Commentaries on Point:Counterpoint: Investigators should/should not control for menstrual cycle phase when performing studies of vascular control
2020; American Physiological Society; Volume: 129; Issue: 5 Linguagem: Inglês
10.1152/japplphysiol.00809.2020
ISSN8750-7587
Tópico(s)Hormonal and reproductive studies
ResumoPoint-CounterpointCommentaries on Point:Counterpoint: Investigators should/should not control for menstrual cycle phase when performing studies of vascular controlPublished Online:16 Nov 2020https://doi.org/10.1152/japplphysiol.00809.2020MoreSectionsPDF (350 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat COMMENTARY ON POINT:COUNTERPOINT: INVESTIGATORS SHOULD CONTROL FOR MENSTRUAL CYCLE PHASE WHEN PERFORMING STUDIES OF VASCULAR CONTROL—WHEN POSSIBLEGabrielle E. W. Giersch12 and Nisha Charkoudian1.Author Affiliations1Thermal and Mountain Medicine Division, United States Army Research Institute for Environmental Medicine, Natick, Massachusetts.2Oak Ridge Institute for Science and Education, Oak Ridge, Tennnessee.to the editor: We were delighted to read the recent Point:Counterpoint debate published in the Journal of Applied Physiology. Both Wenner and Stachenfeld (5) and Stanhewicz and Wong (4) provided important insight and, on the surface, opposing perspectives regarding study design with respect to menstrual cycle control when studying women. While both groups made excellent points, we would like to raise two important considerations to add to this discussion. First, the research question itself should be paramount in the determination of whether or not menstrual cycle is controlled. Second, in the context of the question being addressed, is the feasibility in controlling for menstrual cycle. Certainly a population-based study of blood pressure involving thousands of humans would represent a much bigger challenge if it was attempted while controlling for menstrual cycle phase. This might dissuade some investigators from even including women in such a study if menstrual cycle were to be controlled. Additionally, focusing on only one phase in such a study might give erroneous information about women in other phases.However, Wenner and Stachenfeld (5) are correct that, when possible, we should always control for ovarian hormone concentrations and menstrual cycle phase in order to ascertain their effects and continue to inform future research. This is particularly important because currently, we don’t have a thorough understanding of the direct and indirect influences of ovarian hormones. If we ignore hormone status completely, it is possible that our research findings would be inaccurate for certain phases or hormone levels, leaving women in certain phases just as vulnerable as we were decades ago with respect to research results regarding our cardiovascular health.Large-scale field studies of occupational activities (such as military basic training) are an example where investigators may not be able to control for hormone status, but could measure ovarian hormone levels to allow for applicability and greater external validity. Estradiol and progesterone appear to play an important role in vascular control as it relates to thermoregulation, for example (1–3). Thus having some information about hormonal status could be an important covariate in evaluation of thermoregulatory responses (or risk of heat illness) in military basic training, if actual measurements during each phase or hormonal status was not possible. Whenever possible, reproductive hormones should be controlled and measured in order to increase our understanding of their effects on physiological mechanisms. But in some settings, if the only options are to 1) include women without controlling for hormone status, or 2) exclude women, we should always include women.Importantly, advocating for control of the menstrual cycle and direct investigation of it, is not advocating for restricting research of women to the early follicular phase or the placebo phase in oral contraceptive users. As Stanhewicz