Respiratory Physiology & Neurobiology 151 (2006) 124131

Does gender affect pulmonary function and exercise capacity?

Craig A. Harms
1A Natatorium, Department of Kinesiology, Kansas State University, Manhattan, KS 66506, USA Accepted 21 October 2005

Abstract It is well established that women exhibit several anatomic and physiologic characteristics that distinguish their responses to exercise from those of men. These factors have been shown to inuence the training response and contribute to lower maximal aerobic power in women. Additionally, the reproductive hormones, estrogen and progesterone, can inuence ventilation, substrate metabolism, thermoregulation, and pulmonary function during exercise. Pulmonary structural and morphologic differences between genders include smaller vital capacity and maximal expiratory ow rates, reduced airway diameter, and a smaller diffusion surface than age- and height-matched men. These differences may have an effect on the integrated ventilatory response, respiratory muscle work, and in pulmonary gas exchange during exercise. Specically, recent evidence suggests that during heavy exercise, women demonstrate greater expiratory ow limitation, an increased work of breathing, and perhaps greater exercise induced arterial hypoxemia compared to men. The consequence of these pulmonary effects has the potential to adversely affect aerobic capacity and exercise tolerance in women. 2005 Elsevier B.V. All rights reserved.
Keywords: Gender; Sex differences; Exercise; Gas exchange; Ventilatory limitations

1. Introduction Participation in regular physical activity is well recognized as having important health benets. As a result of increased awareness and emphasis in physical activity, research investigating the effect of exercise on varThis paper is part of the Special Issue entitled New Directions in Exercise Physiology, guest-edited by Susan Hopkins and Peter D. Wagner. Tel.: +1 785 532 0706; fax: +1 785 532 6486. E-mail address: caharms@ksu.edu. 1569-9048/$ see front matter 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2005.10.010

ious physiologic systems has dramatically increased over the past several decades. However, the vast majority of this research has investigated the physiologic responses in men while comparatively few articles have focused on women or on sex differences. Consequently, research investigating gender on various components of physical performance and on various physiological systems is still evolving. For example, it is known that there are important sex differences with regard to cardiovascular function (Wiebe et al., 1998; Spina et al., 1993), thermoregulation (Stephenson and Kolka, 1985; Grucza et al., 1993), substrate metabolism (Horton et

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al., 1998; Tarnopolsky, 2000; Mittendorfer et al., 2002), and pulmonary function (Harms et al., 1998b; Hopkins et al., 2000; McClaran et al., 1998) during exercise which may have implications for exercise tolerance. Specic in regards to the pulmonary system, there has been considerable interest in dening sex-based differences in the pulmonary systems response to exercise. Important sex differences exist in resting pulmonary function that might have an effect on the integrated ventilatory response, respiratory muscle work, and on gas exchange during exercise which may in turn affect exercise capacity in health.

2. Basis for sex differences in pulmonary function The basis for sex differences in pulmonary function and exercise tolerance is primarily from two sources; namely hormones (especially progesterone and estrogen), and in structural/morphological differences. This review will address the role of each of these mechanisms and how they can affect pulmonary function. 2.1. Hormones Great strides have been made in existing knowledge about the interactions of physical activity with the neuroendocrine reproductive hormones. Much less in known, however, about the effects of specic female steroid hormones on physical performance. Studies to date suggest that there may be subtle physiological variations in vascular volume dynamics, ventilation, thermoregulation, and substrate metabolism throughout the normal menstrual cycle (Lebrun et al., 1995; Lebrun, 1993). With the exception of a possible luteal phase improvement in endurance exercise, there does not appear to be any conclusive evidence of the effects of the menstrual cycle on actual athletic performance (Lebrun et al., 1995; De Souza et al., 1990). The menstrual cycle can affect pulmonary function during exercise primarily through changes in circulating levels of progesterone and estrogen. Progesterone is found in high concentrations in the luteal phase of the menstrual cycle (Dombovy et al., 1987) and during pregnancy. Effects of progesterone on the pulmonary system include hyperventilation (Moore et al.,

