect determination.

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D ID YOU KNOW ?

NEO Five-Factor Inventor

NEO Five-Factor Inventory (NEO-FFI) was developed to provide a concise measure of the five basic personality factors . For each scale, 12 items were selected from the pool of 180 NEO Personality Inventory (NEO-PI) items, chiefly on the basis of their correlations with validimax factor scores. The instrument uses a five-point Likert response format. Two-week retest reliability is uniformly high, ranging from 0.86 to 0.90 for the five scales, and internal consistency ranges from 0.68 to 0.86 . The NEO-FFI has been translated into several different languages and shown validity and utility in a number of different contexts; it is one of the most widely used measures of the Five-Factor Model.

Between 1989 and 1995, 259 final stage astronauts completed the Personal Characteristic Inventory (PCI) which assesses personality characteristics related to the broad traits of Instrumentality and Expressivity.

In addition, 147 of these individuals also completed an abbreviated version of the NEO Five Factor Inventory (NEO-FFI) which assesses the "Big Five" traits of Neuroticism, Extraversion, Openness, Agreeableness, And Conscientiousness.

References: Personality characteristics and trait clusters in final stage astronaut selection

Cockpit Resource Management (CRM)

Over the last decade, an increasing amount of evidence has accumulated suggesting that some 70 per cent of air carrier incidents and accidents have been caused, at least in part, by a failure of the flight crew to make use of readily available resources.Research programmes have demonstrated that these types of occurrences have many common characteristics. One of the most compelling observations of these programmes is that often the problems encountered by flight crews are associated with poor group decision-making, ineffective communication, inadequate leadership, and poor management. In addition, many traditional training programmes emphasize the technical aspects of flying almost exclusively, and do not deal effectively with various types of crew management strategies and techniques that are also essential to flight safety.

These observations have led to a consensus in both industry and government that more emphasis needs to be placed upon the factors which influence crew co-ordination and the management of crew resources.

Briefly defined, cockpit resource management (CRM) is the effective use of all available resources, i.e. equipment, procedures and people, to achieve safe and efficient flight operations. CRM training programmes have been or are being developed by several major operators. Although the concept is receiving widespread acceptance, limited progress has been made in the industry as a whole. Moreover, there is some confusion with respect to the key elements of CRM training, and how to go about developing a CRM training programme.

CRM training is but one practical application of Human Factors. Although CRM can be approached in many different ways, there are some essential features. The training should focus on the functioning of the

Special Issue ’Long-duration Spaceflight’

flight crew as an intact team, not simply as a collection of technically competent individuals; and should provide opportunities for crew members to practise their skills together in the roles they normally perform in flight. The programme should teach crew members how to use their own personal and leadership styles in ways that foster crew effectiveness. The programme should also teach crew members that their behaviour during normal, routine circumstances can have a powerful impact on how well the crew as a whole functions during high-workload, stressful situations. During critical emergency situations, rather basic skills and knowledge come into play, and it is unlikely that any crew member will be able to take the time to reflect upon his or her CRM training to determine how to act. Similar situations experienced in training increase the probability that a crew will handle actual stressful situations more competently.

References: Flight Crew Training: Cockpit Resource Management (CRM) and Line-Oriented Flight Training (LOFT)

Line-Oriented Flight Training (LOFT)

LOFT refers to aircrew training which involves a full mission simulation of situations which are representative of line operations, with special emphasis on situations which involve communications, management and leadership. In short, LOFT means realistic, "real-time", full mission training. Most of the information in this chapter has been gleaned from NASA Conference Publication 2184, "Guidelines for Line-Oriented Flight Training, Volume II. The assessed value of LOFT is such that several States’ aviation administrations permit its use instead of the usual semi-annual proficiency checks, provided that certain specified conditions are met.LOFT can have a significant impact on aviation safety through improved training and validation of operational procedures. LOFT presents to aircrews scenarios of typical daily operations in their airline with reasonable and realistic difficulties and emergencies introduced to provide training and evaluation of proper flight deck management techniques.

The result is an appreciation by the air carrier of operational shortcomings on the part of line crews and an evaluation of the adequacy of flight deck procedures and instrumentation, as well as over-all crew training effectiveness.

References: Flight Crew Training: Cockpit Resource Management (CRM) and Line-Oriented Flight Training (LOFT)

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9.KSC HEARING LOSS PREVENTION PROGRAM,Kennedy NASA Procedural Requirements,KNPR 1820.3 Rev. C1,NASA. 10.Douglas A. Vakoch,On Orbit and Beyond,Psychological Perspectives on Human Spaceflight,2013,10.1007/9783-642-30583-2.

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Extreme Physiology & Medicine, 1, 12. doi:10.1186/2046-7648-1-12.

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ISOPTWPO The International Space Agency (ISA) was founded by Mr. Rick Dobson, Jr., a U.S. Navy Veteran, and established as a non-profit corporation for the purpose of advancing Man’s visionary quest to journey to other planets and the stars.

ISOPTWPO(International Space Flight & Operations - Personnel Recruitment, Training, Welfare, Protocol Programs Office) is part of ISA, which support research on Human Space Flight and its complications. ISOPTWPO will research on NASA’S Human Research Roadmap. It will also research on long duration spaceflight and publish special issues on one year mission at ISS and twin study.

Mr. Martin Cabaniss is director and Mr. Abhishek Kumar Sinha is Assistant Director of ISOPTWPO. Ad Astra ! To The Stars! In Peace For All Mankind !

Mr. Rick R. Dobson, Jr.(Veteran U.S Navy) — International Space Agency (ISA)

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Ad Astra ! To The Stars! In Peace For All Mankind !

Mr. Rick R. Dobson, Jr. (Veteran U.S Navy)

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