UTMB Health Aerospace Medicine Residency Grand Rounds
Tuesday, April 28, 2015
Graham B.I. Scott, Ph.D.
Vice President, Chief Scientist, and Institute Associate Director
National Space Biomedical Research Institute, (NSBRI)

Introduction / Decadal Survey
Astronaut / Cosmonaut Demographics
Sex & Gender Differences In Space & On Earth
Publications / Major Findings & Recommendations
Media Response to Sex & Gender Study
Policy Implications

Recommendations and Priorities
There is a critical lack of information about the effects of spaceflight on gonadal function and bone loss, as well as about effects of cosmic radiation on women’s health. Basic information is needed about the effects of microgravity and circadian disruption on gonadotropin release and on estrogen and progesterone concentrations.
In general, development of countermeasures should account for gender differences.
Also, whenever feasible, modifications to the EVA suit design should accommodate smaller individuals or crew members with less upper body strength, to enhance mobility during
EVA tasks.
Summary and Conclusions
The most significant gender issues that should be addressed in the next decade include an understanding of possible differences in bone loss and radiation risks and development of effective countermeasures. For crew selection, the most important consideration should be to choose the people most qualified to perform the required tasks. A critical issue is to select crews that work well together. Antarctic studies have found that mixed-gender teams may experience sexual jealousies and rivalries but often are more stable than all-male teams.

http://www.nasa.gov/pdf/740566main_current.pdf

“All Transits” to International Space Station (1998 – 2013)
Number
Males % Males Females % Females
188 83% 39 17%
Military Experience
Doctoral Degree
Masters Degree
Average Age 46.2 years
At Least One Child
73%
28%
85%
43.7 years
33%
50%
58%
67% 38%

“All Transits” to International Space Station (1998 – 2013)
FD- Flight Day
R- Return to Earth
NET- No earlier than nmS- Soyuz flight number http://online.liebertpub.com/doi/abs/10.1089/jwh.2014.4911

“All Transits” to International Space Station (1998 – 2013) http://online.liebertpub.com/doi/abs/10.1089/jwh.2014.4911

> 6100 applicants, including
~ 1000 women.
Five military pilots;
1 medical doctor; 2 Ph.D. level scientists
Women:
•
2 Pilots
•
2 Scientists

304 applicants – including 43 women

http://www.spacenews.com/article/civil-space/41006russia-appoints-6-new-cosmonauts-excludes-sole-female-candidate

“All Transits” to International Space Station (1998 – 2013)
FD- Flight Day
R- Return to Earth
NET- No earlier than nmS- Soyuz flight number http://online.liebertpub.com/doi/abs/10.1089/jwh.2014.4911

“All Transits” to International Space Station (1998 – 2013) http://online.liebertpub.com/doi/abs/10.1089/jwh.2014.4911

Space Radiation
5 instances of
Chromosome 2
Visual Impairment –
Intracranial
Pressure, (VIIP)
Neurobehavioral and Psychosocial
Decrements