1987), a partially compensated respiratory alkalosis (England and Farhi, 1976), and an increase in both the resting hypercapnic ventilatory response (HCVR) and the hypoxic ventilatory response (HVR) (Moore et al., 1987; Schoene et al., 1981). Progesterone also increases central ventilatory drive, which may affect breathing responsiveness during exercise (Dombovy et al., 1987). However, no studies have been able to correlate actual progesterone levels with the alterations in ventilatory responsiveness. An augmented ventilatory drive associated with increased progesterone levels coupled with a reduced airway diameter in women (see below) may contribute to an increased prevalence of expiratory ow limitation during exercise (McClaran et al., 1998). Increased estrogen levels tend to increase uid retention and therefore increase blood volume (Carlberg et al., 1984), which could potentially affect gas exchange in the lung. Sansores et al. (1995) 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 to the late follicular and mid luteal phases. The authors speculate that this difference is likely attributed to changes in pulmonary blood volume. These effects during exercise have not been directly investigated, although our lab has recently shown that pulmonary capillary blood volume and lung diffusing capacity are reduced during high intensity exercise during the early follicular phase of the menstrual cycle compared to the late follicular and mid luteal phases (Brown et al., unpublished). In addition, progesterone and estrogen receptors have recently been identied in mast cells in human airways (Zhao et al., 2001). This discovery may help explain and account for some of the effects of sex hormones in airway function and differences in ventilation. Obviously, the responses of the respiratory system to endogenous variations in the female steroid hormones during the menstrual cycle are extremely complex and are not yet completely understood. 2.2. Morphology Under normal circumstances, for the standard young healthy normally t adult male, it is clear that structural and functional capacity of the pulmonary system, including the lung and chest wall and the supporting

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neural control system, exceeds the demands placed on them for ow rate, volume, and O2 and CO2 exchange (Dempsey, 1986). Women, however, may be an exception as morphological differences in lung structure between sexes have been documented. For example, prediction equations for lung function show a significant sex difference in adults (Crapo et al., 1982). Specically, height-matched men have larger diameter airways (Mead, 1980) and larger lung volumes and diffusion surfaces (Schwartz et al., 1988; Thurlbeck, 1982) compared with postpubertal women. It has been suggested that sex differences in lung diffusing capacity can be explained by fewer total number of alveoli (smaller surface area) and smaller airway diameter relative to lung size in women (lower maximum ow rates), and these differences probably become signicant relatively late in the growth period of the lung (Mead, 1980; Thurlbeck, 1982). Also, adult women consistently have smaller lung volumes and lower maximal expiratory ow rates even when corrected for sitting height relative to men (Crapo et al., 1982). Sitting height or differences in trunk length for the same standing height account for some, but not all, sex differences in lung volumes and maximal expiratory ow rates in teenagers and young adults (Crapo et al., 1982). There does not, however, appear to be a sex difference in the elastic properties of the lungs (Rohrbach et al., 2003) and chest wall or pulmonary compliance (Johnson et al., 1993). Therefore, given these pulmonary structural differences that exist between men and women, and recognizing that physical training sufcient to increase maximal aerobic capacity has no measurable effect on lung function or structure, it could be predicted that women would be more susceptible to pulmonary limitations during exercise compared to men given similar metabolic demands.

does not lead to increased arterial desaturation) and by decreasing the subjective sensation of dyspnea that may be a factor in limiting maximal exercise performance, as well as allowing them to continue exercising despite the onset of hypoxia. However, it is not known whether this decrease is linked to prolonged training or if it is an innate characteristic. It is currently debatable whether or not there is a sex difference in chemosensitivity in the ventilatory response to hypoxia and hypercapnia. It is known that there are sex related differences in HVR that tend to vary with ovarian hormones (Aitken et al., 1986; White et al., 1983). 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 raises both alveolar ventilation and HVR via central (Bayliss and Millhorn, 1992) and peripheral (Tatsumi et al., 1997) receptor-mediated mechanisms. However, Regensteiner et al. (1988) have shown no sex differences in resting HVR or HCVR, although mild exercise did increase HVR in men but not in women. 3.2. Hyperventilation of exercise The hyperventilation of heavy exercise leads to signicant increases in both inspiratory and expiratory muscle work and in both the resistive and elastic work of breathing. Nevertheless, a substantial reserve exists for increases in ventilation in the young to middle aged normal, healthy untrained man, even at maximal exercise (Dempsey et al., 1984). However, the endurance trained man with a higher maximal oxy gen uptake (V O2 max ) and CO2 production, producing a high ventilatory demand, begins to approach the mechanical limits for inspiratory and expiratory pressure and ow development (Johnson et al., 1992). Thus, as the tidal loop begins to intersect the maximal owvolume loop (MFVL), end expiratory lung volume begins to increase in order to permit further increases in ow rate within the MFVL. This relative hyperination results in further increases in the elastic work of breathing, and inspiratory muscle work approaches 8595% of capacity of the inspiratory muscles to produce pressure (Johnson et al., 1992). Expiratory ow limitation in turn causes reex inhibition of the hyperventilatory response (Johnson et al., 1993), constrains ventilation, and increases the work associated with breathing. A

