Menstrual phase does not influence ventilatory responses to group III/IV afferent signaling in eumenorrheic young females
Introduction
Estrogen, an essential female sex hormone, has been shown to inhibit the activity of the sympathetic nervous system (Charkoudian, 2001). Estrogen can blunt group III/IV afferent activity, which transmits sensory feedback from skeletal muscle to multiple brainstem compartments, including the ventral respiratory column, dorsal respiratory group, and pontine respiratory group (Smith et al., 2009). Group III/IV afferents are key to ventilatory control during exercise (Amann et al., 2010, 2015). These afferents mediate the ergoreflex, in which mechanical activation (mechanoreflex) and metabolite accumulation (metaboreflex) in active skeletal muscles provoke cardiorespiratory responses to support the metabolic demands of exercise (Amann et al., 2020; Rowell and O'Leary, 1990). Estrogen’s blunting effects on these fibers thereby elicits an attenuated metaboreflex in females (Ettinger et al., 1996; Koba et al., 2012; Minahan et al., 2018; Schmitt et al., 2006; Schmitt and Kaufman, 2003a,b, 2005). Estrogen may play a role in ventilation, potentially mediating resistance of the upper airways and acting synergistically with progesterone to promote ventilation (Behan and Wenninger, 2008). However, its impact on ventilation has not been well defined.
Circulating levels of sex hormones during the menstrual cycle have been shown to alter the ventilatory response to group III/IV afferent stimulation. Exercise immediately activates group III/IV afferents; the physiological response to exercise stimulation of these afferents is termed the ergoreflex. The luteal phase, where progesterone is highest with moderately high estrogen levels (Reed and Carr, 2018), has been associated with a greater ventilatory response with dynamic exercise (England and Farhi, 1976; Jurkowski et al., 1981; Saperova and Dimitriev, 2013; Schoene et al., 1981; Slatkovska et al., 2006; Williams and Krahenbuhl, 1997). However, some studies have reported no influence of menstrual phase on resting or exercise ventilation (Beidleman et al., 1999; De Souza et al., 1990; Dombovy et al., 1987; Lamont, 1986; Lebrun et al., 1995; Matsuo et al., 2003; Packard et al., 2011). Thus, more clarity is needed on the role of estrogen in the ventilatory response to group III/IV afferent activation during dynamic exercise.
Group III/IV afferent activation is enhanced through sub-systolic vascular occlusion (Keller-Ross et al., 2019, 2016; McClain et al., 1993). While partial circulatory occlusion activates both group III and group IV afferents, supra-systolic vascular occlusion after exercise produces an increase in metabolic buildup in the active tissue with minimal to no stimulation of group III stretch receptors, thereby allowing for isolation of the activity of group IV muscle afferents (i.e., metaboreflex) (Haouzi et al., 2004). The role of estrogen levels in ventilatory responses to metaboreflex activation in human females, however, remains unclear.
Although prior work has investigated the effects of female sex hormones on ventilatory responses to exercise, how these factors specifically influence ergoreflex and metaboreflex activation are unclear. Furthermore, most studies have compared the luteal phase, when high levels of progesterone may obscure effects of estrogen, to the low-hormone follicular phase. Therefore, the purpose of this study was to determine how fluctuations of estrogen between the early follicular (low estrogen) and ovulatory (high estrogen) phases influence the ventilatory responses to group III/IV afferent activation during sub-systolic occlusion (activating the entire ergoreflex) and supra-systolic occlusion (isolating the metaboreflex) of the lower-extremity muscles. Based on previous research findings, we hypothesized that the ventilatory responses to ergoreflex and metaboreflex activation would be greater during the follicular phase than the ovulatory phase.
Section snippets
Participants
Participants reported natural menstrual cycles and no current use of hormonal contraceptives. Inclusion criteria consisted of being between ages 18–35 years and having no prior history of cardiovascular, pulmonary, neuromuscular, or orthopedic disorders. Participants were excluded if they were currently pregnant or breastfeeding.
All participants gave written informed consent. The study was approved by the University of Minnesota Institutional Review Board (study authorization number:
Results
Nine participants completed the study; their anthropometric and demographic characteristics are presented in Table 1. The participants were 25 ± 4 years old with a body mass index of 21.6 ± 1.5 kg/m2, and they reported no medical conditions that would influence their physiological responses to study procedures.
Discussion
The main findings of the present study were that menstrual phase influenced the ventilatory response to ergoreflex activation during upright cycling exercise, whereby VE was higher during the follicular phase than the ovulatory phase in healthy eumenorrheic females. The observed increase in VE during FOL was driven by an elevated VT, which was similarly elevated in the follicular phase compared to the ovulatory phase. However, menstrual phase did not affect ventilatory responses to metaboreflex
Author contributions
MKR, KV, NA-J, DC, and ML conceived and designed research; MKR, KV, NA-J, DC, ML, and EL performed experiments; EL and MKR analyzed data; EL and MKR interpreted results of experiments; EL prepared figures; EL drafted manuscript; EL, MKR, KV, NA-J, DC, and ML revised and edited manuscript; EL, KV, NA-J, DC, ML, and MKR approved final version of manuscript.
Funding
The authors were supported by the National Institutes of Health (NIH) K01 (AG064038-01A1) (MKR) and a University of Minnesota Grant-in Aid (MKR & EL).
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgements
We would like to thank all of the individuals who participated in this study.
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