Effect of Spaceflight on Female Reproduction
There is a paucity of evidence highlighting the effects of microgravity, space radiation, and spaceflight on the male and female reproductive systems, with significantly less for the female system based on the lack of women being exposed to GCR in the Apollo missions and past inequities. Most of our current knowledge on the female reproductive system stems from animal studies and are summarized in. Notably, the past decade has witnessed a dramatic increase in the number of women living and working in space. NASA astronaut candidate class ratios of men to women have achieved parity since 2013, making it likely that the future of long-duration spaceflight may also feature equal numbers of men and women, thus warranting further study into how the cosmic environment affects reproductive health.
Microgravity
Microgravity exposure poses multiple female reproductive health concerns. These include effects of weightlessness on gonadal function and fertility as well secondary spaceflight stressors, such as sleep disruption, that may degrade female reproductive health during and after spaceflight. However, the scientific literature on reproductive changes in female astronauts during and after spaceflight or exposure to simulated microgravity (bedrest) remains sparse. While female astronauts have successfully conceived and born children after spaceflight, detailed information on post-spaceflight fertility, pregnancy complications, and birth outcomes in women is not available. Further, female astronauts tend to delay pregnancy, making it difficult to separate the effects of spaceflight stressors from maternal aging on fertility and pregnancy outcomes. However, some animal studies attempting to understand reproductive outcomes in spaceflight have occurred, the first was in 1979 aboard an 18.5-day COSMOS 1129 mission, where a barrier between the two male and five female rats was removed on day two of orbit to allow for mating. Upon return to Earth, no pregnancies were observed. However, no pregnancies were observed in the control group of rats maintained on Earth either. It is not clear whether the absence of pregnancy was due to an inability to copulate in the weightless space environment, or to secondary more complex endocrine and/or embryonic developmental causes, or even attributable to housing/caging concerns.
Studies of female mice that were maintained on the International Space Station (ISS) for 37 days prior to euthanasia in space (eliminating re-entry stressors) revealed evidence that these female mice could be detected at different stages of the estrous cycle post-mortem, suggesting that some females were likely exhibiting estrous cyclicity. Mouse embryos flown on China’s SJ-10 biosatellite completed a series of cell divisions leading to blastocoel morphology during spaceflight, but both the rate of blastocyst formation and blastocyst quality were impaired. Severe DNA damage was observed in the embryonic cells, and the genome of the blastocysts developed in space was globally hypomethylated with a unique set of differentially methylated regions (DMRs). The authors suggest that these changes are similar to developmental defects, DNA damage, and epigenetic abnormalities that occur with exposure to ground-based low-dose radiation. However, given the dramatic differences already noted between cosmic radiation and that of gamma irradiation that they used in their experiments, as well as to the inability to separate out the effects of microgravity from the impact of space radiation in these studies, much remains to be determined.
While a large effort in understanding fertility outcomes is still needed, a few studies have been performed evaluating mammalian pregnancy and embryonic/prenatal development in space.