3. Gender and alveolar ventilation 3.1. Gender and chemosensitivity It is currently believed that endurance athletes commonly have altered respiratory drives, with a decreased ventilatory response to hypoxia (HVR) and hypercapnia (HCVR) (Byrne-Quinn et al., 1971; Schoene et al., 1981). Such changes may benet these athletes by allowing less ventilation during exercise (providing it

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Fig. 1. Response to progressive exercise, showing group mean tidal ow-volume loops for less-t (n = 15); (A) and highly t women (n = 14); (B) at rest and during light (55% V O2 max ), moderate (74% V O2 max ), heavy (90% V O2 max ), near-maximal (96% V O2 max ), and maximal exercise plotted relative to group mean maximal voluntary ow-volume loop. VE max , maximal ventilation. Flow limitation is present when expiratory tidal ow-volume loop intersects boundary of volitional maximal ow-volume loop. Data are from McClaran et al. (1998).

greater work of breathing likely leads to more rapid respiratory muscle fatigue (Babcock et al., 1995). Thus, the effects of mechanical constraints of the lung on volumes and maximal expiratory ow rates become very important to control of breathing during high intensity exercise. Because women tend to show reduced airway diameter compared to men (see above), women are more likely to show greater mechanical limits to expiratory ow creating a smaller maximal ow:volume envelope compared to men (McClaran et al., 1998). Fig. 1 shows ensemble averaged tidal ow:volume loops for rest through maximal exercise in highly t and less-t women. This gure demonstrates that the combination of increased ventilatory demand with airways vulnerable to closure in women likely leads to signicant expiratory ow limitation sooner (i.e., at a lower VE O2 ) than their 70100 l/min) and at a much lower V male contemporaries. As a result, women would probably show increased hyperination, marked increases in both the elastic and ow resistive work of breathing, and dyspnea at a given VE compared to the average man. Also, it would be expected that women would experience a lack of substantial hyperventilation at a V O2 (and V CO2 ) that men would typically would not. As a consequence of greater EFL, the active healthy female may be especially vulnerable to high fatiguing

levels of the work of breathing during heavy exer cise. During exercise at intensities >80% V O2 max of sustained exercise, the diaphragm consistently shows fatigue at end-exercise, as demonstrated using bilateral phrenic nerve stimulation (Johnson et al., 1993). An important consequence of high levels of respiratory muscle work and respiratory muscle fatigue is vasoconstriction and reduction in blood ow to the working locomotor muscles, accompanied by changes in vascular resistance (Harms et al., 1997, 1998a) which can compromise exercise tolerance (Harms et al., 2000a). Therefore, it is likely, although not yet proven, that respiratory muscle fatigue would be more readily incurred during heavy exercise in women versus men and women would perhaps show a greater distribution of blood ow from the respiratory muscles to the locomotor muscles than men.

