Abstract
We appreciate Berger et al.s' (2020) interest in our recent research findings on the potential association of low-altitude cortisol levels with acute mountain sickness (AMS) (Gatterer et al., 2019). They highlight several limitations of our study that merit a response from us with the ultimate aim to contribute constructively to the scientific discourse on the potential mechanisms underlying AMS, a syndrome that is still to be fully understood.
First, the limitations of our study pointed out by Berger et al. (2020), such as small sample size and missing data were duly acknowledged in our article (Gatterer et al., 2019). We also made clear that the data were collected in the course of a study primarily designed to investigate the effects of low-dose acetazolamide pretreatment on AMS development. We controlled for the acetazolamide effect on AMS and fluid homeostasis, finding a nonsignificant small to medium effect (Cohen's d: 0.3, p > 0.25), likely due to the limited efficacy of the low acetazolamide dosage (Kayser et al., 2012). Importantly, we also reported the results in the placebo group separately, which still showed a significant relationship between AMS score and low-altitude cortisol levels (r2 = 0.799, p < 0.001). Also, if anything, the purported bias from any diuretic effect of acetazolamide mentioned by Berger et al. (2020) would have had a mitigating effect on the relationship between fluid retention and AMS that we report. Lastly, any potential effect that acetazolamide intake might exert on plasma cortisol levels was duly addressed (Frayser et al., 1975; Young et al., 1987).
Sure enough, our study has its limitations and these should give rise to criticism, but at the same time, our article should be put in perspective to what else is reported in the extant literature. Specifically, Berger et al. (2020) cite the recently published results by Estoppey et al. (2019), but these are in support of our study. Estoppey et al. (2019) showed that also low-altitude cortisol levels (i.e., 382 m ± 309 m) were higher in AMS-sensitive than in AMS-resistant subjects. They also found that mountain guides, who had lower AMS scores than all other participants at high altitude, had lower cortisol levels at low altitude (Estoppey et al., 2019). In support of their argument, Berger et al. (2020) cite data from their previous research, which also has some limitations. In particular, spot values of plasma adrenocorticotropic hormone (ACTH) and cortisol are not very informative given their diurnal fluctuations, whereas the 24 hours low-altitude urine cortisol interestingly showed a tendency (p = 0.082) for higher levels in AMS-sensitive participants (Berger et al., 2020), which makes us wonder what the results might have been for larger sample size.
Overall, we find that the extant literature suggests a role for the hypothalamic–pituitary–adrenal axis in the pathophysiology of AMS, which might be an interesting hypothesis to pursue. We, therefore, believe that it was reasonable to state (Gatterer et al., 2019): “This study suggests that resting low altitude cortisol levels, which are associated with fluid retention at high altitude, may be connected to AMS risk. This suggests a link between individual stress regulation, cortisol homeostasis, water balance and AMS risk that merits to be further investigated.” Based on our and others' findings in animal models (Chen et al., 2014; Song et al., 2016), we propose that corticotrophin releasing factor (CRF) and the CRF-receptor-1 might be implicated in AMS and high-altitude cerebral edema (HACE). For some unknown reason AMS-sensitive persons would have a stronger stress response to altitude exposure, secreting higher levels of CRF, which would lead to greater ACTH release, in turn, leading to higher cortisol levels. This increase in cortisol would be secondary to the stimulation of CRF-receptor-1 and its manifold other effects. This contention fits with the efficacy of dexamethasone to prevent and treat AMS and HACE, possibly by decreasing CRF secretion through negative feedback (Joyce et al., 2018). Future collective efforts testing these ideas with designs specifically adapted to the research questions raised will hopefully clarify the so far still unclear mechanisms underlying the variance in who is at greater risk of AMS at high altitude.