and Wong (4) suggest, this limits the applicability of the findings and drastically reduces external validity. Rather, researchers should seek to investigate specific phases and variability among them systematically. Understanding the hormonal variations across the menstrual cycle and their impact on physiological function is central to understanding how women differ from men.We cannot currently say that the effect of ovarian hormones on vascular function is unequivocal or that the variability produced by ignoring the fluctuations of these hormones will not wash out potential differences. Our challenge as human integrative physiologists is to balance both aspects of this debate, by continuing to investigate and control for influences of reproductive hormones in some settings, but also not limiting our ability to perform studies or the external validity of our results (in others). The ultimate decision regarding which category a given study falls into will lie with each investigator–so we have to continue to educate our trainees on the importance of both sides of this debate. The wide fluctuations in endogenous ovarian hormones are part of what make women, women, and as researchers we can neither ignore those fluctuations, nor allow them to compromise our ability to conduct meaningful research about integrative cardiovascular control in women.DISCLAIMERSThe views, opinions, and/or findings contained in this article are those of the authors and should not be construed as an official United States Department of the Army position, or decision, unless so designated by other official documentation. Approved for public release; distribution unlimited. Citations of commercial organizations and trade names in this report do not constitute an official Department of the Army endorsement or approval of the products or services of these organizations.REFERENCES1. Charkoudian N. Skin blood flow in adult human thermoregulation: how it works, when it does not, and why. Mayo Clin Proc 78: 603–612, 2003. doi:10.4065/78.5.603. Crossref | PubMed | ISI | Google Scholar2. Charkoudian N, Hart ECJ, Barnes JN, Joyner MJ. Autonomic control of body temperature and blood pressure: influences of female sex hormones. Clin Auton Res 27: 149–155, 2017. doi:10.1007/s10286-017-0420-z. Crossref | PubMed | ISI | Google Scholar3. Kolka MA, Stephenson LA. Effect of luteal phase elevation in core temperature on forearm blood flow during exercise. J Appl Physiol (1985) 82: 1079–1083, 1997. doi:10.1152/jappl.1997.82.4.1079. Link | ISI | Google Scholar4. Stanhewicz AE, Wong BJ. Counterpoint: Investigators should not control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00427.2020. Link | ISI | Google Scholar5. Wenner MM, Stachenfeld NS. Point: Investigators should control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00443.2020. Link | ISI | Google ScholarREFERENCES1. Charkoudian N. Skin blood flow in adult human thermoregulation: how it works, when it does not, and why. Mayo Clin Proc 78: 603–612, 2003. doi:10.4065/78.5.603. Crossref | PubMed | ISI | Google Scholar2. Charkoudian N, Hart ECJ, Barnes JN, Joyner MJ. Autonomic control of body temperature and blood pressure: influences of female sex hormones. Clin Auton Res 27: 149–155, 2017. doi:10.1007/s10286-017-0420-z. Crossref | PubMed | ISI | Google Scholar3. Kolka MA, Stephenson LA. Effect of luteal phase elevation in core temperature on forearm blood flow during exercise. J Appl Physiol (1985) 82: 1079–1083, 1997. doi:10.1152/jappl.1997.82.4.1079. Link | ISI | Google Scholar4. Stanhewicz AE, Wong BJ. Counterpoint: Investigators should not control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00427.2020. Link | ISI | Google Scholar5. Wenner MM, Stachenfeld NS. Point: Investigators should control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00443.2020. Link | ISI | Google ScholarCOMMENTARY ON POINT:COUNTERPOINT: INVESTIGATORS SHOULD/SHOULD NOT CONTROL FOR MENSTRUAL CYCLE PHASE WHEN PERFORMING STUDIES OF VASCULAR CONTROL THAT INCLUDE