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Effects of the Follicular Menstrual Phase on Forearm Vascular Conductance in Abdominal Obese Premenopausal Women During Graded Handgrip Exercise

Effects of the Follicular Menstrual Phase on Forearm Vascular Conductance in Abdominal Obese... Purpose: Previous studies have reported a sympatholytic action of estrogen on the vasculature in response to increased sympathetic outflow, an effect most notable during exercise, providing for necessary increases in blood flow to working muscle. In contrast, elevated concentrations of progesterone can inhibit this action of estrogen, impairing increases in blood flow. We hypothesize that the peak concentration of estrogen during the proliferative portion of the follicular phase of the menstrual cycle in female humans will increase vascular conductance during exercise when the effects of progesterone are negligible. In addition, we hypothesize that overweight abdominally obese females will have an attenuated conductance response to dynamic exercise during the same menstrual phase. Methods: Participants engaged in graded forearm exercise using an isotonic handgrip dynometer with sequential increases in resistance at a cadence of 30 contractions/minute until task failure. They performed exercise at time points of the menstrual cycle corresponding to low concentrations of both sex hormones and elevated estrogen, while progesterone remained low. Blood flow and vascular conductance were measured using Doppler ultrasound. Results: This revealed a trend that abdominal obese women during a phase of low estrogen had a lower overall blood flow and vascular conductance response than healthy controls at matching resistance stages during rest and exercise. This group difference was attenuated during the proliferative phase with elevated circulating estrogen. There is not a statistically significant interaction between Ovarian Phase and Weight group (P = 0.778). Conclusion: The results indicate that overweight women are at a disadvantage during exercise in increasing blood flow to working muscles, which can be detrimental to overall fitness improvement during the early and potentially late follicular phase of the menstrual cycle. Keywords: Abdominal obese, Pre-menopausal females, Brachial artery exercise, Blood flow, Menstrual cycle During exercise, estrogen can facilitate increased blood 1 Introduction flow to working muscles through endothelial-depend - Estrogen provides a protective role in maintaining proper ent dilation via activation of endothelial nitric oxide endothelial function in pre-menopausal women [28]. synthase (eNOS). This action of estrogen proves to be sympatholytic as it occurs with increased sympathetic *Correspondence: matthew.barlow@enmu.edu outflow via activation of the exercise pressor reflex. In contrast, progesterone can act to block this sympatho- Department of Biology, Eastern New Mexico University, Station 33, 1500 S. Ave K, Portales, NM 88130, USA lytic mechanism of estrogen limiting increases in blood Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Restaino et al. Artery Research (2022) 28:79–88 80 flow during exercise [4]. In healthy women, this bal - follicular phase of the menstrual cycle in female humans ance in hemodynamic effects of sex hormones serves to will increase vascular conductance during exercise when regulate increases in blood flow and vascular conduct - the effects of progesterone are negligible. In addition, we ance. Overweight and abdominal obese conditions, how- hypothesize that overweight abdominal obese females ever, correlate to disturbances in the menstrual cycle. will have an attenuated conductance response to graded These menstrual disturbances could potentially lead to isotonic handgrip exercise during the same menstrual decreases in estrogen production and an increased level phase. of androgens in young women who are overweight [21]. Potentially, the hormonal imbalance could leave over-2 Methods weight women at a disadvantage during exercise due 2.1 Participants to decreased blood flow and conductance to working 20 women (11 controls and 9 abdominal obese) aged muscle. 