Acute Mountain Sickness and High Altitude Cerebral Edema in Women: A Scoping Review—UIAA Medical Commission Recommendations

Introduction and Definition

Acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) are illnesses associated with rapid ascent to altitudes over 2,500 m in unacclimatized lowlanders (Roach et al., 2002). AMS is defined by a cluster of symptoms including primarily headache, along with malaise, poor appetite, nausea, dizziness, and sleep disturbances. Research tools used to define AMS include the Lake Louise Scoring System (LLSS) (Roach et al., 2018), the Environmental Symptoms Questionnaire III (ESQ-III) (Sampson et al., 1983), the Acute Mountain Sickness-Cerebral score (AMS-C) (Ahluwalia and Underwood, 2023), and the Hackett AMS score (Roeggla et al., 1996). HACE, thought to be the extreme manifestation of AMS, is notable for neurological signs such as ataxia, difficulty speaking, and decreased consciousness (Hackett and Roach, 2004; Wu et al., 2006).

Approximately 10%–25% of individuals suffer from AMS at a sleeping altitude of around 2,500 m (Honigman et al., 1993; Maggiorini et al., 1990; Mairer et al., 2010), but symptoms are usually mild and unlikely to affect daily activities. However, AMS can occur in 50%–90% of individuals between 3,500 and 5,500 m, and symptoms can be debilitating (Beidleman et al., 2013; Hackett et al., 1976; Maggiorini et al., 1990). HACE usually develops after 2 days at altitudes above 4,000 m and typically affects only 0.5%–2% of people (Hackett and Roach, 2004; Hackett et al., 1976; Wu et al., 2006; Zafren et al., 2017) but can be life-threatening if left untreated.

For both illnesses, rapid ascent, increased physical exertion, first night of sleep at altitude, and prior history of AMS or HACE are major risk factors in unacclimatized lowlanders ascending to high altitude (Bärtsch and Swenson, 2013; Luks and Hackett, 2022). Acetazolamide and dexamethasone can be used for prophylaxis and treatment (Luks et al., 2019). Sex-differences in AMS and HACE are an ongoing topic of discussion (Jean et al., 2005). Early work suggested that there were no sex differences in the incidence of AMS and HACE (Hackett et al., 1976), whereas a more recent review lists female sex as a possible risk factor (Bärtsch and Swenson, 2013).

There have been several studies investigating sex hormones and their effect on high-altitude physiology and AMS. Progesterone is a respiratory stimulant (Behan and Wenninger, 2008; Wright et al., 2004), with estrogen potentiating this effect (Regensteiner et al., 1989) as well as increasing cerebral blood flow (Krause et al., 2006). There are also effects of testosterone and other androgens at altitude that may affect acclimatization and susceptibility to AMS. Testosterone increases erythropoiesis and maximal oxygen uptake (VO₂ max) (Shahani et al., 2009) but may also decrease cerebral vascular tone and blood flow (Krause et al., 2006). While these differences would seem to imply a possible difference in outcomes for men and women at altitude, we know that sex as a health and disease modifier is often much more complicated (Mauvais-Jarvis et al., 2020).

The aim of this scoping review is to summarize the current knowledge on sex differences in epidemiology, pathophysiology, symptomatology, and treatment of AMS and HACE. With an increasing number of women ascending to high altitude for work, recreation, religious pilgrimages, athletic competitions, and military deployments, addressing whether there should be medical recommendations specific for the female traveller to high altitude has become increasingly important.

Methods

The general methodological aspects of this series on women at altitude have already been published in detail (Horakova et al., 2023). A total of 7,165 publications were screened, and titles suggesting topics relating to AMS and HACE, their incidence, pathophysiology, and treatment were initially extracted from the total. Examination of these publications and their citations led to finding additional publications by hand search. We excluded case reports, narrative reviews, and consensus papers. Finally, each publication was evaluated for its relevance to sex-related differences regarding altitude illness. Studies without any female-specific findings were excluded. Included studies were then categorized as demonstrating female sex, male sex, or neither sex as a risk factor for AMS or HACE if p < 0.05 in their analyses. Studies that reported either sex as a risk factor for AMS or HACE due to absolute percentages, but without significant statistical differences, were categorized as “neither” for the purposes of this review.