In 1982, COSMOS 1514 examined the effect of a 4.5-day flight exposure on gestational days 13–18 of a 21-day rat pregnancy. Dams were euthanized immediately upon landing and the fetuses exhibited neurobiological aberrations and impaired bone development. Four of five dams successfully delivered their litters postflight. Additional findings included poor maternal weight gain and evidence of fetal growth restriction in comparison to controls, possibly related to the potato diet used to provision both water and food, but no change in litter dynamics. Male and female offspring from these litters that developed to adulthood were fertile and reproduced successfully. In 1994 and 1996, two jointly sponsored NASA-National Institutes of Health missions (NIH.R1) (STS-66) and NIH.R2 (STS-70) launched pregnant (gestational day 9 and 11, respectively) dams that were returned to Earth on gestational day 20 prior to parturition. Space-flown pregnant rats gave birth at the expected time; however, they exhibited twice as many ‘lordosis’ contractions during labor coupled with decreased uterine myometrial connexin 43 (gap junction) protein expression relative to controls, suggesting changes to the uterine smooth musculature tone with exposure to microgravity. However, the duration of labor, maternal weight gain, miscarriage/stillbirth rate, litter size, neonatal birthweight, placentophagia, and maternal care patterns were not significantly different from ground controls. Importantly, NIH.R1 and R2 offspring were flown for the second half of the rats’ gestational period, after organogenesis was complete, and returned to Earth for parturition. There have been no additional studies of mammalian pregnancy during spaceflight, and no mammal has yet given birth in space. Analysis of mammary glands from G20 dams revealed a strong negative correlation between metabolic rate and gravity loads spanning 0, 1.5, 1.75, and 2 g. Approximately 98% of the variation in glucose oxidation and 94% of the variation in glucose incorporation into lipids was accounted for by differences in gravity ‘dose’. These data demonstrate a remarkable continuum of response across the microgravity and hypergravity environments for this reproductive parameter. REDACTED: Research factors needed – rodent pregnancy utilizing terrestrial analogs for microgravity, age at first pregnancy, parity, and breastfeeding, which are all inversely linked with gynecologic and breast cancers terrestrially / link between reproductive fitness after spaceflight and future risks of cancer occurring in these same organs.
Hormonal Modalities in Spaceflight
A unique operational consideration for premenopausal female astronauts is the use of hormonal contraception to suppress ovarian function, prevent pregnancy, and reduce menstrual flow or induce amenorrhea during pre-flight training and spaceflight. With the pathway that astronauts follow to reach candidate selection and the mission training phase, female astronaut candidates often opt to use hormonal contraception through the phases of candidate selection and training, while awaiting mission selection, during mission-specific training, and during the mission itself, potentially amounting to 11 or more years of reproductive suppression. The combined oral contraceptive pill and levonorgestrel intrauterine device are the most commonly used hormonal contraceptive options.
However, it is difficult to predict how hormonal contraception use in combination with the complex deep space environmental exposure will affect female astronaut health as it relates to the intertwined nature of reproductive function on multiple organ systems. It is unknown how the environment of deep space, especially for long durations, will impact the shelf-life, pharmacokinetics, and pharmacodynamics of the contraceptive agents as well as contraceptive efficacy, menses/abnormal uterine bleeding, ovarian cysts/torsion, venous thromboembolism, cardiovascular health, musculoskeletal health during exploration-class missions, or indeed gynecological cancers.
Space Radiation
In females, the ovary is extremely radiosensitive. Radiation-induced cessation of hormone production can lead to temporary or permanent infertility. The vagina is similar to other mucous membranes in terms of radiosensitivity, but the vulva, labia, and clitoris are more radiosensitive. The uterus is radioresistant. Transient sterility can occur after doses as low as 1250 mGy, although most report the threshold dose for temporary sterility as being 1700 mGy. The dose required for permanent sterility in women ranges from 3500–20,000 mGy, with lower doses needed for women older than 40 years. Radiation damage to the female gonads is cumulative because gametogenesis essentially stops at the time of birth.
Effect of Space Travel on Cancer
REDACTED: Carcinogenesis is the multi-step transformation of normal cells into malignant tumors, requiring the accumulation of several genetic and epigenetic aberrations. Cancer is characterized by the continuous proliferation of tumor cells, accompanied by resistance to cell death, induction of angiogenesis, invasion, and metastasis. DNA mutations altering protein-coding genes and signal transduction pathways involve tumor-suppressor genes, transmembrane proteins, platelet-derived growth factors, sex hormones, components of the insulin-like growth factor axis, transcription factors of the forkhead/winged helix-box transcription factor (Fox), and the SMAD families. Signal transduction pathways involved in carcinogenesis include sonic hedgehog (SHH), Wnt, and Notch. / Viruses – like the human papillomavirus (HPV), Epstein–Barr virus, and Hepatitis B and C, also highlight the role of microenvironments.