WOMENT. Pereira and H. Edgell.Author AffiliationsSchool of Kinesiology and Health Sciences, York University, Toronto, Ontario, Canada.to the editor: Many more foundational studies are needed before combining the menstrual phases in vascular studies. There is an overwhelming body of literature which has found physiological influences of estrogen and/or progesterone, and therefore the possibility always exists that when women are studied in a particular phase (e.g., luteal phase), they might have a different response compared with other phases (e.g., follicular/ovulatory phases). Further, it is important to consider concentrations of estrogen, progesterone, and their ratio as these hormones often have opposing effects (3, 5). Until proven that there is no effect on a particular response, the menstrual cycle should be considered for all physiological studies as suggested by Wenner and Stachenfeld (5). For example, Hazlett and Edgell recently found that women in the luteal phase have higher ventilation compared with the early follicular phase; however, the cardiovascular and cerebrovascular responses to tilt were the same between the phases (1). Therefore, we suggest that in future studies concerning the cardiovascular (but not respiratory) responses to tilt, women could be combined in a group consisting of both the early follicular and luteal phases. Similarly, Jarvis et al. found that women in the early follicular and luteal phases have similar hemodynamic and sympathetic responses to circulatory occlusion after handgrip exercise (2), suggesting that women in these two phases could now be combined in future metaboreflex studies. Once it has been determined that menstrual phase is not a contributing variable, only then should women be combined at all timepoints as suggested by Stanhewicz and Wong (4).REFERENCES1. Hazlett C, Edgell H. Chemoreflex function and brain blood flow during upright posture in men and women. Physiol Rep 6: e13571, 2018. doi:10.14814/phy2.13571. Crossref | PubMed | ISI | Google Scholar2. Jarvis SS, VanGundy TB, Galbreath MM, Shibata S, Okazaki K, Reelick MF, Levine BD, Fu Q. Sex differences in the modulation of vasomotor sympathetic outflow during static handgrip exercise in healthy young humans. Am J Physiol Regul Integr Comp Physiol 301: R193–R200, 2011. doi:10.1152/ajpregu.00562.2010. Link | ISI | Google Scholar3. Oosthuyse T, Bosch AN. The effect of the menstrual cycle on exercise metabolism: implications for exercise performance in eumenorrhoeic women. Sports Med 40: 207–227, 2010. doi:10.2165/11317090-000000000-00000. Crossref | PubMed | ISI | Google Scholar4. Stanhewicz AE, Wong BJ. Counterpoint: Investigators should not control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00427.2020. Link | ISI | Google Scholar5. Wenner MM, Stachenfeld NS. Point: Investigators should control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00443.2020. Link | ISI | Google ScholarREFERENCES1. Hazlett C, Edgell H. Chemoreflex function and brain blood flow during upright posture in men and women. Physiol Rep 6: e13571, 2018. doi:10.14814/phy2.13571. Crossref | PubMed | ISI | Google Scholar2. Jarvis SS, VanGundy TB, Galbreath MM, Shibata S, Okazaki K, Reelick MF, Levine BD, Fu Q. Sex differences in the modulation of vasomotor sympathetic outflow during static handgrip exercise in healthy young humans. Am J Physiol Regul Integr Comp Physiol 301: R193–R200, 2011. doi:10.1152/ajpregu.00562.2010. Link | ISI | Google Scholar3. Oosthuyse T, Bosch AN. The effect of the menstrual cycle on exercise metabolism: implications for exercise performance in eumenorrhoeic women. Sports Med 40: 207–227, 2010. doi:10.2165/11317090-000000000-00000. Crossref | PubMed | ISI | Google Scholar4. Stanhewicz AE, Wong BJ. Counterpoint: Investigators should not control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00427.2020. Link | ISI | Google Scholar5. Wenner MM, Stachenfeld NS. Point: Investigators should control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00443.2020. Link | ISI | Google ScholarCOMMENTARY ON POINT:COUNTERPOINT: INVESTIGATORS SHOULD/SHOULD NOT CONTROL FOR MENSTRUAL CYCLE PHASE WHEN PERFORMING STUDIES OF VASCULAR CONTROL THAT INCLUDE WOMENKaitlin A. Freeberg and Daniel H. Craighead.Author AffiliationsDepartment of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado.to the editor: The recent Point:Counterpoint series (3–6) provided an excellent debate on whether or not to control for menstrual cycle phase when studying vascular control. The discussion emphasized the need for rigorous study designs which balance reducing variability with increasing generalizability. We wish to highlight the importance of assessing vascular function at multiple time points across the menstrual cycle, not only for determining physiological differences between sexes but also to understand how vascular function changes in women throughout the lifespan. Indeed, characterizing vascular control throughout the menstrual cycle is needed to elucidate the changes in vascular function and associated mechanisms which link menopause to increased risk of cardiovascular diseases (2). For example, estrogen receptor-alpha (ERα) expression, a key determinant of vascular function, is 30% lower during the early (EF) versus late follicular (LF) phase (1). Moreover, ERα expression in estrogen-deficient postmenopausal women is equivalent to the EF phase and 33% lower than the LF phase of premenopausal women (1). Despite the general notion that premenopausal women are estrogen-replete, the above findings highlight that 1) modulators of vascular control in premenopausal women cannot be assumed to be superior compared with estrogen-deficient postmenopausal women across the entire menstrual cycle; and 2) testing premenopausal women only during the low-estrogen EF phase may bias the interpretation of vascular aging studies in women. This example highlights the need to assess vascular function across the entire menstrual cycle to enhance our understanding of healthy premenopausal women and the changes in vascular control that occur across the female lifespan.REFERENCES1. Gavin KM, Seals DR, Silver AE, Moreau KL. Vascular endothelial estrogen receptor alpha is modulated by estrogen status and related to endothelial function and endothelial nitric oxide synthase in healthy women. J Clin Endocrinol Metab 94: 3513–3520, 2009. doi:10.1210/jc.2009-0278. Crossref | PubMed | ISI | Google Scholar2. Moreau KL, Hildreth KL. Vascular aging across the menopause transition in healthy women. Adv Vasc Med 2014: 204390, 2014. doi:10.1155/2014/204390. Crossref | PubMed | Google Scholar3. Stanhewicz AE, Wong BJ. Counterpoint: Investigators should not control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00427.2020. Link | ISI | Google Scholar4. Stanhewicz AE, Wong BJ. Rebuttal to Drs. Wenner and Stachenfeld. J Appl Physiol (1985). doi:10.1152/japplphysiol.00621.2020. Link | ISI | Google Scholar5. Wenner MM, Stachenfeld NS. Point: Investigators should control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00443.2020. Link | ISI | Google Scholar6. Wenner MM, Stachenfeld NS. Rebuttal to Drs. Stanhewicz and Wong. J Appl Physiol (1985). doi:10.1152/japplphysiol.00620.2020. Link | ISI | Google ScholarREFERENCES1. Gavin KM, Seals DR, Silver AE, Moreau KL. Vascular endothelial estrogen receptor alpha is modulated by estrogen status and related to endothelial function and endothelial nitric oxide synthase in healthy women. J Clin Endocrinol Metab 94: 3513–3520, 2009. doi:10.1210/jc.2009-0278. Crossref | PubMed | ISI | Google Scholar2. Moreau KL, Hildreth KL. Vascular aging across the menopause transition in healthy women. Adv Vasc Med 2014: 204390, 2014. doi:10.1155/2014/204390. Crossref | PubMed | Google Scholar3. Stanhewicz AE, Wong BJ. Counterpoint: Investigators should not control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00427.2020. Link | ISI | Google Scholar4. Stanhewicz AE, Wong BJ. Rebuttal to Drs. Wenner and Stachenfeld. J Appl Physiol (1985). doi:10.1152/japplphysiol.00621.2020. Link | ISI | Google Scholar5. Wenner MM, Stachenfeld NS. Point: Investigators should control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00443.2020. Link | ISI | Google Scholar6. Wenner MM, Stachenfeld NS. Rebuttal to Drs. Stanhewicz and Wong. J Appl Physiol (1985). doi:10.1152/japplphysiol.00620.2020. Link | ISI | Google ScholarCONTROLLING MENSTRUAL PHASE IN CEREBROVASCULAR RESEARCH: PUTTING THE CART BEFORE THE HORSEMatthew Neill,1 Elric Y. Allison,2 Andrea K. Zapcic,1 and Kurt J. Smith3.Author Affiliations1Department of Kinesiology, Lakehead University, Thunder Bay, Ontario, Canada.2Department of Kinesiology, McMaster University, Hamilton, Ontario, Canada.3Integrative Physiology Lab, Department of Kinesiology and Nutrition, University of Chicago, Chicago, Illinois.to the editor: The majority of vascular studies including male and female participants investigate vascular function during the early follicular phase of the menstrual cycle, to reduce the confounding effect of estrogen and progesterone on vascular mechanics (5). This methodological approach controls for the acute response triggered by the nadir of female sex hormone fluctuations (6). In many studies, estrogen and progestogen are considered vasoprotective; thus arbitrarily utilizing this approach to assess male and female vascular function likely disguises vascular outcomes, or incites unfavorable misinterpretation caused from assuming the observed vascular mechanics are independent of sex (3).Pronounced sex differences exist across human vasculature, notably in the brain. Females have smaller middle cerebral arteries (MCA), increased MCA autoregulation (4), and improved cerebrovascular reactivity compared with their male counterparts (7). These sex differences are mainly consistent irrespective of menstrual phase (1, 2) but disappear after the onset of menopause (2), indicating that at least a proportion of the vascular effect of estrogen and progesterone is based on prolonged exposure.Subsequently, controlling for acute hormone changes without considering prolonged hormone exposure places the cart before the horse, since the main driver of the sexually dimorphic vascular mechanics (the prolonged female sex hormone exposure) is left uncontrolled, yet the smaller influence of a fluctuating menstrual cycle is removed. Results become neither a comprehensive representation of female vascular mechanics, nor provide insight into defining vascular mechanisms irrespective of sex. Thus, in agreement with Stanhewicz and Wong (6), menstrual phase should be considered not controlled for when assessing cerebrovascular structure and function.REFERENCES1. Barnes JN. Sex-specific factors regulating pressure and flow. Exp Physiol 102: 1385–1392, 2017. doi:10.1113/EP086531. Crossref | PubMed | ISI | Google Scholar2. Krejza J, Mariak Z, Huba M, Wolczynski S, Lewko J. Effect of endogenous estrogen on blood flow through carotid arteries. Stroke 32: 30–36, 2001. doi:10.1161/01.STR.32.1.30. Crossref | PubMed | ISI | Google Scholar3. Matteis M, Troisi E, Monaldo BC, Caltagirone C, Silvestrini M. Age and sex differences in cerebral hemodynamics: a transcranial Doppler study. Stroke 29: 963–967, 1998. doi:10.1161/01.STR.29.5.963. Crossref | PubMed | ISI | Google Scholar4. Minhas JS, Panerai RB, Robinson TG. Sex differences in cerebral haemodynamics across the physiological range of PaCO2. Physiol Meas 39: 105009, 2018. doi:10.1088/1361-6579/aae469. Crossref | PubMed | ISI | Google Scholar5. Stachenfeld NS, Taylor HS. Challenges and methodology for testing young healthy women in physiological studies. Am J Physiol Endocrinol Metab 306: E849–E853, 2014. doi:10.1152/ajpendo.00038.2014. Link | ISI | Google Scholar6. Stanhewicz AE, Wong BJ. Counterpoint: Investigators should not control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00427.2020. Link | ISI | Google Scholar7. Xing CY, Tarumi T, Meijers RL, Turner M, Repshas J, Xiong L, Ding K, Vongpatanasin W, Yuan L-J, Zhang R. Arterial pressure, heart rate, and