Integrated Path to Risk Reduction, Revision B PCN-1 (2014)
C
C
B
C
A
ISS 1-Yr
Mission
Asteroid
Phase A EM-1 CCP EM-2
ISS
End
Asteroid
Initiative
Mars -
Phase A
Planetary DRM (Mars)
Risks
Cardiac Rhythm
Problems (Arrhythmia)
Decompression
Sickness (DCS)
Incompatible Vehicle/
Habitat Design (Hab)
Inadequate Nutrition
(Nutrition)
Sleep Loss/Work
Overload (Sleep)
Reduced Muscle Mass
(Muscle)
Reduced Aerobic
Capacity (Aerobic)
Orthostatic Intolerance (OI)
Team Performance (Team)
Intervertebral Disc Damage
(IVD)
Host-Microorganism
Interactions (Microhost)
Human-Computer
Interaction (HCI)
Occupant Protection (OP)
Early Onset
Osteoporosis (Osteo)
Altered Immune
Response (Immune)
Bone Fracture (Fracture)
Intracranial Hypertension/
Vision (VIIP)
Errors Due to Training
Deficiencies (Train)
Unpredicted Effects of
Medication (Stability)
Inadequate Food
System (Food)
In-Flight Medical Capabilites
(ExMC)
Vestibular/Sensorimotor
Impacts (Sensorimotor)
Behavioral Conditions
(BMed)
Critical Task Design (Task)
Inadequate EVA Suit (EVA)
Human & Automation/
Robotic (HARI)
Exposure to Dust & Volatiles
(Dust)
Renal Stone
Formation (Renal)
Radiation Exposure on
Human Health
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
2
2
1
3
2
4
4
4
1
5
2
2
1
1
1
2
2
2
1
1
1
3
1
1
2
2
2
2
HSRB
Haz LxC
1 3 x 1
3 x 4
Inc
3 x 3
3 x 3
2 x 4
3 x 4
3 x 4
3 x 4
Inc
Inc
3 x 4
3 x 4
3 x 3
3 x 3
2 x 4
3 x 4
2 x 3
Inc
3 x 3
3 x 3
3 x 3
3 x 3
3 x 2
2 X 3
3 x 3
3 x 3
3 x 3
3 x 2
FY14 FY15 FY16 FY17 FY18 FY19 FY20 FY21 FY22 FY23 FY24 FY25 FY26 FY27 FY28
Risk Understood
NHV Process Developed
Standard
Updated
Standard
Updated
Standard
Updated
HAB Charactarized- ISS
Prelim CM Identifed
Inflight Monitor
Validated
Monitoring Tools
Developed/Validated
Standard
Updated
Standard
Updated
CM
Validated
NHV/HAB
Tools Developed
Treatment
Identified
AFT Trade Study
Risk Understood -Microbiome, CMs and Affected Microorganisms
Validated Analytical Tool
Risk
Understood
Identify
Analog Altered Immune Response
Risk Charactarized
Treatment Validated
Factors Identified
Cognition/Motor Control
Risk Understood
Potential CMs Identified
Risk Model
Defined
CM
Validated
CMs Indiv/
Validated
Standard
Validated
Standard
Validated
NHV/HAB
Tools Validated
AFT Trade
Risk Understood
Risk Understood
CM Identified
Risk Understood -Virulence Mechanisms
Risk
Characterized
Risk Characterized
Standard Updated
Risk Quantification
Updated
Study
Risk Understood
Inflight CM Validated
Current Hardware
Inflight CM Validated
Current Hardware
In/Post-flight
CM Validated
Measures Developed/
Validated
Inflight CM Validated
Risk Characterized
CMs Validated
Risk
Understood
Integrated CMs/ Tools
Validated
Standards Developed
Inflight CM Validated
Exploration Hardware
Inflight CM Validated
Exploration Hardware
CMs Developed/Validated
CM Validated
Risk Understood
Environment
Inflight CM Validated
Treatment Validated
Risk Maintenance
CM Developed
CM/Tools Validated
CM Optimized
CMs Optimized
Usage
Determined
Ground Stability
Testing Complete
Flexible Ultrasound
Standard
Updated
Exp Medical
Suit Injury Data Identified
System
Stability Risk
Determined
Updated Suit
Requirements
Risk Characterized
Framework Developed
Skills Characterized
Usage Understood
Packing Validated
Risk Understood - Nutritional Stability
Oxygen Concentrator
Risk Understood
Validated Stability Device
Tools Identified
Lab Analysis
CMs Developed
Standard Validated
Factors Understood
Standards Informed
Risk Understood - Food System Acceptability
Musculoskeletal
CM
Monitoring Tools
Developed
Medical Suction/
Sterilization
CMs/Treatments
Developed
Inflight
CMs Validated
Methods/Tools Developed and Validated
Updated Suit/Crew/Ops
Requirements
HAR Interactions/Roles
Characterized
Design Tools/ Metrics
Developed
Requirements/Tools
Validated
Design Tools/ Metrics
Validated
Initial Risk Characterization Mars Dust
CMs Validated
Degen (Cardiovascular)
Risk Characterized
FY14 FY15 FY16
Treatment Validated
FY17
Acute Radiation
CM Identified
FY18 FY19
Treatment Validated
Acute CNS
Risk Characterized
FY20 FY21 FY22
Late CNS Risk Characterized
Acute CNS&Degen CM Identified
FY23 FY24 FY25 FY26
Acute CNS CM Validated
FY27 FY28
Human System Risk Board (HSRB) Hazards: 1. Altered Gravity; 2. Hostile/Closed Environment; 3. Isolation; 4. Distance; 5. Radiation Y - HSRB Approved
ISS Required
ISS Not Required Milestone Requires ISS
Uncontrolled
Partially
Controlled
Controlled
Optimized
Insufficient
Data
Assumptions:
450 crew hrs/increment
6 crew/increment
6 month missions
Updated
06/16/14
Rev B PCN-1
HRPCB-approved