REDACTED: Moreno-Villanueva and Wu studies show that ionizing radiation is a known carcinogen, irradiation with particles in space differs quantitatively and qualitatively from γ-radiation or X-rays. But in order to improve the estimation of carcinogenesis risk of long-duration space travel, there needs to be more mechanistic analysis and biological insight of radiation quality effects and long-duration exposure to low radiation dose rates. The relationship between multiple space–environmental factors that can influence the development of cancer should be investigated separately and also in combination. To date, there have been a limited number of studies investigating the combined effect of space radiation and microgravity on cancer development.
Sex-specific cancers (involving the breast, ovary, or uterus) together contribute heavily to overall cancer incidence and mortality in women. Breast cancer is the largest contributor to cancer incidence following terrestrial radiation and the three organs combined make up over 30% of the risk of exposure-induced cancer. Breast cancer is also the second largest contributor to cancer mortality following terrestrial radiation, and the three organs combined make up over 20% of the risk of exposure-induced death. Both ovarian and uterine cancers have 5-year survival rates of 49.1% and 66.3%, respectively.
Gynecological Cancers and Space – Brief Overview on Gynecological Cancers
Gynecological cancers (GCs) arise in the female reproductive organs and include tubo-ovarian, uterine/endometrial, cervical, vaginal, and vulvar cancers. GCs pose a serious global health burden due to their high incidence among women of all ages. There is a high mortality rate among women with GCs, which can be attributed to several factors including lack of screening, limited awareness of specific symptoms, or even misdiagnosis.
In advanced GCs, delayed diagnosis, together with limited treatment options, are major contributing factors leading to high mortality. In the case of rare GCs (for example gestational trophoblastic neoplasia, malignant germ-cell tumors, sex cord-stromal tumors, vaginal/vulvar carcinoma, etc.), these issues are even more problematic. These tumors are generally associated with an overall poor prognosis. The low incidence of each of these rare tumors, with an annual incidence of <6 per 100,000 women, poses a major hurdle in the management of patients due to limited therapy options.
Worldwide, cervical cancer (CC) is the second leading cause of cancer-related deaths in women.
REDACTED
Viral Reactivation
A potential inducer of gynecological cancers during space travel may be linked to oncogenic virus reactivation. It has been reported that HPV is responsible for 4.5% of CCs and 630,000 new cancer cases per year. HPV can infect both genders and can also cause anal, penis, vagina, vulva, and oropharynx cancers.
REDACTED: In 2017, Mehta et al. reported reactivation of latent EBV, varicella-zoster virus, and cytomegalovirus in a population of astronauts (male and female), as well as increases in viral copy numbers during long-duration space travel in comparison to short-duration space missions (10 to 16 days). During spaceflight, immune dysregulation, impaired NK cell function, and reduced T cell activation have all been reported / Long and short duration spaceflights – reactivation of the latent herpes virus infections / varicella zoster virus (VZV), cytomegalovirus (CMV), and EBV shedding increased in ISS missions.
Current Challenges in Gynecological Cancer Risk Prediction for Spaceflight
Currently, there is no evidence to suggest that female astronauts have an increased incidence of gynecological cancers. However, we should note that given the low number of female astronauts, conducting studies to determine whether spaceflight increases gynecological cancer risk is difficult. Another possibility could be that the current limitations enforced on the time females spend in space are effective at reducing the incidence of gynecology-specific cancers. At present, studies focusing on subjects that experience similar occupational risk factors to astronauts is the closest form of data we can use to address cancer risk in female astronauts. For example, there are epidemiological studies that have found that there is an increased incidence of breast cancer in female commercial flight attendants. Since female astronauts are exposed to similar occupational risk factors and may also have piloting experience, they may also be at an increased risk for breast cancer.
