Sex as a biological variable in exercise prescription: a critical consideration in developing a road map for sex-related differences in cardiovascular research

BACKGROUND AND STUDY OVERVIEW

Regular engagement in endurance and resistance training has long been recommended as the cornerstone of a lifestyle intended to foster the prevention and treatment of cardiovascular and metabolic diseases. However, there is an increasing recognition that exercise prescription is not a “one size fits all” regime. Indeed, there is emerging evidence of potential sex-related differences in the physiological responses to exercise (1). Therefore, additional investigation into exercise training-induced changes in biomarkers of cardiovascular health in males and females is warranted, as an improved understanding of this aspect of physiology may represent a critical step toward optimizing personally tailored exercise prescription that would lead to better health outcomes for both sexes. In this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Thomas et al. (2) sought to elucidate whether males and females exhibited similar changes in traditional cardiovascular risk factors following 12 wk of endurance and resistance training and whether the degree of responses, as well as the frequency of responders following each training modality, differed between males and females. To address these interesting and important research questions, Thomas et al. (2) employed a randomized crossover study design, whereby 68 participants engaged in center-based, supervised exercise interventions for 12 wk, separated by a 12-wk washout period between each training modality. In addition to this rigorous study design, an exceptionally novel aspect of the study by Thomas et al. (2) was the recruitment of only participants who were monozygotic and same-sex dizygotic twin pairs, which serves to help reduce variability in findings that may be due to heritability-related issues. From the study design standpoint, the authors should be commended for their excellent effort in conducting a high-caliber investigation that is clinically significant and timely and contributes to the recent effort to enhance rigor, reproducibility, and inclusivity in cardiovascular research by considering sex as a biological variable (3).

The study by Thomas et al. (2) documented an improvement in exercise capacity, assessed as peak oxygen uptake (V̇o_2peak), following endurance, but not resistance training in both sexes. The degree of improvement (i.e., a change from baseline) appeared to be numerically higher in male volunteers compared with female volunteers when V̇o_2peak was expressed in an absolute unit (L/min) (P = 0.051), but not when expressed relative to body weight (mL/min/kg) (2). Strength, determined as one repetition maximum during bench and leg press, also increased in both sexes, but only in response to resistance training, with a greater degree of increase in male volunteers (2). In separate analyses, sex-related differences in training-induced changes in exercise capacity and strength disappeared when accounting for group differences in baseline values, though the frequency of responders versus nonresponders was unaffected (2). Using dual X-ray absorptiometry scans, Thomas et al. (2) observed that resistance training increased lean mass without any changes in fat mass in both sexes, which were accompanied by slight increases in body weight and body mass index (BMI). In contrast, endurance training increased lean mass in male volunteers and decreased fat mass in female volunteers, though the degree of responses was not different between sexes and without changes in body weight or BMI (2). Taken together, despite slight variations in training-induced changes in body composition, these findings suggest that 1) both endurance and resistance training were efficacious in improving physical fitness (as assessed by both exercise capacity and strength) in males and females, 2) both males and females were equally responsive to both training modalities, and 3) the degree of improvement was related to baseline values and not biological sex. These findings are clinically important, as changes in physical fitness are an independent predictor of improvements in traditional cardiovascular risk factors, regardless of changes in body weight (4). Furthermore, given a higher risk of incident cardiovascular diseases in females with advancing age (5), the finding of similar efficacy and frequency of responders in males and females following both training modalities highlights the usefulness of these exercise prescriptions as a preventative lifestyle strategy to improve physical fitness and potentially reduce the risk of incident cardiovascular diseases in females.

Interestingly, despite improvements in exercise capacity and strength, Thomas et al. (2) documented that several other traditional cardiovascular risk biomarkers (i.e., waist and hip circumferences, brachial blood pressure, blood lipid profiles, glucose, and homeostatic model of assessment for insulin resistance) did not improve following either training modality. The only two variables that responded to exercise training were resting heart rate and proinflammatory cytokine C-reactive protein (CRP), such that resting heart rate was reduced in both sexes while CRP concentrations were reduced in females and increased in males following endurance training, though without any group differences in the degree of responses or frequency of responders (2). The lack of improvements in these cardiovascular risk factors is not surprising, as the participants were young, healthy adults without evidence of existing cardiovascular disease. In fact, it is noteworthy that the cardioprotective benefits of exercise training extend far beyond changes in traditional cardiovascular risk factors and may manifest as training-induced improvements in endothelial function and sympathetic nervous system activity, which are independent predictors of morbidity and mortality (6). Indeed, using a cross-sectional study design, DeSouza et al. (7) documented that an age-related decline in endothelial function, assessed via acetylcholine-mediated forearm vasodilation, was not evident in older males who engaged in regular endurance exercise (7). Interestingly, while Grassi et al. (8) have reported attenuated muscle sympathetic nerve activity (MSNA) in young adults following 10 wk of endurance training (i.e., long-distance running for 2 h; 5 days/wk), Sheldahl et al. (9) observed no such changes in MSNA following 12 wk of high-intensity endurance training (i.e., 40 min of treadmill running and cycling at 70%–85% of heart rate reserve; 3 times/wk) in middle-aged and older males. Given that there remains a significant knowledge gap regarding sex-related differences in vascular and autonomic responses to different exercise training modalities in different age groups (1), findings from Thomas et al. (2) set the stage for important future studies to focus on this aspect of physiology to better improve our understanding of sex-related differences and exercise training in cardiovascular research.

In addition, recent findings from Iannetta et al. (10) have suggested that contemporary exercise prescription, which is based on fixed percentages of V̇o_2peak, peak work rate, or peak heart rate, may not adequately control for the metabolic stimulus that is critical for subsequent training-induced adaptations. Instead, prescribing exercise intensity based on a well-established and underused “domain” schema (i.e., moderate, heavy, and severe) may represent an ideal metabolic stimulus that takes into consideration the lactate threshold and the critical power, whose changes coincide with the VO₂ kinetics response to step increases in exercise work rate (10). Given that Thomas et al. (2) used fixed percentages of V̇o_2peak progressing from 60% to 90% and that V̇o_2peak was lower in females compared with males at baseline, some questions remain as to whether both males and females experienced similar levels of metabolic stimulus based on the domain schema and whether an improvement in cardiovascular risk factors following endurance training may be observed if the participants were matched on domains of training intensity. Thus, another future direction for research in this area may compare the efficacy of different methods of exercise prescription (i.e., fixed percentages vs. domains of intensity) to improve V̇o_2peak and induce positive physiological adaptations in males and females (1). However, whether a similar dogma related to domains of intensity exists for resistance exercise training remains to be elucidated and may also explain, at least in part, the sex-related differences in strength gains documented in the study by Thomas et al. (2), thereby also warranting future studies in this important area of cardiovascular research.

In summary, Thomas et al. (2) should be highly commended for their contribution toward a better understanding of sex as a biological variable in cardiovascular research. Their work, which incorporated a rigorous study design, marks significant milestones and paves the way for exciting future research in this area of physiology that may serve to enhance our understanding of sex-related differences in physiological responses to exercise training as well as identifying potential exercise prescriptions that are geared toward optimizing cardiovascular health in women.

GRANTS

This work was funded, in part, by the U.S. Department of Veterans Affairs Grants IK2RX003670 (to K.B.) and E6910-R, E1697-R, E3207-R, E9275-L, and E1572-P (to R.S.R.).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

K.B. and R.S.R. conceived and designed research; drafted manuscript; edited and revised manuscript; approved final version of manuscript.