Ovary
Bone marrow
Testes
Eye (lens)
Mucosa
Gastrointestinal
Single Dose (Gy)
2–6
2–10
2–10
2–10
5–20
5–10
Testes
Ovary
Eye (lens)
Kidney
Thyroid
Lung
Fractionated Dose (Gy)
1–2
6–10
6–12
20–30
20–40
23–28
Lung
Colorectal
Kidney
Vasculoconnective tissue
Liver
Skin
Peripheral nerve
Spinal cord
Brain
Heart
Bone and cartilage
Muscle
7–10
18–20
>30
>70
10–20
10–20
10–20
15–20
15–20
15–20
15–20
15–25
Skin
Liver
Bone marrow
Heart
Gastrointestinal
Vasculoconnective tissue
Spinal cord
Brain
Peripheral nerve
Mucosa
Muscle
Bone and cartilage
30–40
*From Rubin P. Law and order of radiation sensitivity: absolute versus relative. In: Vaeth JM,
Meyer JL, eds. Frontiers of radiation therapy and oncology. Basel: Karger; 1989:7–40.
35–40
40–50
43–50
50–55
50–60
50–60
55–70
65–77
65–77
>70
>70

• Solar Min Maximum Days in Deep Space (heavy shielding) to 95% Confidence to be below
NASA Limits for cancer risk: (parenthesis is deep solar min of 2009) a
E
, y
35
45
55
35
45
55
NASA 2005
158
207
302
129
173
259
NASA 2012
U.S. Avg. Population
Males
209 (205)
232 (227)
274 (256)
Females
106 (95)
139 (125)
161 (159)
NASA 2012
Never-smokers
271 (256)
308 (291)
351 (335)
187 (180)
227 (212)
277 (246)
•
Solar Max Maximum Days in Deep Space (heavy shielding) to 95% Confidence to be below NASA Limits for cancer risk alone (parenthesis is for case of ideal storm shelter which negates any SPE cancer risk):
~ 46% “Sex” difference in terms of days that can be spent in deep a
E
, y
35
45
55
35
45
NASA 2012
U.S. Avg. Population
306 (357)
344 (397)
367 (460)
144 (187)
187 (232)
Males
Females
NASA 2012
Never-smokers
395 (458)
456 (526)
500 (615)
276 (325)
319 (394)
55 227 (282) 383 (472)

• Similar VIIP prevalence in males and females:
– 82% among males, 62% among females (difference in prevalence not significant)
– Numbers of subjects are small: 17 male astronauts studied; 8 female astronauts studied
• Severity of signs/symptoms much milder in females (to date!):
– Six clinically significant cases (optic disc edema) in males; none in females.
– Two of the clinically significant cases have opening pressures > 25 cm H
2
O
– Higher vascular compliance in females may be protective
– Female crew also younger (younger age = higher compliance)
Fundoscopy on ISS
Eye Ultrasound on ISS

(But Spaceflight Does NOT Appear To Exacerbate This Trend)
40
50
20
30
-10
0
10
60
70
80
90
30 40 50
Age
Right Average (Females)
60 70 80
Left Average (Females) Left Average (Males) Right Average (Males)
Hearing trends of male versus female astronauts, by age, for averaging audiometric thresholds at 2k, 3k, and 4k Hz.
Data courtesy of NASA LSAH and Richard W. Danielson, Ph.D.

~ 28% incidence of orthostatic intolerance in female astronauts
(versus 7% in males)
There is a gender-related difference in the occurrence of postflight orthostatic intolerance (presyncope during a stand or tilt test) after space shuttle missions. Presyncope is defined as a sudden dip in systolic blood pressure of > 25 mmHg or in diastolic blood pressure of >15 mmHg, a sudden and sustained drop in heart rate > 15 beats/min, an absolute heart rate < 40 beats/min for those whose resting absolute heart rates were > 50 beats/min, and absolute systolic blood pressure of <70 mmHg.

