Women comprise approximately 10% of all pilots and the proportion is in the single digits within the tactical aviation community (Air Force Personnel Center, 2022; Women in Aviation Advisory Board, 2022). Though women represent a growing force essential to flight-mission success, several unique challenges faced by women act as barriers to entering the aviation community, such as meeting current anthropometric standards for the cockpit and gear fit (da Silva et al., 2018; Marintseva et al., 2022; Moczynski et al., 2020; Women in Aviation Advisory Board, 2022). For example, prospective female aviators’ typically smaller stature and weight can create challenges in securely sitting in the cockpit and wearing issued flight attire, which may disqualify them from continuing with advanced training more so than male aviators (da Silva et al., 2018; Marintseva et al., 2022; Moczynski et al., 2020; Women in Aviation Advisory Board, 2022). Additional recruitment (e.g., no visibility and limited access to aviation), training (e.g., perceptions of tokenism and hegemonic masculine culture), and retention (e.g., restricted family planning policies and lack of promotion opportunities) blockades avert women from joining or further advancing with aviation careers (Ferla and Graham, 2019; Gorlin and Bridges, 2021; Women in Aviation Advisory Board, 2022). Nonetheless, women’s representation in aviation continues to rise, recently achieving in 2020, the first Black female Navy fighter pilot flying an F-16 Fighting Falcon, and in 2022 the first female demonstration pilot for the Blue Angels Squadron (Pawlyk, 2020; Toropin, 2022).

In addition to these barriers that impede women from entering and completing the military aviation training pipeline, human performance research lags in considering potential psychophysiological differences between male and female aviators due to little inclusion of females during the design and development of aircraft systems, contributing to their difficulties in meeting initial aviation program requirements (Bustamante-Sánchez et al., 2019; Hormeño-Holgado and Clemente-Suárez, 2019; Moczynski et al., 2020; Marintseva et al., 2022; Women in Aviation Advisory Board, 2022). Thus, a poor understanding of how male and female aviators differ in aircraft human performance results in unknown potential sex differences on aeromedically-relevant environmental stressors, perchance leading to suboptimal performance, safety, and health guidelines towards servicewomen, negatively impacting their duties (Braun et al., 2015; Eichler, 2021). Most of the work cited above that has examined the aviation community has focused on gender (e.g., men, women), demonstrating that there are fewer women compared to men in the military aviation community. While this is accurate, in the current paper, we focus instead on sex (i.e., male vs. female), as our questions of interest are primarily focused on factors that are physiologically based, such as respiratory and neural measures as well as, cognitive performance.

To illustrate, the threat of hypoxia and its possible contribution to recent unexplained physiological events (UPEs) are at the forefront of human performance research and operations in tactical aviation (Elliot and Schmitt, 2019). Reduced levels of breathable oxygen harmfully impact sensory, cognitive, and motor functioning and decision-making (McMorris et al., 2017; Niedermeier et al., 2017; Bouak et al., 2018; Hormeño-Holgado and Clemente-Suárez, 2019; Blacker et al., 2021). These hypoxia-induced performance impairments are associated with aircrews’ inability to maintain a constant airspeed, altitude, and directional heading during simulated flights (Temme et al., 2010; Kowalczuk et al., 2016; Steinman et al., 2017; Bouak et al., 2018). Hypoxia risks operational errors, mission failures, loss of aircraft, injuries, and even death (Petrassi et al., 2012; Steinman et al., 2017; Bouak et al., 2018). Therefore, efforts to precisely characterize performance impairments and recognize symptoms during hypoxia to initiate emergency procedures are demanded (Petrassi et al., 2012; Kasture et al., 2021; Leinonen et al., 2021; Blacker and McHail, 2022). While these performance deficits during acute hypoxia are well-documented, progress toward sensor development and improving hypoxia familiarization training are stunted due to limited knowledge of how individual differences, including sex, may or may not underlie hypoxia symptoms and performance impairment.

