Sex differences exist in pulmonary structure and resting pulmonary function that may affect airway responsiveness, ventilation, and gas exchange during exercise. It has been known for some time that adult women consistently have lower resting lung diffusing capacity ([Hb] corrected), smaller lung volumes, and lower maximal expiratory flow rates, even when corrected for age and standing height relative to men (30,41). Women have also been reported to have significantly smaller lung volumes and lower maximal expiratory flow rates compared with predicted values for men at the same age and standing height (8,15). It has been suggested that these sex differences in part can be explained by fewer total number of alveoli (smaller surface area) and smaller airway diameter relative to lung size in women (lower maximum flow rates), and these differences probably become significant relatively late in the growth period of the lung. Unfortunately, the majority of research investigating pulmonary sex differences in the literature has suffered from inappropriate research design. Specifically, these include not controlling for lung size, menstrual cycle phase, and aerobic capacity. Each of these factors has been shown to contribute to sex differences. Nevertheless, given these pulmonary structural differences that exist between men and women, women may be more likely to have ventilatory limitations and gas-exchange disturbances during exercise compared with men with similar metabolic demand. This brief review will address current knowledge regarding pulmonary sex differences during exercise in healthy subjects in ventilatory differences, with an emphasis on airway hyperresponsiveness and expiratory flow limitation, and in gas exchange.
AIRWAY FUNCTION AND VENTILATION
It is currently debatable whether there is a sex difference in chemosensitivity in the ventilatory response to hypoxia and hypercapnia (1,14,46). What is known is that there are sex-related differences in hypoxic ventilatory response (HVR) that tend to vary with ovarian hormones (1,38,43). Effects of progesterone on the pulmonary system include hyperventilation (34), a partially compensated respiratory alkalosis (13,33), and an increase in both the resting hypercapnic ventilatory response (HCVR) and the HVR (34,39). Progesterone also increases central ventilatory drive, which may affect breathing responsiveness during exercise (39). It has been suggested that the endogenous surge of progesterone during the menstrual cycle may exert a deleterious effect on performance through alterations in these respiratory drives. Progesterone and estrogen raise both alveolar ventilation and HVR via central (3) and peripheral (40) receptor-mediated mechanisms. However, Regensteiner et al. (35) have shown no sex differences in resting HVR or HCVR, although mild exercise did increase HVR in men but not in women. Guenette et al. (14) also found no difference in HVR between trained or untrained men and women. In general, therefore, it seems that chemosensitivity tends to fluctuate with changes in ovarian hormones, which may contribute to differences between sexes.
Expiratory Flow Limitation.
Because women tend to show reduced airway diameter compared with men, women are more likely to experience greater mechanical limits to expiratory flow, creating a smaller maximal flow:volume envelope compared with that of men (25,29). Also, an increased ventilatory drive associated with increased progesterone levels during the luteal phase of the menstrual cycle, coupled with this reduced airway diameter in women, may further contribute to an increased prevalence of expiratory flow limitation during exercise (29). Figure 1 shows ensemble-averaged tidal flow:volume loops for rest through maximal exercise in highly fit and less-fit women and for similarly aged men. This figure demonstrates that the combination of increased ventilatory demand with airways vulnerable to closure in women likely leads to significant expiratory flow limitation sooner (i.e., at a lower V˙E (70-100 L·min−1) and at a much lower V˙O2) than their male contemporaries. As a result, an interesting postulate is that a woman would show increased hyperinflation, marked increases in both the elastic and flow resistive work of breathing, and dyspnea at a given V˙E compared with the comparable man (29). Also, it would be expected that women would experience a lack of substantial hyperventilation at a V˙O2 (and V˙CO2) that men typically would not. Recent evidence in our lab (unpublished) and well as from Guenette et al. (15) has confirmed greater expiratory flow limitation and increased end-expiratory and inspiratory lung volumes in women at end exercise, which led to increased work of breathing.
As a consequence of greater expiratory flow limitation, the active healthy female may be especially vulnerable to high fatiguing levels of the work of breathing during heavy exercise (26). During exercise at intensities > 80% V˙O2max of sustained exercise, the diaphragm consistently shows fatigue at end exercise (2,26). An important consequence of high levels of respiratory muscle work and respiratory muscle fatigue is vasoconstriction and reduction in blood flow to the working locomotor muscles, accompanied by changes in vascular resistance (17,18), which can compromise exercise tolerance (21). Therefore, it is likely, although not yet established, that respiratory muscle fatigue would be more readily incurred during heavy exercise in women versus men, and that women would perhaps show a greater distribution of blood flow from the respiratory muscles to the locomotor muscles than would men. Presumably, these effects would be even greater in conditions with an increased work of breathing, such as aging, pulmonary disease, and altitude.
Airway Hyperresponsiveness and Inflammation.
Prevalence statistics indicate that after puberty, women consistently have higher rates of asthma and exercise-induced asthma than men (12). Airway hyperresponsiveness (AHR) is a hallmark symptom of asthma. Nonasthmatic female adults seem to have more severe AHR than nonasthmatic male adults, which may contribute to the increased prevalence later in life (12). Some evidence shows that nonasthmatics who have AHR are more at risk for development of chronic obstructive pulmonary disease later in life (28). Greater AHR in women, however, apparently is not attributable to their having smaller lung size or airway size than men, although this theory remains somewhat controversial and may be related in part to smoking trends (28).