Results

A total of 37 publications were ultimately included, ranging from 28 to 3,140 participants, and all but one were cohort studies. The total number of unique female participants in the cohort studies reviewed was 6,215 compared to 11,453 male participants. Included studies defined AMS using LLSS, ESQ-III, AMS-C, or the Hackett score. Thirty-five publications reported AMS incidence or severity by sex. Only four of these included sex-specific data for HACE (Basnyat et al., 2000; Canoui-Poitrine et al., 2014; Karinen et al., 2008; Richalet et al., 2012). There were three studies with exclusively female cohorts looking at the correlation of AMS symptoms and menstrual cycles (Rock et al., 2001), oral contraceptive pills (OCPs) (Harrison et al., 2013), and menopause (Richalet et al., 2020). There was extremely limited sex-specific data on risk factors or treatment for AMS (Harrison et al., 2013; Richalet et al., 2020; Richalet et al., 2012; Rock et al., 2001; Ziaee et al., 2003).

Of the 35 publications with analysis including sex as a risk factor for AMS, 13 showed higher incidence in women, 2 showed higher incidence in men, and 20 found neither sex as a statistically significant risk factor (Table 1). There were similarly mixed data in the four studies summarizing sex-specific differences in HACE (Table 1).

Summary and Discussion

Despite the likelihood that humans have known about altitude-related illnesses as far back as 32 BC (Gilbert, 1983), there are relatively limited prospective studies regarding the incidence, pathophysiology, symptoms, and prevention/treatment of AMS and HACE in women compared to men. Recent guidance to include sex-specific analyses in medical research (Liu and Mager, 2016) has no doubt paved the way for many of the studies included in this review. However, despite the increase in recent publications on the topic, there is still lack of consensus regarding sex as a risk factor for altitude-related illnesses.

The majority of publications reviewed here largely showed similar incidence of AMS in men and women. This finding is supported by a meta-analysis that showed no significant sex differences in incidence of AMS after multivariate analysis of 20 prior studies (Beidleman et al., 2013). Another meta-analysis (Hou et al., 2019) summarizing 18 research studies showed an increased prevalence of AMS in women compared to men. However, the authors of this meta-analysis excluded 14 studies that showed no sex differences, thus biasing the results away from the possibility that no sex differences exist.

There were only four studies pertaining to sex differences in HACE, and the results were mixed. One found higher incidence of HACE in women (Basnyat et al., 2000). Another found higher rates in men (22% vs. 13% in women), but no analysis was presented to determine whether the findings were statistically significant (Karinen et al., 2008). The other two publications looked at severe high-altitude illness (SHAI), a term encompassing severe AMS, HACE, and HAPE. There were subgroups of women with increased risk of SHAI, including women without prior high-altitude experience (Canoui-Poitrine et al., 2014) or women not taking prophylactic acetazolamide (Richalet et al., 2012). However, HACE made up <4% of the total SHAI cases, making the data difficult to interpret in this context.

Beyond the occurrence of AMS, some work suggests the possibility of sex-related differences in acclimatization. One study showed female participants had a lower arterial oxygen saturation (oxygen saturation as measured by pulse oximetry [SpO₂]) after ascent than male participants (Shen et al., 2020), while a meta-analysis showed lower peak AMS severity scores in female participants (Beidleman et al., 2013). Men are more likely to experience altitude-related sleep disordered breathing, but had either a similar (Caravita et al., 2015) or lower incidence (Li et al., 2022) of AMS compared to women in those studies.