Some previous hypoxia studies have excluded female participants entirely (Kowalczuk et al., 2016; Dart et al., 2017; Steinman et al., 2017; Bouak et al., 2018; Bustamante-Sánchez et al., 2019; Lucertini et al., 2020). Whereas those that did include females lacked a large enough sample size to look at sex comparisons (Blacker et al., 2021; Fehrenbacher et al., 2021; Leinonen et al., 2021). Temme et al. (2010) and Kasture et al. (2021) do not specify participants’ sex, referring to them as pilots or volunteers. However, very recently, a few studies have begun to examine the role of sex on response to hypoxia. One such study evaluated diaphragmatic fatigue between sexes during acute hypoxia compared to normoxia (Archiza et al., 2021). The study found diaphragmatic fatigue magnitude significantly increased in female (−27.6% ± 7.7%) compared to male (−23.4% ± 9.6%) participants after induced inspiratory loading under acute hypoxia (Archiza et al., 2021). Also looking at respiratory effects of hypoxia, Camacho-Cardenosa et al. (2022) found that males had an increase in minute ventilation and a steeper initial decrease in peripheral oxygen saturation (SpO₂) compared to females during a 7 h moderate hypoxia exposure (15% O₂). Two additional studies examined sex differences in the effects hypoxia have on cold stress (Hohenauer et al., 2022) and muscle endurance (Karayigit et al., 2022), but both studies found no difference in SpO2 between sexes during those moderate hypoxia exposures. These inconsistent findings suggest that there may be sex differences in physiological response to hypoxic challenge. Still, differences in altitude used, normobaric versus hypobaric hypoxia, and length of exposure make interpretation challenging. Moreover, all of these studies had modest sample sizes (range 8–15 per sex) and none were done in an aeromedical setting. As a result, sex comparisons regarding acute hypoxia, at equivalent altitudes relevant to aviation, are non-existent, and symptoms, experiences, and performances may differ, which is critical when employing timely emergency procedures, recovery from exposure, and designing in-cockpit sensor systems.

The gravity of hypoxia adversely affecting performance and the urgency to address sex disparities within aerospace medicine merits exploring male and female aviators’ responses to low-oxygen events to equip early warning systems better. Examining sex comparisons in hypoxic challenge is an initial step towards addressing the numerous aircrew occupational stressors and environmental exposures that have been ignored, along with G-tolerance, workload, spatial disorientation, inflammatory responses, and urinary relief systems (Lewkowicz et al., 2018; Lefèvre et al., 2019; Belt et al., 2020; Chiang et al., 2021; Schultz et al., 2022). Female aircrew play an integrative role in aviation, and as their occupational opportunities expand, so should the operational health sciences to best support all aircrew needs.

Investigating sex differences bridges the gap between aerospace medicine and operational health, and addressing hypoxia is one of many facets yet to be studied. Therefore, we retrospectively examined six hypoxia studies with male-female participant samples. We explored sex as a predictor of physiological response, sensory deficits, the severity of cognitive performance declines, and symptom manifestation via stepwise linear and binary logistic regression analyses. We hypothesized sex (i.e., male vs. female) as a predictor of response to hypoxic challenge. The alternative hypothesis was sex would not be a predictor of the response outcomes during hypoxia.

The current study retrospectively examined sex as a predictor of physiological response, neural modulation, cognitive performance, and hypoxia-related symptom manifestation during hypoxic challenge. Using regression analyses, we found female sex predicted lower SpO₂ and higher headache reports in response to hypoxia. However, sex did not predict HR changes, hypoxia-related symptom frequency, or other individual symptom presentation. While sex was our primary independent variable of interest, we also examined age, BMI, altitude, and exposure minutes. Age significantly predicted decreased HR and was associated with increased reports of hot flashes, headaches, and fatigue. Surprisingly, exposure minutes were associated with a decrease in hot flashes, possibly influenced by the initial apprehension of a participant perceiving a hypoxic exposure. The results for ERPs and cognitive performance yielded poorly fitted models and, therefore, cannot be determined as the findings could be misleading when making inferences about the predictors in the model. Lastly, and expectedly, increased altitude significantly predicted lower SpO₂, higher hypoxia-related symptom frequency scores, and increased reports of several individual symptoms documented in previous studies (Kasture et al., 2021; Blacker ad McHail, 2022).