Why is there greater airway hyperresponsiveness in women? Many studies have focused on hormones as a possible contributor for changes in AHR prevalence and severity over time. Progesterone and estrogen receptors have recently been identified in mast cells in human airways (49). These findings may help explain and account for some of the effects of sex hormones in airway function and differences in ventilation throughout the menstrual cycle. Also, approximately 25% of females in the reproductive phase of their lives have perimenstrual aggravation of asthmalike symptoms, indicating that estrogen levels may contribute to inflammatory changes in the airways (12). One possible mechanism includes increased adherence of eosinophils to airway endothelial cells. Potentially, estrogen may enhance eosinophil function and accelerate allergic inflammation. Estrogen is known to suppress T-cell-mediated immune responses and enhance B-cell-mediated immune responses, whereas androgens suppress both types of immune reactions (22). Estrogen acts via estrogen receptor alpha (ESR 1) and ß. Evidence supports the possibility of increased asthma prevalence and severity, as ESR 1 polymorphisms have been linked with other inflammatory diseases such as coronary heart disease and rheumatoid arthritis (12). Estradiol is also thought to affect the concentration of ACH, the quality of mucus secretion, the production or prostaglandins, and the density of ß1- and ß2-adrenergic receptors in the lung (4).
Exhaled NO (eNO) is also used as a marker of airway inflammation (42). eNO values are significantly higher in asthmatics than in nonasthmatics, and its level correlates with markers of disease such as airway eosinophilic infiltration and hyperresponsiveness (27,42). Chimenti et al. (7) also have shown an increase in inflammatory cells in small airways, but not in active inflammation of mice. Research shows that levels of peak eNO are about 50% higher in men than in women (42). Additionally, levels of eNO have been shown to fluctuate with a woman's menstrual cycle. In nonasthmatic women, during the premenstrual or perimenstrual phases, eNO values tend to be about half those seen at midcycle (4). Interestingly, Bonsignore et al. (5) report that in nonasthmatic, middle-aged runners, eNO was higher after running a marathon than at baseline. Additionally, polymorphonuclear neutrophil counts in induced sputum were higher in runners than in sedentary controls, showing the association of eNO with other inflammatory markers. Monci et al. (32) have shown that intense exercise will produce increased total cell and bronchial epithelial cell counts. This increase is in direct response to increased V˙E. Finally, Wetter et al. (45) have demonstrated that airway inflammation was of insufficient magnitude to cause impairments in gas exchange and did not seem to be linked to hypoxemia in young athletes. Collectively, these studies are inconclusive concerning sex differences in exercise-induced airway inflammation. Clearly, future research should examine the link between airway inflammation/hyperresponsiveness on gas exchange and exercise performance between sexes.
Exercise-induced arterial hypoxemia (EIAH) is well documented in both men and women (9-11,16,19,20,23,24,34). To date however, there are few published, temperature-corrected arterial blood gas data directly comparing pulmonary gas exchange (i.e., PA-PaO2 difference) between sexes. Therefore, it is not known whether women demonstrate greater EIAH than men, or whether similar mechanisms are responsible for the EIAH for both sexes, because previous studies have been conflicting (19,23,36,43,44), perhaps because of menstrual cycle differences. A recent review has discussed in detail sex and pulmonary gas exchange during exercise (24). Future comparisons in gas exchange between sexes should control for lung size and fitness level, as both of these factors may influence reported differences.
Increased fluid retention and blood volume associated with increased estrogen levels (6) may affect gas exchange in the lung. That is, increased blood volume would likely increase pulmonary artery pressure, which would increase capillary surface area and, therefore, increase pulmonary diffusion. However, an argument could be made that elevated pulmonary artery pressures may cause edema and a deterioration in gas exchange, although this has never been determined. Sansores et al. (37) have demonstrated that resting diffusing capacity (DLCO) is reduced during the early follicular phase of the menstrual cycle (when progesterone and estrogen levels are low) compared with the late follicular and midluteal phases, although pulmonary capillary blood volume did not change. These effects during exercise to date have not been directly investigated, although Zavorsky et al. (47,48) have recently shown that intense interval training can create mild pulmonary edema in women. However, it was determined that the edema was not related to a decrement in gas exchange (48). It is not known whether men showed a similar response, because these studies did not use a male control group. Although it is an intriguing hypothesis that women might be more susceptible to gas-exchange impairments than men, there is a need for more descriptive data in women to be certain. Future research should look to determine (a) the prevalence of EIAH among the normal population of women, (b) whether women are more susceptible to EIAH than men, and (c) the mechanisms responsible for the EIAH.
Research investigating sex differences on various components of physical activity and on various physiological systems is still evolving. There has been considerable interest in recent years in defining sex-based differences in the pulmonary system's response to exercise. In particular, women have pulmonary structural differences and hormonal influences that may lead to greater airway hyperresponsiveness, expiratory flow limitation, and gas-exchange disturbances than men, although future studies are certainly needed to confirm this. In turn, these effects may place women at a greater disadvantage regarding exercise response compared with men.
The authors wish to express their appreciation to the American College of Sports Medicine for the Integrative Physiology of Exercise conference held in September 2006. Special thanks goes to Dr. Susan Hopkins, who organized the symposium where the majority of these data were presented.
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