1. Endocrinopathies in Space
Humans on Mars Sustainability Workshop Kennedy Space Center Visitor Center – Feb 08/09, 2018
Endocrinopathies in Space
Kevin CJ Yuen, MD, FRCP (UK), FACE
Neuroendocrinologist and Medical Director
Barrow Pituitary Center
Barrow Neurological Institute
University of Arizona College of Medicine
Phoenix, AZ 85013

2. “Imagination is more important than knowledge
“Imagination is more important than knowledge. Knowledge is limited, whereas imagination embraces the entire world, stimulating progress, giving birth to evolution”
Albert Einstein (1929)

3. The Endocrine System in Humans
Functions
Stimulation of growth and development
Maintenance of internal environment
Adaptation to emergency demands of the body
Coordination of male/female reproductive system
General characteristics
Specific rates and rhythms of secretion
- diurnal, pulsatile, and cyclical
Operate within feedback systems (+/-)
Affect only target cells with appropriate receptors
Regulation of Hormone Release
Hormones are released:
In response to alteration in cellular environment
To maintain regulation of certain substances and hormones
Mechanisms of release:
Chemical factors
Endocrine factors
Neural control
Sleep and circadian rhythms
Temperature changes
Nutrition
The endocrine system comprises of a diverse group of tissues known as the endocrine glands that produces hormones, chemical messengers, that are mainly controlled by the brain. Hormones then are secreted in the bloodstream and transported to almost every part of the body where they can then exert their actions.
The endocrine system, together with the nervous and immune systems, play an important role in regulating the human response to spaceflight and the readjustment processes that follow landing.
Mechanisms of release:
Chemical factors (blood sugars, calcium levels)
Endocrine factors (TSH → thyroid gland → T4)
Neural control (CRF → pituitary → ACTH)
Sleep and circadian rhythms
Nutritional status

4. Basic Understanding of Endocrinopathies in Space
Fluid shifts
Occurs only after entry into microgravity environment and again after return to Earth
Perturbed circadian rhythms
Loss of red blood cell mass
Unknown if these are short- or long-term problems
Changes in the immune system
Loss of bone mineral density and muscle mass
Maintenance of energy balance
Chronic responses in microgravity
System physiology research will need to shift from the investigation of the acute responses to spaceflight to the long-term effects.
ACUTE RESPONSES: Associated with large, immediate changes in certain hormones. Thus, the change in blood volume, red cell mass, and the associated fluid shifts are acute responses to the novel environment, with appropriately large and immediate changes in hormone levels such as vasopressin, aldosterone, and norepinephrine.
What is needed is a focus on the problems of long-term spaceflight, specifically calcium loss from bone, muscle atrophy, energy balance, and the possible perturbation of circadian rhythms

5. Endocrine Changes During Stress, Microgravity and Space Flight
Hormone
Stress
Microgravity
Space flight
Cortisol 
 or  
Insulin
Catecholamines
 or 
ACTH
Growth hormone  
 or 
Testosterone
Estrogen

6. Effects of Spaceflight and Mars Habitation on Human Physiology
Effects of isolation: depression, anxiety, insomnia, fear, boredom, emotional instability
Zero G
Decompressive illness
Sleep disturbance
Headaches, ocular discomfort, impaired vision
Changes in immune and endocrine system
Bone density drops – 1% per month
Muscle atrophy – 5% per week
Blood volume drops by 22%
Heart atrophies due to blood volume loss

7. Effects of Spaceflight and Mars Habitation on the Endocrine System (1)
Metabolic stress response
Hypothalamic-pituitary-adrenal axis
- little in-flight data beyond the initial response period (> 7 days)
- diet, varying activity levels, and changes in circadian rhythm and
hormone receptor/signaling activity
Recommendations:
Studies should obtain a baseline in-flight human hormone profile early and late in-flight. As a control, the measurement set should include preflight measurements on the same individual over an extended period.
Studies should continue to evaluate the relevance of ground- based models of hormone receptor/signaling activities.
The human body seems to have little difficulty in restoring and maintaining homeostasis in those systems that must respond rapidly—specifically, the resetting of the cardiovascular, vestibular, and hematopoietic systems, together with the regulation of fluid and electrolyte balance. The problems that arise are in systems that acclimate slowly to a new situation, particularly muscle, bone, and energy balance, and possibly the circadian timing system.
Endocrine changes associated with the chronic effects of spaceflight (bone calcium loss, muscle atrophy, and possible shifts in energy balance) are likely to be small and therefore difficult to detect except under very carefully controlled conditions. Nevertheless, the cumulative effects of small changes in endocrine response can result in the characteristic bone loss and muscle atrophy that are found.
Absence of reliable endocrine measurements can preclude drawing conclusions about the in-flight mechanism. Collection of data of the quality needed to detect small changes has proven problematic for individual experiments because of the time and resources needed to collect a quality set of controlled endocrine measurements for an individual experiment. Without these data, an understanding of the human response and adaptation to spaceflight will be impossible. Integrating experiments encompassing the best of several different investigator groups into one program offer the best hope of obtaining quality data using limited in-flight resources.
Obtaining a baseline data set and when in-flight measurements should be performed will be challenging, because many hormones are released in a pulsatile manner.