Gynecologic Medical Standards for Career and Private Astronauts
The prevention of gynecologic morbidity in space begins with the selection process and continues with personalized preventive medicine programs during the astronaut’s Earth-based career. The medical selection criteria for female astronauts with different space agencies undertaking short- and long-term journeys in LEO are identical to those of males except for reproductive system standards and radiation exposure limits. Until 2022, career exposure limits for women of all ages were lower than those for men. The difference in radiation exposure limits reflected the increased incidence of breast, thyroid, and OC in women compared to the incidence in men and the increased risk of lung cancer among female atomic bomb survivors. Moreover, due to reduced cardiovascular and trauma risks, women live approximately 5–7 years longer than men, thus allowing for more time for post flight radiation-induced carcinogenesis. However, the new radiation standard for the radiation exposure limit is now set to be less than 600 mGy and is universal for all ages and sexes. For example, the updated value has been fully integrated into the NASA Space Flight Human-System Standard on Crew Health that sets standards for fitness for duty, space permissible exposure limits, and permissible outcome limits, as well as levels of medical care, medical diagnosis, intervention, treatment and care, and countermeasures.
Gynecologic selection standards for astronauts have evolved and generally have been relaxed as spaceflight experiences progress. Current medical standards allow for a history of endometriosis but would disqualify candidates with endometriosis that results in severe dysmenorrhea, endometriomas, or extensive pelvic adhesive diseases. Premenstrual syndrome must interfere with performance of duties to disqualify a female candidate during selection. Any gynecologic malignancy is disqualifying for selection and for flight except for successfully treated cervical carcinoma in situ. As part of the final astronaut selection process, each female candidate finalist undergoes pelvic and abdominal sonography, colposcopy, gynecologic examination, pap smear, and screening for high-risk HPV. Up to the 2013 selection, no female finalists have been disqualified because of gynecologic conditions found at the time of the selection examination. However, several female astronaut finalists were required to undergo surgical procedures or biopsies to rule out disqualifying pathology or neoplasia in ovarian masses, breast masses, or breast microcalcifications, or to remove large leiomyomata uteri.
Gynecologic selection standards for astronauts have evolved and generally have been relaxed as spaceflight experiences progress. Current medical standards allow for a history of endometriosis but would disqualify candidates with endometriosis that results in severe dysmenorrhea, endometriomas, or extensive pelvic adhesive diseases. Premenstrual syndrome must interfere with performance of duties to disqualify a female candidate during selection. Any gynecologic malignancy is disqualifying for selection and for flight except for successfully treated cervical carcinoma in situ. As part of the final astronaut selection process, each female candidate finalist undergoes pelvic and abdominal sonography, colposcopy, gynecologic examination, pap smear, and screening for high-risk HPV. Up to the 2013 selection, no female finalists have been disqualified because of gynecologic conditions found at the time of the selection examination. However, several female astronaut finalists were required to undergo surgical procedures or biopsies to rule out disqualifying pathology or neoplasia in ovarian masses, breast masses, or breast microcalcifications, or to remove large leiomyomata uteri.
In the case of future female spaceflight participants on NASA-sponsored commercial crew orbital flights (Boeing and SpaceX), Axiom missions, and Inspiration 4 missions, they will probably come under standards and medical selection testing that evolved from a previously published ISS Medical Evaluation Document Volume C and Appendix F. The published standard finds certain gynecologic conditions disqualifying, and individuals outside the standards can be assessed for a waiver based on a risk assessment/mitigation approach. Disqualifying conditions include: (1) disease, injury, or other disorders of the gynecologic tract that could require emergency treatment or interfere with mission completion; (2) any disabling disorders of the reproductive system or associated anatomical structures that could potentially require emergency medical care; and/or (3) history of tumors or pathological growth will be reviewed by the MSMBIP. However, totally private spaceflight participants traveling to LEO or on suborbital flights will have limited flight-related responsibilities and come under the jurisdiction of the US Federal Aviation Administration and each company’s medical policy. Proposed gynecology guidance for private spaceflight participants includes assessing the history of surgery, medication use, current pregnancy, recent postpartum state, or recent pregnancy loss status.
Countermeasures
There are numerous protective measures specific to ionizing space radiation exposure that could be considered, particularly for exploration-class missions. As discussed, space radiation remains one of the primary factors limiting human tolerance to long-term spaceflight. At present, one of the principal countermeasures to protect astronauts from the biological effects of space radiation is limiting the time spent in space. However, this is not feasible for long-term interplanetary space travel, so other remaining measures will have to be implemented.