4. Gender and gas exchange Sufcient studies in young adult men have been conducted to document clearly that untrained subjects normally widen their A-aDO2 two- to three-fold from rest to maximal exercise, and that they also hyperventilate, which raises alveolar PO2 sufciently during strenuous exercise to prevent PaO2 from falling below

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resting levels. However, a signicant reduction in the arterial partial pressure of oxygen (PaO2 ) (<90 mmHg) during heavy exercise, termed exercise induced arterial hypoxemia (EIAH) has been well documented in some t adult men over the past several decades (Dempsey and Wagner, 1999; Harms and Stager, 1995; Dempsey et al., 1984). The cause of EIAH is believed to be due to an excessive widening of the alveolar arterial oxygen difference, an insufcient hyperventilatory response (Dempsey and Wagner, 1999), and to a lesser extent, intrapulmonary arteriovenous shunts (Eldridge et al., 2004). Evidence suggests that even mild EIAH can have a signicant detrimental effect on limiting O2 transport during heavy exercise (Harms et al., 2000b; Powers et al., 1989). Gas exchange limitations are more common in those individuals capable of a high level of aerobic work. Given gender-based pulmonary structural differences that exist between men and women (see above), it is tempting to propose that women are more susceptible to EIAH than men. To date, there are few published temperature corrected arterial blood gas data directly comparing pulmonary gas exchange between genders. A recent review has discussed in detail gender and pulmonary gas exchange during exercise (Hopkins and Harms, 2004). From this review, data in Fig. 2 compiled from previously published studies (Dempsey et al., 1984; Harms et al., 1998b; Hopkins et al., 2000; Hopkins et al., 1994; Olfert et al., 2004; Rice et al., 1999) in 57 women (V O2 max 3270 ml/kg/min) and 135 men (V O2 max 3083 ml/kg/min) show that the slope of the relationship of the A-aDO2 V O2 relationship during heavy to maximal exercise is greater in women than men. From these data, 12% of the women with a V O2 max of less than 50 ml/kg/min had evidence of gas exchange impairment. For men of the same tness level, less than 2% have evidence of gas exchange impairment. These differences in gas exchange are reected in the PaO2 data and women have a greater negative slope of the PaO2 /V O2 relationship than do men. Approximately 10% of women with a V O2 max less than 50 ml/kg/min had a PaO2 of less than 90 mmHg during heavy and maximal exercise compared to less than 2% of the men. It should be kept in mind that when lung size and tness level are controlled for, many of the gas exchange differences between genders seem to be lost. These data suggest that women may be more susceptible to gas exchange

Fig. 2. Gender differences in arterial blood gases during exercise at 90100% of V O2 max . Closed symbols are data from women, open symbols are data from men. Circles are cycle data, squares are running data. Faint dotted line represents level at which impairment is suggested to occur (see text for details). The A-aDO2 (A) is increased and the PaO2 (B) is less in women compared to men at any level of V O2 . However, alveolar ventilation is not reduced in women compared to men, as the PaCO2 if anything, is lower in women at any given VO2 . Data from Dempsey et al. (1984); Harms et al. (1998b); Hopkins et al. (2000); Hopkins et al. (1994); Olfert et al. (2004); Rice et al. (1999).

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impairments than men, although there is a need for more descriptive data in women to be certain. Clearly, more testing is needed to determine: (a) the prevalence of EIAH among the normal population of women; (b) if women are more susceptible to EIAH than men; and (c) the mechanisms responsible for the EIAH.

capacity. In particular, a greater ventilatory work associated with increased expiratory ow limitation during exercise and gas exchange impairments seem to be of primary concern. It should be emphasized, however, that the amount of literature investigating these issues is limited. Certainly, much more research is needed to substantiate these ideas.

5. Aging Healthy aging causes reductions in lung elastic recoil, vital capacity, diffusion surface area, and chest wall compliance. Accordingly, in highly t elderly individuals, signicant expiratory ow limitation with an accompanying increase in the EELV and increased ventilatory work begins during submaximal exercise at VE values in the 7080 l/min range (Johnson et al., 1991). Furthermore, longitudinal studies shows that habitual physical activity does not alleviate the normal age related reduction in the maximal ow:volume envelope and increased lung volume at airway closure throughout the latter stages of life (McClaran et al., 1995). Exercise induced arterial hypoxemia also occurs in the highly t elderly persons at V O2 max values in the 4060 ml/kg/min range (1.52.5 times age predicted normal V O2 max values), but the prevalence of hypoxemia is less than in younger highly t males at much higher V O2 max values (Johnson et al., 1994). Apparently then in most t, healthy subjects the age related decline in V O2 max and in pulmonary O2 transport capacity are similar. Given the gender effects on lung structure and function in young adults, aging females might be even more susceptible to pulmonary limitations in exercise performance. References
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