• No sex differences in performance on
Psychomotor Vigilance Test (PVT) in-flight (1376 total tests) or post-flight (231 total tests).
• On Earth – with the PVT …. women are biased slightly towards accuracy. Men are biased slightly towards speed.
• No sex differences in self-ratings of workload, tiredness and stress, or sleep quality in-flight or post-flight.
• While in spaceflight ~ 75% of astronauts use sleep medications (e.g., zolpidem or “Ambien”) and an unknown number use wake-promoting medications (e.g., modafinil or “NUVIGIL”).
• Astronauts reported use of sleep-promoting drugs (mostly zolpidem) on 500 (52%) of 963 inflight shuttle nights and in 96 (11%) of 852 ISS sleep logs.
• 16 Women participated in the “Barger et al 1 ” study – which enrolled 114 subjects in total. 1 Barger et al , Lancet Neurol, 2014; 13: 904-12

• No sex differences in neurobehavioral performance following sleep loss.
• Males gain more weight than females during chronic sleep restriction (CSR).
• Females fall asleep faster, have better sleep efficiency, with more time asleep and less time awake than males.
• Chronotype: females show a greater skew toward “morningness”, than males, (i.e. women are often so-called “larks”).

• Polar literature indicates that women tend to assume a more cooperative and supportive role than men in their interactions with other members of their group. Women have a somewhat more difficult interpersonal experience than men in polar work groups which may impact performance.
• A recent Earth-based, 520-day simulated mission to Mars, conducted by the Russian
Institute of Biomedical Problems used an allmale crew of six. The majority of crewmembers developed disturbances of sleep and other behavioral changes that would be undesirable in prolonged space missions.
Hi-Seas, (Hawaii)
Human Exploration Research
Analog or “HERA,”
(Johnson Space Center)

Astronauts Sleep “Differently” In Space &
Analog Environments, e.g. NEK Chamber
“Free-running” subject
“Well-adapted” subjects
Basner, M., et al “Mars 520-d mission simulation reveals protracted crew hypokinesis and alterations of sleep duration and timing”, PNAS , 2013 Feb 12 110(7), 2635-40

• On Earth, anxiety disorders and major depressive disorders are ~ twice as prevalent in women compared to men.
• There is no evidence to date that astronauts experience the same risk for depression and anxiety disorders as their counterparts in the general population.

• Women show heightened stress sensitivity & increased prevalence of stress-related affective disorders.
• Women display greater physiological stress response than men as demonstrated by higher cortisol levels following a variety of stressors.

• Results from the “Journals Flight Experiment” on ISS suggest slight differences between men and women in terms of netpositivity/negativity.
– Men exhibited greater positivity than women overall and particularly during the first and fourth quarters of ISS expeditions.
– The relevant entries of women fluctuated less than those of their male comrades.
• Achievement was the most frequently mentioned value for both male and female astronauts in their memoirs pre-flight and for male astronauts post-flight.

HUGE Individual Variability In Bone Mineral
Density Change; No Clear “Sex” Differences

HUGE Individual Variability In Muscle
Change; No Clear “Sex” Differences

http://www.nasa.gov/exploration/library/events/gender-workshop.html

http://connect.arc.nasa.gov/p5wok9171zu/

http://www.liebertpub.com/global/pressrelease/new-nasa-and-nsbrireport-on-sex-and-gender-differences-in-adaptation-to-space-flight/1560/

http://online.liebertpub.com/doi/abs/10.1089/jwh.2014.4911

Executive Summary
Behavioral Health
Cardiovascular
Alterations
Immune System http://online.liebertpub.com/doi/abs/10.1089/jwh.2014.4911

Commentary
Musculoskeletal Health
Neurosensory Systems
Reproductive Health http://online.liebertpub.com/doi/abs/10.1089/jwh.2014.4911

http://www.nasa.gov/content/men-women-spaceflight-adaptation/

Summary of Major Findings – Page 1
•
Orthostatic Intolerance, or the inability to stand without fainting for protracted periods, is more prevalent upon landing in female astronauts than in their male counterparts. One possible reason for this observed difference in orthostatic intolerance between the sexes is reduced leg vascular compliance, which was demonstrated in bed-rest studies – which is a ground analog for spaceflight.
•
Women have greater loss of blood plasma volume than men during spaceflight, and women's stress response characteristically includes a heart rate increase while men respond with an increase in vascular resistance. Still, these Earth observations require further study in space.
•
The VIIP syndrome (visual impairment / intracranial pressure) manifests with anatomical ocular changes, ranging from mild to clinically significant, with a range of corresponding changes in visual function. Currently 82% of male astronauts vs. 62% of women astronauts (who have flown in space) are affected. However, all clinically significant cases so far have occurred in male astronauts.

