Author: Dr. Randen Patterson is an Award-winning Systems Biologist, who retired in 2014 at only 43 years old due to the decline…
Author: Gayathri Delanerolle, Digital Evidence Based Medicine Lab and the Southern Health NHS Foundation Trust
Despite over 60 years of human space travel, conception in space has not occurred, with numerous challenges posed by the space environment. Space affects human physiology significantly due to factors such as microgravity, higher radiation exposure, altered circadian rhythms, and the stress of space travel. While the overall adaptation to space is similar for male and female astronauts, subtle differences exist in various body systems due to sex and gender. Given the distinct nature of male and female reproductive systems, independent research is necessary to understand the short and long-term effects of spaceflight. Unfortunately, research on reproductive physiology in space has been limited so far. The representation of women among U.S. astronauts has historically been low, with only 15% of astronauts being women. However, there has been a positive shift, with women achieving parity with men in the 2013 NASA Astronaut Class. As space missions transition from short-duration shuttle missions to longer-duration International Space Station (ISS) expeditions, there is a need to re-evaluate and update biomedical research priorities. While the physiological responses of men and women during spaceflight appear generally similar, there are significant gaps in our knowledge. Research recommendations from the 2002 report titled “Sex, Space, and Environmental Adaptation” have not been adequately addressed. Recent biomedical studies on Earth have also emphasized fundamental differences in the physiology and health of men and women. Therefore, it is crucial to pay close attention to the influence of sex and gender in the adaptation to space, as this is not only warranted but long overdue. The sex and gender perspective to examine the significant influences of the space environment, including radiation, microgravity, and stress, on reproductive processes and the physiological systems that play a central role in reproduction, such as the endocrine and urogenital systems. It offers a comprehensive overview of the existing evidence related to sex and gender in the context of space adaptation, highlights areas where our understanding is lacking, sets the groundwork for future research, and presents key recommendations for guiding future translational research and infrastructure development in this field.
Recently, the European Space Agency (ESA) published a white paper on reproductive and developmental systems in space demonstrating a roadmap that acknowledge sex and gender affect physiological systems. It acknowledges that sex and gender affect physiological systems but does not delve into gender identity. The ESA SciSpacE white papers explore space travel’s implications on male and female reproductive systems, including the human reproductive hormone axis, conception, gestation, and birth considerations. The ESA SciSpacE white papers outline the research needed to advance our understanding in this crucial area of space physiology to support progress in human space travel and habitation. Our current understanding of how spaceflight stressors, such as altered gravity (microgravity, hypo- and hyper-gravity), increased radiation, social isolation, confinement, sleep disturbances, and dietary changes, affect the hypothalamic-pituitary-gonadal (HPG) axis in both females and males, as well as their impact on reproductive organ functionality, is limited. The small number of astronauts who have experienced long-duration spaceflight makes it challenging to distinguish between the effects of spaceflight stressors or space radiation and the natural aging process, which naturally influences reproductive outcomes. Therefore, it is crucial to acquire knowledge about how increased and prolonged space radiation exposure, both for short and long periods, affects the functionality of the reproductive organs in both genders. Additionally, understanding the overall impact on cancer risk, not only for the astronauts themselves but also for their offspring and future generations through effects on gametes, is essential. This review underscores the significant knowledge gaps that pertain to the female and male reproductive systems, conception, embryo development, and birth in the context of space travel.
Major influences within the space environment include the following;
- Radiation exposure: The radiation exposure experienced by astronauts varies depending on factors like mission duration, destination, vehicle design, habitat, and solar conditions. For a typical 6-month mission on the International Space Station (ISS) in low-Earth orbit, astronauts are exposed to radiation levels ranging from 54 to 108 mSv, with variations related to solar activity and ISS altitude. However, interplanetary travel to Mars and surface missions result in much higher radiation exposures, ranging from 210 to 1,070 mSv annually during interplanetary travel and 80 to 330 mSv on the Martian surface. The reproductive organs, particularly the gonads, are highly sensitive to radiation. Temporary infertility can occur with high-dose acute radiation exposure. For men, this threshold is around 150 mSv from acute x-rays, and for women, it ranges from 650 to 1500 mSv from acute x-rays or gamma rays to the ovaries. However, how these tissues respond to radiation exposure in the space environment, considering factors like dose, dose-rate, radiation quality, and the combined effects of microgravity, remains largely unexplored. Cancer risk assessment in space requires evaluating organ doses (measured in Sv) combined with age- and gender-dependent risk coefficients. Women have a higher incidence of radiation-induced cancers, primarily in the lung, thyroid, breast, and ovaries, which means they reach their maximum safe radiation exposure limits in space earlier than men. Due to the limited number of humans exposed to space radiation, there is insufficient data to accurately assess the differential effects on men and women. While NASA has conducted studies on cancer risk in animals exposed to space radiation, there has been limited attention given to sex differences in these studies.