Preventing space radiation exposure through shielding remains a major challenge for space travel. Reasons for this include restrictions on cost, spacecraft mass, and the nature of ionizing particles, which can penetrate spacecraft hulls and result in secondary intra-vehicular radiation. Spacecraft shielding can be divided into two main categories: passive shielding, constructed of specific materials and always present on spacecraft, and active shielding, which utilizes magnetic or electrostatic fields. In 2019, Barthel and Sarigul-Klijn reviewed shielding optimization methods for space travel beyond the influence of the Earth’s magnetic fields.
REDACTED: optimization of shielding placement / materials with lighter nuclei atoms / special space suits with built-in shielding have been proposed to eradicate the cost of shielding an entire spacecraft but to still provide reasonable protection to astronauts. Active / Electrostatic / Magnetic shielding suggested. The shielding technology described still has a long way to go in its development but holds the potential to provide effective protection to astronauts on exploration class missions.
REDACTED: Proposed pharmacological measures include, but are not limited to, pharmaceutical radioprotectors and immunomodulation – Immunomodulation-based agents include prospective DNA- and RNA-based anti-radiation vaccines in addition to anti-radiation antidotes. These would work via a group of antibodies and natural inhibitory proteins that prevent inflammation, pathological apoptosis, and necrosis of radiation-exposed tissues.
REDACTED: Consideration may need to given for genetic screening, especially of female astronauts for certain mutations such as BRCA1/BRCA2 and others associated with breast cancer. If a carrier condition has been identified, screening and risk-reduction protocols can be discussed depending on the type of mutation.
While work is ongoing in categorizing the radiosensitive/radioresistant genes, we should note that this may be an interesting application of gene/epigenetic modification technologies as radiation countermeasures. Recent advances in these methods have shown improved overall outcomes, where approaches altering the epigenome are readily reversible. Successful identification and modulation of these genes could allow for a significant reduction in negative outcomes experienced by future generations of astronauts.
Future Perspectives
REDACTED: The 2014 NASA GeneLab data repository contains no data on female human gynecological cancers. Interestingly, there exists only one dataset relevant to females, and the study only investigated the mammary gland of mice. Therefore, there is a significant need for studies that investigate female physiology in space.
There are a number of research opportunities that remain for considering the risks and management of breast and gynecologic cancers pre- and postflight. These include the following: histological differences of any tumors that have occurred in astronauts, characterizing molecular pathways involved in carcinogenesis in analog mammalian models, exploratory omics endpoints, the possibility HPV reactivation, the role of radiation countermeasures in prevention, optimizing in-flight or postflight screening protocols, changes in the microbiota of the reproductive tract during spaceflight and their relation to gynecological cancers, and evaluating the role that artificial intelligence and machine learning will play in cancer detection and prevention. Further study on gynecological cancers, including the incidence of the rare types, in space will build a knowledge base that will help to ensure the safety and health of female astronauts by giving them access to prevention, diagnosis, and countermeasures during their space missions.
It would be extremely beneficial to the community to come with a roadmap of studies that needs to be conducted so gynecological risks associated with exploration class missions to the Moon and Mars are minimized. Further, as commercial and private astronauts become more common, obtaining gynecologic and reproductive endpoints following spaceflight will be critical for the creation of preflight, in-flight, and postflight protocols for the screening, diagnosis, and management of gynecologic morbidity and overall astronaut safety.
Conclusions
The current data reveal a scarcity of knowledge about the impact of space radiation and microgravity on gynecologic cancer, as there have been insufficient numbers of female astronauts exposed to long-duration, low-dose rate, and proton and heavy ion radiation to reliably determine the impact on the female reproductive system. With the upcoming Artemis missions set to place the first females on the Moon, there will be longer duration of exposures to both microgravity and space radiation; hence, the influence of flight length on risks related to gynecological cancers will demand a larger focus in ensuring astronaut safety during flight and postflight. Indeed, among all body tissues, the male and female gonads are among the most sensitive to radiation. Therefore, these tissues may be one of the best to study to determine space radiation related exposures. << BACK
