Sex differences in loop gain measured via superimposed end-expiratory breath holds and inspired steady-state hypoxia

Acute low oxygen exposure (hypoxia) elicits a hypoxic ventilatory response (HVR), which increases ventilation and mitigates hypoxaemia. During sustained exposure to hypoxia, ventilatory acclimatization increases peripheral chemoreflex (HVR) sensitivity or chemoreflex loop gain (LG). Although increased ventilation protects oxygenation, increased LG contributes to ventilatory instability during sleep (central sleep apnoea; CSA). The HVR is highly variable between individuals, and the impact of sex on HVR variability and LG is unclear. At low altitude (1100 m), we aimed to characterize a novel breath hold method to quantify LG using a standardized series of short (∼10 s), voluntary, end-expiratory breath holds (EEBH), using a background of steady-state normobaric inspired hyperoxia (fraction of inspired oxygen; $F_{I{O}_2}$  = 1.0), normoxia (i.e., ambient air; $F_{I{O}_2}$  = 0.21) and hypoxia ( $F_{I{O}_2}$  = 0.14; equivalent to ∼4300 m altitude). Further, we investigated sex differences in LG during differential oxygen exposure using this novel EEBH protocol to quantify LG. We hypothesized that (a) LG magnitude would follow an inverse oxygen-dependent pattern with each inspired gas condition, and (b) that males would have higher LG than females. We recruited 36 healthy participants (18 females; 18 males). We found (a) a graded, inverse oxygen-dependent effect on LG magnitude (P < 0.0001), and (b) a sex-specific effect, whereby males had significantly larger LG magnitudes than females, but only in steady-state inspired hypoxia (P < 0.032). Our EEBH protocol illustrates an intrinsic sex difference in chemoreflex LG in hypoxia, which may underlie known sex differences in CSA at high altitude and in heart failure populations.