- Duration: The shift from shorter spaceflight missions, which lasted up to approximately 2 weeks during the space shuttle era, to longer missions on the International Space Station (ISS) that now extend from 6 to 12 months is significant. This transition to longer exposures to both microgravity and space radiation has implications for reproductive health. In men, this prolonged exposure may affect the physiology of sperm production in the testes. For women, it may influence the oestrogen cycle in the ovaries. These changes become especially relevant because longer missions can span multiple reproductive cycles in both men and women. This shift to longer-duration missions highlights a significant knowledge gap in our understanding of how long-term spaceflight impacts reproductive health, and further research is needed to address these concerns
- Stress linked to microgravity: Reproductive health concerns for both men and women in space, which could be related to microgravity and stress (including sleep disruption), have been noted. In men, spermatogenesis may be adversely affected beyond the impact of radiation exposure. A 120-day Russian bed rest study found reductions in live spermatozoa with active mobility and an increase in structurally altered spermatozoa after 50–60 days and 100 days of bed rest. Research on male rats exposed to 6 weeks of simulated microgravity has reported severe testicular and epididymal degeneration, including extensive testicular cell death six months later. These effects have been attributed to chronic testicular hyperthermia, inflammatory cell infiltration, or catastrophic cell death, leading to a spermatogenic dysfunction. However, there has been no post-spaceflight research involving humans on this topic. Regarding female astronauts, reproductive changes during or after spaceflight have not been systematically studied. In female adult mice that were cycling at launch, spaceflight led to the cessation of cycling, loss of corpora lutea, and significantly reduced oestrogen receptor mRNA levels in the uterus. However, similar assessments in women are lacking. Systematic data on the reproductive history of male and female astronauts are lacking. While many male astronauts have fathered children after spaceflight, there is no information on conceptions and birth outcomes upon their return from space. The incidence of infertility following prolonged spaceflights in both genders, as well as pregnancy complications in women, remains unknown. For female astronauts who delay pregnancy, distinguishing the effects of space travel (microgravity, radiation exposure) from natural aging effects may be challenging. Furthermore, female astronauts who experience hypertensive pregnancy disorders may require additional monitoring for cardiovascular disease, as these disorders on Earth are associated with an increased risk of future adverse cardiovascular events like stroke and heart attacks.
- Endocrine system: The hypothalamic–pituitary–gonadal (HPG) and hypothalamic–pituitary–adrenal (HPA) axes interact through neural signals and hormonal feedback. In the space environment, several neurotransmitters in the hypothalamus are known to be altered, including increased histamine, decreased serotonin, oxytocin, norepinephrine, and to a lesser extent, glutamate. These changes may result from the altered gravitational environment, affecting neural signalling directly or indirectly through hormonal responses from downstream axes. Spaceflight has been linked to changes in HPG and HPA axis functioning. In men, reduced levels of circulating testosterone have been observed during spaceflight, although they seem to rebound upon return to Earth. This pattern has been seen in both short- and long-duration spaceflight and head-down bed rest studies. Recent findings showed no significant decrease in testosterone levels during long-duration spaceflight or bed rest but did observe a decrease upon landing after long-duration flights and short-duration spaceflight. The HPA axis, responsible for cortisol release in response to stressors, becomes more active during spaceflight, simulated microgravity, and long-duration stress studies. However, like gonadal hormones, cortisol levels quickly recover upon return to Earth. In contrast, the effects of spaceflight and simulated microgravity on oestrogen and gonadal function in women are not well-studied. Oxytocin, which helps regulate the HPA axis and dampen stress responses in women, shows long-lasting reductions after spaceflight. Oral contraceptives (OCs), which some female astronauts take, also affect hormone levels involved in stress responses and the regulation of the HPG and HPA axes. Circulating levels of hormones like testosterone, dehydroepiandrosterone, corticosteroid-binding globulin, prolactin, and sex hormone–binding globin are influenced by OCs. Given the changing formulations of OCs, periodic evaluation of their benefits and costs is necessary. Overall, the complex interactions between neural signalling, hormonal feedback, and space-related factors like microgravity and stress have significant implications for the hormonal and reproductive health of astronauts, both male and female.