As discussed in the introduction section, sex hormones could theoretically affect adaptation at altitude. However, several small studies that address this directly did not clearly demonstrate an effect on incidence of AMS. One study found luteal versus follicular phase of the menstrual cycle had no effect on ventilatory acclimatization for lowlander women rapidly ascending to 4,300 m, nor did the women have increased acclimatization compared to reports in men (Muza et al., 2001). Pretreatment with medroxyprogesterone did not significantly reduce the incidence of AMS in either female or male participants in one study with 44 participants (Wright et al., 2004). An observational study looking at a female-only cohort demonstrated an increased incidence of AMS in OCP users, and that acetazolamide prevented AMS only in those not using OCPs (Harrison et al., 2013). Another female-only cohort study showed no difference in incidence of AMS with regard to phases of the menstrual cycle (Rock et al., 2001).

A group of 336 premenopausal women not on OCPs had increased hypoxic ventilatory response at exercise (HVRe) and increased oxygen saturation in hypoxia at exercise during the early luteal/midluteal phase of the menstrual cycle during hypoxia testing at sea level (Richalet et al., 2020). However, when the authors analyzed the total cohort of 1,060 pre-/postmenopausal women, they found menopause had no effect on HVRe. An additional analysis of 260 women who then sojourned to altitude showed no difference in severe AMS between four groups: pre- and postmenopausal women who were taking or not taking OCPs/hormone therapy (Richalet et al., 2020). In summary, despite the known effects of female sex hormones on ventilation, there is little evidence to suggest they lead to sex differences in acclimatization or illness.

One observational study of a male-only cohort demonstrated that a higher testosterone to estradiol ratio on blood sample analysis was associated with the presence of AMS (Ding et al., 2018). However, similarly to the female-sex hormone studies, there are no conclusive studies to demonstrate advantage or disadvantage of higher testosterone levels at high altitude.

Overall, there are several limitations to drawing a definite conclusion regarding sex as a risk factor for AMS and HACE. Some of the included studies relied on participants to accurately recall symptoms after the fact, leading to recall bias. Although there were several larger studies with more than 1,000 participants, many were smaller and possibly underpowered. Furthermore, three of the studies had overlapping populations (Canouï-Poitrine et al., 2014; Richalet et al., 2020; Richalet et al., 2012).

Another limitation to sex-analysis of AMS and HACE is the subjective scoring which requires self-reporting of symptoms. There are possibly sex-differences in how people self-report symptoms. For example, in one study, adolescent girls were more likely to report AMS-like symptoms than adolescent boys on a low altitude trip (Dallimore et al., 2012), but this has not been documented in adults. One study reported that women were more anxious at altitude, with the authors commenting on the overlap between LLSS symptoms and recognized features of generalized anxiety (Boos et al., 2018). Even if men and women report symptoms similarly, other sex-related factors may account for differences regarding AMS. For example, one publication observed that female Nepali pilgrims may have closer adherence to fasting while trekking than male pilgrims (Basnyat et al., 2000), which in turn could contribute to symptoms like fatigue and headache.

Another consideration is that female participants are underrepresented in medical literature compared to male subjects (Liu and Mager, 2016). This phenomenon is seen in the studies included in this review. There were almost twice as many male as female study participants in all studies combined. While this affects the statistics, it also paints a picture of the social surroundings of female trekkers and mountaineers. The male-dominated mountaineering environment could lead to differences in how female participants respond to surveys or perceive their own symptoms and could lead to either under- or over-reporting symptoms.

Conclusions

Data are limited on female-specific findings regarding AMS, with most publications addressing only prevalence or incidence of AMS with regard to sex. Of these, the majority did not find sex to be a risk factor for AMS or HACE. While there were a couple of publications that looked at acetazolamide and women, more data are needed on sex-specific prevention and treatment for AMS and HACE. As such, the general established recommendations for going to altitude are applicable to women, and can be found in Table 2.