All is fair in menstruation, POTS and… war?

While the stretch-sensitive baroreceptors are first called to mind in acute control of blood pressure (BP), other acute reflex adjustments are necessary to maintain allostasis, notably central and peripheral chemoreflexes. Induced via hypoxia and/or hypercapnia, central and/or peripheral chemoreflex activation is a potent sympathetic stimulus that has been shown to elicit augmentations in efferent sympathetic traffic (i.e. muscle sympathetic nerve activity; MSNA). Within the context of cardiovascular control, MSNA is sine qua non for the sympathetic arm of the autonomic nervous system. Importantly, notable sex-differences have been found in neurovascular regulation, with females – who reap the cardio-protective benefits of oestrogen – tending to have lower basal MSNA, blunted sympathetic transduction, lower BP, and decreased risk of developing hypertension, when compared with age-matched males. Furthermore, females display MSNA undulations, with augmented basal MSNA observed during the mid-luteal (ML) phase when compared with the early-follicular (EF) phase of the menstrual cycle, where oestradiol is generally lowest (Usselman et al., 2015). Females have also displayed lower BP in times of MSNA quiescence, when compared with males, suggesting differences in neurovascular transduction during periods of no sympathetic traffic. Further, postmenopausal females display exaggerated sympathetic transduction to BP, when compared with premenopausal females, indicating the influence of circulating sex hormones – with oestrogen, generally, being sympathoinhibitory in the context of MSNA. Along with such sex differences in neurocirculatory regulation (Robinson et al., 2019), there is also an interaction between both central and peripheral chemoreflex activation (hypercapnic hypoxia) and menstrual cycle phase, with the sympathoexcitatory responses (burst frequency, incidence, and total MSNA) to combined central and peripheral chemoreflex activation being greater in the EF phase (low hormone) when compared with the ML (high hormone) phase (Usselman et al., 2015). Furthermore, peak sympatho-excitation via central and peripheral chemoreflex activation has been found to be greater in females when compared with males, but not during peripheral chemoreflex activation, raising the possibility that central chemoreflex control of MSNA may be augmented in females. This foreshadowing in the literature was addressed in a recent article in The Journal of Physiology by Sayegh et al. (2022). The authors recruited (n = 20, 10F) young adults free of cardio-metabolic disease, with females studied during the EF phase of their menstrual cycle (n = 8), or during the placebo phase of their oral contraceptive (OC; n= 2). Themain findings of this study were that females displayed augmented MSNA reactivity, but blunted ventilatory responses to central and combined central and peripheral chemoreflex activation, when compared with males. Participants underwent two visits to the laboratory, day 1 consisting of familiarization and collection of anthropometrics, and day 2 being the experimental visit. Following instrumentation and achieving a satisfactory MSNA signal, participants were subject to 20 min baseline eucapnia, followed by chemoreflex testing: isocapnic hypoxia to stimulate peripheral, hypercapnic hyperoxia to stimulate central and inhibit peripheral, and hypercapnic hypoxia to stimulate both central and peripheral chemoreflexes. These breathing trials were randomized 5 min time courses, followed by a 10 min recovery period. Sayegh et al. found females displayed augmented MSNA reactivity to central (burst amplitude; P = 0.017, total MSNA; P = 0.017) and combined central and peripheral (burst frequency; P = 0.034, total MSNA; P < 0.0001) chemoreflex activation when compared with males. In contrast, no sex-differences were detected in MSNA reactivity or ventilation in the peripheral chemoreceptor activation condition. Similarly, there were no sex-differences in arterial baroreflex function or heart rate variability over all conditions. Sympathetic neurovascular transduction was similar between the sexes in eucapnic and experimental breathing trials. Interestingly, the raised MSNA and raised ventilation during combined central and peripheral chemoreflex activation was greater than the sum of the individual central and peripheral chemoreceptor responses – and this response was similar between the sexes. However, it’s important to note that while there were differences in sympathetic activation patterns between the sexes, they were not coupled with changes in hemodynamic measures. The authors suggest some potential mechanisms for their divergent findings of attenuated ventilation with concomitant augmented MSNA responses in females. Perhaps the increased tidal volume response in males, which was observed in this study, triggered the pulmonary stretch receptors in the lungs, ultimately causing sympatho-inhibition. Or maybe, divergent cerebral blood flow impacted the central chemoreflex response; however, results from previous studies are inconclusive in females. Here, Sayegh et al. found augmented sympathetic responses during central and peripheral chemoreflex activation. Acute increases in MSNA result in release of neurotransmitter (i.e. noradrenaline), which bindsα-adrenergic receptors in the vascular smooth muscle, initiating vasoconstriction and increasing BP. Previous findings suggest that in females, noradrenaline induces vasoconstriction to a lesser degree when compared with males, perhaps due to β-adrenergic receptor-mediated vasodilator responses blunting the α-adrenergic