- Genitourinary system: Reproductive health concerns, while not a primary focus of space travel, have had an impact on mission duration. For example, a cosmonaut in 1985 suffered from serious prostatitis during a mission, which affected the mission’s length. Sexual activity in space is not well understood, and infrequent ejaculation can lead to the accumulation of prostate secretions, potentially supporting bacterial growth. Therefore, addressing the risk of prostatitis may be necessary during extended exploratory space travel. Renal and urinary tract problems are recurring issues in space travel. Microgravity and privacy concerns can lead to infrequent and incomplete bladder emptying, increasing the risk of urinary tract infections. Medications for motion sickness can also reduce bladder emptying. Inadequate hydration, combined with microgravity, can increase the likelihood of kidney stone formation. Untreated stones and urinary tract infections could eventually impair kidney function. On Earth, urinary tract stones are more common in Caucasian men, while struvite stones are more common in women. Urinary tract infections are also more common in women. The long-standing belief that the urinary tract is sterile is being questioned with emerging research on the urinary microbiome. There is no data available regarding sex differences in spontaneous or unprovoked urinary retention in the age range of astronauts. However, data on provoked urinary retention after surgery, involving nearly equal numbers of men and women of similar age to astronauts, do not show a sex difference. Cumulative experiences in space travel suggest that 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 compared to men. Possible explanations for this sex difference include anatomical predisposition in women’s urethra, adaptation to voiding in microgravity, a higher incidence of urinary retention, and a higher incidence of catheterization.
- Brain health: Spaceflight-induced changes in the release of gonadal hormones may have non-reproductive outcomes, such as alterations in sleep patterns. Sleep-wake cycles are disrupted during long-duration microgravity simulations on Earth, and sleep quality is influenced by various stressors and is correlated with circulating levels of testosterone and Estradiol. Conversely, sleep deprivation can disrupt normal gonadal hormone secretion and increase glucocorticoid release, potentially creating a positive feedback loop. Gonadal hormones also impact brain neurotransmitters involved in maintaining wakefulness, sleep states, and transitions between them. While it is speculated that human reproduction may occur in space in the distant future, the current literature lacks sufficient information to speculate on whether intricate phases of reproduction in mammals, including mating, fertilization, implantation, prenatal and postnatal development, and more, can take place in space. In adult animals exposed to spaceflight, difficulties with fertilization could potentially arise due to disruptions in hypothalamic neurochemistry, particularly in aspects related to mating. Several hypothalamic neurotransmitters are affected by the physical factors encountered during spaceflight. Oxytocin, which is crucial for female sexual receptivity and also plays a role in stress response regulation, remains reduced at 18 weeks following spaceflight in rodents. This effect may be more significant in women, especially when considering the use of oral contraceptives (OCs), which reduce circulating oxytocin levels. Further research is needed to determine the potential long-term effects of spaceflight and OC use on reproductive health. Persistent changes in oxytocin levels following spaceflight may have implications for postpartum behaviours and social bonding. Therefore, the consequences of long-duration spaceflight on the viability of immediate and subsequent generations of offspring within families participating in such missions are unknown and possibly long-lasting.
The decline in multiple physiological systems induced by spaceflight may involve a common mechanism related to the dysregulation of reproductive steroid receptor-dependent signalling pathways. If this is indeed the case, then spaceflight is likely to have an impact on gonadal function in both men and women. A key question for both space and ground-based research is whether there are sex differences in the altered oestrogen receptor (ER) signalling in systems affected by spaceflight and aging. While the role of ER signalling in maintaining function in these systems and the changes associated with aging populations have been studied on Earth, there is a notable lack of published research on this topic in the context of spaceflight. This results in significant knowledge gaps concerning whether changes in these systems during spaceflight may share a common mechanism involving alterations in ER and androgen receptor signalling in both women and men. It’s essential to emphasize that while ER signalling has received more attention, the relative lack of focus on androgens in both sexes should not create false impressions. Oestrogen and androgen receptors play crucial roles in maintaining health, and declining testosterone levels and reduced aromatization to oestrogen can impact bone health in men as well. Thus, it’s essential to consider the impact of both oestrogen and androgens on health in space, as well as the potential for sex-related differences in their effects.
It’s essential to recognize that the effects of sex and gender extend beyond reproduction and have broader implications in the context of space travel. For example, consider sleep deprivation, a well-known stressor in space travel. Research on Earth suggests that sleep disruption affects men and women differently, with women experiencing sleep disruption at higher rates than men. Women often report lower sleep quality compared to men, and sleep disruption tends to increase with age, particularly during middle age through menopause. These findings emphasize the importance of considering sex and gender in understanding how space travel stressors, such as sleep disruption, may affect astronauts’ overall health and well-being. Exploring these interactions can provide valuable insights into optimizing space travel conditions for both men and women.