Summary of Major Findings – Page 2
•
Changes in function and concentration of key constituents of the immune system related to spaceflight have been reported. However, differences between male and female immune responses have not been observed in space. On the ground, women mount a more potent immune response than men, which makes them more resistant to viral and bacterial infections; once infected, women mount an even more potent response. This response, however, makes women more susceptible to autoimmune diseases. It is not clear if these changes on the ground will occur during longer space missions, or missions that involve planetary exploration (exposure to gravity).
•
Radiation presents a major hazard for space travel.
It has been reported that female subjects are more susceptible to radiation-induced cancer than their male counterparts; hence radiation permissible exposure levels are lower for women than men astronauts.

Summary of Major Findings – Page 3
•
Upon transition to microgravity after arriving at the International Space Station (ISS), female astronauts reported a slightly higher incidence of space motion sickness (SMS) compared with men. Conversely, more men experience motionsickness symptoms upon return to Earth. These data were however not statistically significant, due both to the relatively small sample sizes and small differences in the incidence of SMS reported by the men and women astronauts.
•
Hearing sensitivity, when measured at several frequencies, declines with age much more rapidly in male astronauts than it does in female astronauts. No evidence suggests that the sexbased hearing differences in the astronaut population are related to microgravity exposure.

Summary of Major Findings – Page 4
•
The human musculoskeletal response to gravity unloading is highly variable among individuals and a sex-based difference was not observed.
•
Urinary tract infections in space are more common in women and have been successfully treated with antibiotics.
•
There is no evidence of sex differences in terms of behavioral or psychological responses to spaceflight. Analysis of ISS astronauts' neurobehavioral performance and sleep measures showed no sex or gender differences using the
Psychomotor Vigilance Test (PVT) of alertness and
Visual Analog Scales of workload, stress, and sleep quality. Since all astronaut candidates undergo a robust process of psychological screening and selection, the likelihood of an adverse behavioral health condition or psychiatric disorder is greatly diminished.

Summary: Select Sex-Based Health Effects

Recommendations of the Sex and Gender Study
•
Select more female astronauts for spaceflight missions.
•
Encourage and facilitate the participation of more female and male subjects in both ground and flight research studies.
•
Focus on the responses of individual astronauts to spaceflight and return to
Earth.
•
Determine the range of effectiveness of specific countermeasures for individuals.
•
Include sex and gender factors in the design of the experiments.
•
Incorporate sex and gender and other individual risk factors into NASA-funded research programs.

For Females & Males to Explore Deep Space and
Return Safely to Earth We Need To Employ the
FULL POWER of 21 st Century “Personalized” or “Precision” Medicine

“For example, the researchers said, while females experience less hearing loss in advancing age -- a health effect seen on Earth -- and don't display significant evidence of visual impairments after exposure to microgravity -- a health effect seen in space -- men experience more deficits in each of these areas.” http://www.techtimes.com/articles/20505/20141118/mens-and-womensbodies-react-differently-to-zero-gravity-nasa-finds.htm

“Station provides us with years of biological data on male and female astronauts, and many of them continue to participate in ground-based studies to evaluate the lasting effects of spaceflight” a http://thespacereporter.com/201
4/11/study-does-one-sex-have-anatural-advantage-in-space-flight/ a Quote attributed to D. Marshall Porterfield, Ph.D.; NASA’s Director of Space & Physical Life Sciences Research

“As efforts continue, there should be an emphasis on the impact of sex and gender on the development of equipment, machine–human interfaces and countermeasures including the use of personalized
Medicine and genomics or — ‘astro-omics’” b http://www.theblaze.com/stories/
2014/11/19/nasa-looks-at-healthdifferences-spaceflight-has-onmen-and-women-and-includesperceived-gender-in-new-study/ b Quote attributed to Saralyn Mark, M.D.;
Senior Medical Advisor at NASA
Headquarters and Senior Policy Advisor at the Office of Science and Technology Policy
(OSTP)