8. Effects of Spaceflight and Mars Habitation on the Endocrine System (2)
Circadian rhythms
- circadian rhythms coordinate physiology and behavior to be
in synchrony with environment
- out-of-phase circadian rhythms can lead to “human errors”
Recommendations:
Studies on human circadian rhythms needs to be prioritized.
Use of countermeasures (e.g., light therapy +/- melatonin) should be explored.
If significant degradation of performance is found, and can be attributed to the perturbed circadian rhythm, use of countermeasures (e.g., use of light therapy +/- melatonin) should be explored as may help reset the biological clock.

9. Effects of Spaceflight and Mars Habitation on the Endocrine System (3)
Balance of energy and metabolism
- energy expenditure for comparable ground-based activity is
reduced in space
- nutritional intake  physical activity
- principal regulatory hormones: thyroxine, testosterone and GH
Recommendations:
Relationship between the amount of exercise, and in-flight protein and energy balance needs to be investigated.
To evaluate quality, amount, and acceptability of in-flight diets.
The human body seems to have little difficulty in restoring and maintaining homeostasis in those systems that must respond rapidly—specifically, the resetting of the CV, vestibular, and hematopoietic systems, together with the regulation of fluid and electrolyte balance. The problems that arise are in systems that acclimate slowly to a new situation, particularly muscle, bone, energy balance, and the circadian timing system.
Endocrine changes associated with the chronic effects of spaceflight (bone calcium loss, muscle atrophy, and possible shifts in energy balance) are likely to be small and therefore difficult to detect except under very carefully controlled conditions. Nevertheless, the cumulative effects of small changes in endocrine response can result in the characteristic bone loss and muscle atrophy that are found.
Absence of reliable endocrine measurements can preclude drawing conclusions about the in-flight mechanism. Collection of data of the quality needed to detect small changes has proven problematic for individual experiments because of the time and resources needed to collect a quality set of controlled endocrine measurements for an individual experiment. Without these data, an understanding of the human response and adaptation to spaceflight will be impossible. Integrating experiments encompassing the best of several different investigator groups into one program offer the best hope of obtaining quality data using limited in-flight resources.
Obtaining a baseline data set and when in-flight measurements should be performed will be challenging, because many hormones are released in a pulsatile manner.
Ensure adequate dietary input during spaceflight. Energy intake must meet needs, and physiological measurements must be made on subjects that are in approximate energy balance so that measurements are not confounded by an undernutrition response.
Chronic negative energy balance is detrimental to overall health. The relationship between the amount of exercise and the protein and energy balance in-flight needs to be investigated.

10. Effects of Spaceflight and Mars Habitation on the Endocrine System (4)
Reproduction
reduced testosterone in males
effects of radiation on spermatogenesis and ovarian function
Bone
Decalcification of bone potentially the most deleterious
Unanswered questions:
- is the mechanism for in-flight calcium loss the same
as that for osteoporosis on Earth?
- gender difference?
- self-limiting or progressive?
Charged high-linear energy transfer ions are highly damaging to the ovary even at low doses, causing premature ovarian failure.

11. Effects of Spaceflight and Mars Habitation on the Endocrine System (5)
Gender
- differences in body composition
- in women, stress and strenuous exercise can cause
amenorrhea
- women at higher risk of microgravity-induced bone loss
Women may be at higher risk following microgravity-induced bone loss because women have less bone mass to start with.

12. Which Medical Specialties and What Future Research are Needed?
Multi-disciplinary team: neuroendocrinologist, nutritionist, sports medicine, sleep medicine, reproductive/OB, cardiologist, neurologist, radiation oncologist, physiologist and psychiatrist
Studies of effects of “out-of-phase” circadian rhythms on cortisol, GH, thyroxine, and reproduction is a high-priority area for research
Focus on the problems of long-term spaceflight, specifically calcium bone loss, muscle atrophy, energy balance, and gender differences
In the past, post-flight hormone measurements have been used to extrapolate back to the in-flight situations. Post-flight hormone measurements not accurate reflection because half-life of many hormones are too short.
Endocrinologist (interest in brain, metabolism, bone and weight regulation), nutritionist, sports medicine, sleep medicine, reproductive/OB, cardiologist, radiation oncologisr, psychiatrist

13. “We shall not cease from exploration, and the end of exploring will be to arrive where we started and know the place for the first time”
T. S. Eliot
Image courtesy of Bryan Versteeg at spacehabs.com