Overall, personal characteristics had minimal bearing on physiological response (Table 3). Focusing on sex, SpO₂ was significantly lower among female than male participants and in combination with age and BMI, explained 6% of the variance. Though accounting for a small percentage of SpO₂, these results are consistent with Archiza et al. (2020) findings regarding sex differences in diaphragmatic muscle fatigue under acute hypoxia. However, our finding of lower SpO₂ for females is inconsistent with prior work using less severe altitudes that found no sex differences (Hohenauer et al., 2022; Karayigit et al., 2022). The altitudes examined here most closely align with the 8% O₂ used by Archiza et al. (2020). Moreover, given the small sample sizes used in previous work (Hohenauer et al., 2022; Karayigit et al., 2022), their null result for sex differences in SpO₂ was possibly due to inadequate power. The larger sample size used in our study afforded us a better opportunity to assess these differences, and our results did indicate that the effect was quite small with sex, age, and BMI only accounting for 6% variance in SpO₂ (Table 3).

Additionally, the likelihood of reporting a headache was 2.69 times more likely among female than male participants and increased to 3.33 times when adding altitude and exposure minutes (Table 4). Previous work has not specifically examined sex differences in self-reported symptoms following acute hypoxia. In general, headaches and migraines are more common among women in both military and non-military populations (Guo et al., 2019; Moore et al., 2019; Allais et al., 2020; Hesselbrock and Haynes, 2022). Increased report of headache during hypoxia for females is particularly relevant in an aeromedical context because headache frequency is a major factor influencing suitability for aviation service (Hesselbrock and Haynes, 2020). Hormonal contraceptive use is related to cerebrovascular and cognitive changes, which could be further altered during hypoxic conditions; future works should explore the association between hormonal contraceptive use and headache reports (O’Brien et al., 2020; Theunissen et al., 2022). The risk of migraine recurrence is also an important factor for aeromedical readiness, particularly in pilot applicants who incur a substantial training investment.

Here we were interested in whether males and females differ in their neurocognitive response to acute hypoxia because this is particularly relevant to military aviation. However, our ERP and cognitive performance measures yielded a poorly fitted model, which makes the results uninterpretable (see Table 2 and Figure 2 for descriptive statistics). This may have resulted due to the aggregation of several ERP components (i.e., P3a, MMN, and Visual P100) and disparate cognitive performance tasks (i.e., VTT, PVT, CCT, and HAT), which yielded significant variability in relative change scores, contributing to the models’ inability to converge. Independent of any environmental stressors, the literature on sex differences in electrophysiology are mixed, with some studies showing sex differences in ERP amplitude (e.g., Bourisly and Shuaib, 2018) and some showing no effect of sex (e.g., Sangal & Sangal, 1996). Moreover, the literature on sex differences in cognitive function and ability is even murkier due to the inability to control the confounding influence of environmental factors like culture, parenting, and learned behavior. While some evidence of anatomical or functional differences exists, none of these observations demonstrate consistent and meaningful sex differences in cognitive or related brain functions (Purves, 2012). Together, these results suggest that a prospective study using the same neural and cognitive measures during acute hypoxia is needed to determine if there are sex differences in these functional measures.

The current study is among the first to examine sex differences within aerospace medicine research to better support all aviators’ operational health and safety. Strengths include a sizeable male-female participant sample and self-reported and objective physiological data collection to validate the hypoxia exposure responses. Yet, it is not without its limitations. First, participants in these studies were not exclusively military aviators; thus, the findings lack some generalizability to the tactical aviation community. The male-female ratio was unequal, and we encourage studies to recruit balanced male-female participant samples, including sex as a covariate in future works. Finally, retrospective data analyses do not establish cause-and-effect relationships yet provide fruitful information concerning the predictor’s degree of explained variances, founding a strong basis for future experimental research.

In conclusion, we found significantly lower SpO2 and increased report of headache for females compared to males during acute hypoxia exposure. These findings add to the small but recently growing area of research into potential sex differences in response to hypoxic challenge. The study’s results bridge sex-specific disparities in aerospace medicine and operational health to refine hypoxia familiarization training within aviation safety programs, enhance the precision of pilot monitoring sensor development, and update emergency response and recovery protocols in the event of a hypoxia occurrence suitable for all aircrew. We recommend continuing to elucidate the impact of sex and intrapersonal differences in hypoxia and other aeromedically relevant stressors on physiological, sensory, and cognitive performance.

Some authors are military service members or federal employees of the U.S government. This work was prepared as part of their official duties. Title 17 U.S.C. §105 provides that copyright protection under this title is not available for any work of the U.S. Government. Title 17 U.S.C. §101 defines a U.S. Government work as a work prepared by a military Service member or employee of the U.S. Government as part of that person’s official duties.