“The best way of getting more accurate findings on the differences between men and women would obviously be to have more women in space. It’s promising that NASA chose four men and four women in its latest crew selection.” http://motherboard.vice.com/read/we-need-more-women-in-space

“A significant number of astronauts have conceived children after going to space,” said Scott.
“People worry that the radiation could be doing something to the female’s eggs or the male’s sperm, but children are able to be conceived after spaceflight.” However, he notes, NASA recently began offering astronauts the opportunity to bank their eggs or sperm, “so we don’t always know if these are in vitro fertilizations or natural conceptions.” c http://motherboard.vice.com/read/making-babies-in-space-may-be-a-terrible-idea c Quote attributed to Graham Scott, Ph.D.; Chief Scientist at the National Space Biomedical Research Institute (NSBRI)

“So what happens when astronauts return to Earth? At least one researcher who's studied the scenario says that despite the reports, he hasn't seen much evidence of compromised fertility. One doctor, Richard Jennings, an aerospace medicine expert at the
University of Texas Medical Branch, said that he's seen astronauts get their spouses pregnant soon after returning from a space flight. Longer space missions may warrant more study of the reproductive system, Jennings told a newspaper last month.”
“Thirteen female astronauts have given birth to 18 children following spaceflight and have not experienced any increased pregnancy complications or increased assisted reproductive technology failures compared to the general population.”
(E. S. Baker, unpublished data).” http://www.livescience.com/33047-spacesex-pregnancy.html http://online.liebertpub.com/doi
/pdfplus/10.1089/jwh.2014.4914

NIH Website: “Inclusion of Women and Minorities as
Participants in Research Involving Human Subjects”

NIH Policy and Guidelines on the “Inclusion of Women and Minorities as Subjects in Clinical Research

“It is the policy of NIH that women and members of minority groups and their subpopulations must be included in all NIH-funded clinical research, unless a clear and compelling rationale and justification establishes to the satisfaction of the relevant
Institute/Center Director that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.
Exclusion under other circumstances may be made by the Director, NIH, upon the recommendation of an Institute/Center Director based on a compelling rationale and justification. Cost is not an acceptable reason for exclusion except when the study would duplicate data from other sources.
Women of childbearing potential should not be routinely excluded from participation in clinical research. This policy applies to research subjects of all ages in all NIH-supported clinical research studies.
The inclusion of women and members of minority groups and their subpopulations must be addressed in developing a research design or contract proposal appropriate to the scientific objectives of the study/contract. The research plan/proposal should describe the composition of the proposed study population in terms of sex/gender and racial/ethnic group, and provide a rationale for selection of such subjects . Such a plan/proposal should contain a description of the proposed outreach programs for recruiting women and minorities as participants.”

Sex and Gender Guidance Provided In the
2014/2015 NSBRI Crew Health Solicitation
In accordance with the NIH policy that NSBRI has adopted, all applications will also be reviewed with respect to:
• Adequacy of plans to include males and females, members of minority groups, and their subgroups, as appropriate for the scientific goals of the research
Appendix B -33

Sex and Gender Metrics (2015) For
NSBRI Funded Projects
~ 70 % of NSBRI funded- studies employed a female:male ratio of between
70/30 -> 30/70 (or did not perform human or animal testing)

1
Jeffrey P. Sutton, M.D., Ph.D. Lori Ploutz-Snyder, Ph.D. Helen Cohen, Ed.D. Saralyn Mark, M.D.
Catherine Moreno, B.A.
Dorit B. Donoviel, Ph.D.
Jon B. Clark, M.D., M.P.H.
David F. Dinges, Ph.D. Mil Reschke, Ph.D.
•
Erin Mahoney
All co-chairs and members of the six “Sex and Gender Working Groups, viz:
•
Cardiovascular
•
Reproductive
•
Neurobehavioral
•
Immune System
•
Musculoskeletal
•
Sensorimotor
John B. Charles, Ph.D.
Bette Siegel, Ph.D.
Lauren B. Leveton, Ph.D.

1