cerebral hemodynamics across the adult life span. Hypertension 69: 712–720, 2017. doi:10.1161/HYPERTENSIONAHA.116.08986. Crossref | PubMed | ISI | Google ScholarREFERENCES1. Barnes JN. Sex-specific factors regulating pressure and flow. Exp Physiol 102: 1385–1392, 2017. doi:10.1113/EP086531. Crossref | PubMed | ISI | Google Scholar2. Krejza J, Mariak Z, Huba M, Wolczynski S, Lewko J. Effect of endogenous estrogen on blood flow through carotid arteries. Stroke 32: 30–36, 2001. doi:10.1161/01.STR.32.1.30. Crossref | PubMed | ISI | Google Scholar3. Matteis M, Troisi E, Monaldo BC, Caltagirone C, Silvestrini M. Age and sex differences in cerebral hemodynamics: a transcranial Doppler study. Stroke 29: 963–967, 1998. doi:10.1161/01.STR.29.5.963. Crossref | PubMed | ISI | Google Scholar4. Minhas JS, Panerai RB, Robinson TG. Sex differences in cerebral haemodynamics across the physiological range of PaCO2. Physiol Meas 39: 105009, 2018. doi:10.1088/1361-6579/aae469. Crossref | PubMed | ISI | Google Scholar5. Stachenfeld NS, Taylor HS. Challenges and methodology for testing young healthy women in physiological studies. Am J Physiol Endocrinol Metab 306: E849–E853, 2014. doi:10.1152/ajpendo.00038.2014. Link | ISI | Google Scholar6. Stanhewicz AE, Wong BJ. Counterpoint: Investigators should not control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00427.2020. Link | ISI | Google Scholar7. Xing CY, Tarumi T, Meijers RL, Turner M, Repshas J, Xiong L, Ding K, Vongpatanasin W, Yuan L-J, Zhang R. Arterial pressure, heart rate, and cerebral hemodynamics across the adult life span. Hypertension 69: 712–720, 2017. doi:10.1161/HYPERTENSIONAHA.116.08986. Crossref | PubMed | ISI | Google ScholarCONTROLLING FOR MENSTRUAL CYCLE PHASE WHEN PERFORMING STUDIES OF VASCULAR CONTROL – WHAT’S THE QUESTION?Joshua M. Bock1 and Darren P. Casey234.Author Affiliations1Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.2Department of Physical Therapy and Rehabilitation Science, Carver College of Medicine, University of Iowa, Iowa City, Iowa.3Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa.4Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa.to the editor: Recent Point (6) and Counterpoint (3) arguments were made on whether or not to control for the menstrual cycle when assessing vascular function. While both sides present valid arguments for and against controlling for the menstrual cycle phase, we believe this answer is ultimately contingent upon the question(s) being addressed. As noted in the original Counterpoint, inclusion of women in clinical works has been emphasized by the National Institutes of Health (2). From an epidemiological perspective, where outcome measures are large-scale (e.g., mortality), the specific phase of a subject’s menstrual cycle is less likely to play a role particularly as they become post-menopausal. If the menstrual cycle phase was to be accounted for on such a large scale, cost would greatly increase with commensurate decline in feasibility making the study seemingly unrealistic. As such, the specific phases of the menstrual cycle should receive less attention in these settings. During prospective or interventional works, evidence suggests female sex hormone fluctuations influence outcome measures (e.g., flow-mediated dilation) (1, 7), which have guided nearly a decade’s worth of recommendations (4, 5). The physiological justification for this is nicely outlined in the original Point paper (6). Thus, if the experimental aims and outcome measures span multiple phases of a menstrual cycle, or several complete menstrual cycles, than the specific phase needs to be considered. In sum, sex hormone fluctuations can influence vascular function and should be accounted for during interventional works whereas less emphasis should be placed on the menstrual cycle with longer-term studies (e.g., years).REFERENCES1. Adkisson EJ, Casey DP, Beck DT, Gurovich AN, Martin JS, Braith RW. Central, peripheral and resistance arterial reactivity: fluctuates during the phases of the menstrual cycle. Exp Biol Med (Maywood) 235: 111–118, 2010. doi:10.1258/ebm.2009.009186. Crossref | PubMed | ISI | Google Scholar2. Lee SK. Sex as an important biological variable in biomedical research. BMB Rep 51: 167–173, 2018. doi:10.5483/BMBRep.2018.51.4.034. Crossref | PubMed | ISI | Google Scholar3. Stanhewicz AE, Wong BJ. Counterpoint: Investigators should not control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00427.2020. Link | ISI | Google Scholar4. Thijssen DH, Black MA, Pyke KE, Padilla J, Atkinson G, Harris RA, Parker B, Widlansky ME, Tschakovsky ME, Green DJ. Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol 300: H2–H12, 2011. doi:10.1152/ajpheart.00471.2010. Link | ISI | Google Scholar5. Thijssen DHJ, Bruno RM, van Mil ACCM, Holder SM, Faita F, Greyling A, Zock PL, Taddei S, Deanfield JE, Luscher T, Green DJ, Ghiadoni L. Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans. Eur Heart J 40: 2534–2547, 2019. doi:10.1093/eurheartj/ehz350. Crossref | PubMed | ISI | Google Scholar6. Wenner MM, Stachenfeld NS. Point: Investigators should control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00443.2020. Link | ISI | Google Scholar7. Williams MR, Westerman RA, Kingwell BA, Paige J, Blombery PA, Sudhir K, Komesaroff PA. Variations in endothelial function and arterial compliance during the menstrual cycle. J Clin Endocrinol Metab 86: 5389–5395, 2001. doi:10.1210/jcem.86.11.8013. Crossref | PubMed | ISI | Google ScholarREFERENCES1. Adkisson EJ, Casey DP, Beck DT, Gurovich AN, Martin JS, Braith RW. Central, peripheral and resistance arterial reactivity: fluctuates during the phases of the menstrual cycle. Exp Biol Med (Maywood) 235: 111–118, 2010. doi:10.1258/ebm.2009.009186. Crossref | PubMed | ISI | Google Scholar2. Lee SK. Sex as an important biological variable in biomedical research. BMB Rep 51: 167–173, 2018. doi:10.5483/BMBRep.2018.51.4.034. Crossref | PubMed | ISI | Google Scholar3. Stanhewicz AE, Wong BJ. Counterpoint: Investigators should not control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00427.2020. Link | ISI | Google Scholar4. Thijssen DH, Black MA, Pyke KE, Padilla J, Atkinson G, Harris RA, Parker B, Widlansky ME, Tschakovsky ME, Green DJ. Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol 300: H2–H12, 2011. doi:10.1152/ajpheart.00471.2010. Link | ISI | Google Scholar5. Thijssen DHJ, Bruno RM, van Mil ACCM, Holder SM, Faita F, Greyling A, Zock PL, Taddei S, Deanfield JE, Luscher T, Green DJ, Ghiadoni L. Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans. Eur Heart J 40: 2534–2547, 2019. doi:10.1093/eurheartj/ehz350. Crossref | PubMed | ISI | Google Scholar6. Wenner MM, Stachenfeld NS. Point: Investigators should control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol (1985). doi:10.1152/japplphysiol.00443.2020. Link | ISI | Google Scholar7. Williams MR, Westerman RA, Kingwell BA, Paige J, Blombery PA, Sudhir K, Komesaroff PA. Variations in endothelial function and arterial compliance during the menstrual cycle. J Clin Endocrinol Metab 86: 5389–5395, 2001. doi:10.1210/jcem.86.11.8013. Crossref | PubMed | ISI | Google ScholarDOES THE SOLUTION RESIDE IN THE STUDY RATIONALE?Ninette Shenouda1 and Sushant M. Ranadive2.Author Affiliations1Department of Kinesiology and Applied Physiology, University of Delaware, Newark, Delaware.2Department of Kinesiology, University of Maryland, College Park, Maryland.to the editor: We commend the authors of the Point (3) and Counterpoint (2) for initiating this timely and important discussion. It may be prudent to consider the role of vascular homeostasis throughout the menstrual cycle. Previous studies have shown similar increases in estradiol from menstruation to later follicular and ovulatory phases with and without parallel increases in vascular function as discussed in Shenouda et al. (1). Thus, discrepancies in the literature regarding the influence of estradiol on vascular function cannot be completely attributed to di
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