25 ± 1.29  years were examined in this study. All partici- Excessive body weight in young women can poten- pants were volunteers and were non-smokers, sedentary tially intensify the advancement of peripheral vascular (30  min of moderate exercise less than 4 times a week), dysfunction and cardiovascular disease similar to that and not on any form of birth control as determined by seen in normal aging. Impairment in eNOS activity and a physical examination form and a personal question- blunted production of the vasodilator nitric oxide (NO) naire. Participants were screened and separated into has been demonstrated to be the underlying cause of two groups based on physical characteristics: healthy vascular dysfunction with exercise in the elderly with sedentary control and sedentary abdominal obese (AO) evidence in both the arms and legs [26, 19, 20]). Other (having at least two but not ≥ 3 criteria of the NCEP III characteristics and risk factors that arise from being categorization of the Metabolic Syndrome including a overweight are analogous to those seen in an aging popu- waist circumference > 96  cm) [9]. On study days, partici- lation, and specifically in conduit artery sheer stress post- pants refrained from caffeine, aspirin, or ibuprofen inges - menopausal women [24]. Increased oxidative stress and tion 12  h prior to arrival. Participation took place over reduced antioxidant capacity, factors seen in both over- the course of three separate visits. All participants were weight and elderly individuals, impair endothelial func- recruited locally and gave written informed consent prior tion through oxidation of NO and uncoupling of eNOS to any action taken in the laboratory. A schematic of the [15], Hashimoto et  al. 1995, Kawano et  al. 1995 [3, 30]. study design is presented in Fig. 1. All experimental pro- Estrogen may have antioxidant effects at the cellular cedures and protocols conformed to the Declaration of level, protecting young healthy women from dysfunction Helsinki and the study was approved by the Human Sub- [16]. However, young overweight women with poten- jects Committee Institutional Review Board at Eastern tially impaired effects of estrogen could be at a similarly New Mexico University. elevated risk as post-menopausal women. [25, 24]. Fur- ther investigation is necessary to decipher the potential 2.2 Visit 1 disruption of normal vascular physiology during exercise Classification of participants to study groups was based in overweight young women statistically associated with on physical characteristics (BMI, body fat percentage, lower levels of cardiovascular fitness [13, 14]. waist/hip ratio, resting blood pressure, fasted blood glu- The aim of this study is to determine if elevated cose, triglycerides, total cholesterol, and HDL). Group endogenous estrogen has an altered effect on working characteristics are reported in Table  1. All participants muscle vascular conductance in overweight women as were asked to refrain from alcohol, exercise, caffeine, compared to healthy control individuals. Limberg et  al. aspirin, and ibuprofen, for at least 12  h prior to all test- [12] concluded there is a facilitating effect of estrogen on ing. We recorded anthropometric measurements at this increases in vascular conductance with reduced alpha2- physical screening visit with participants arriving fasted aderenergic vasoconstriction during isometric handgrip 10–12 h prior to arrival. BMI and percent body fat were exercise. However, there was no significant difference measured through bioimpedance using an Omron Fat between the male group and early follicular phase. The Loss Monitor (HBF-306C). Triglycerides, HDL, total lack of change between the Early Follicular Menses cholesterol, and fasted blood glucose were measured phase and the luteal phase could have been from vascu- from capillary blood sample obtained through finger lar antagonist effects of the rise in progesterone during prick (CardioChek Portable Blood Test System, PTS this phase, although Limberg et  al. unfortunately lacked Panels, for cholesterol; OneTouch Ultra 2 Blood Glucose the plasma measurement of estrogen and progesterone Monitoring System for glucose measurement). Two 6 mL in the study. We hypothesize that the peak concentra- venous blood samples were collected in 10.8  mg EDTA- tion of estrogen during the proliferative portion of the treated 6  mL vacutainers (BD, Franklin Lakes, NJ) and R estaino et al. Artery Research (2022) 28:79–88 81 Plasma collecon for hormone analysis Visit 1: Physical Measurements, Familiarizaon 10 minute resng ECG and Blood Pressure No specific me interval Visit 2: Experimental visit, Exercise bout I, Exercise Protocol Early Menses 7 days between 30 seconds 2 minutes Increase in Visit 2 and Visit 3 Rest unloaded workload, 0.25 contracons Was/minute Visit 3: Experimental visit, Exercise bout II, Brachial artery diameter and blood velocity Proliferave Phase recorded throughout exercise Fig. 1 A Overall schematic of participation in study; B, description of experimental visits and exercise protocol Table 1 Physical characteristics of overall experimental groups displayed as averages ± SD; categories statistically different between groups are marked by * (W:H waist-to-hip ratio, BMI Body Mass Index, BF% percent Body Fat) Control/healthy (n = 11) Abdominal obese (n = 10) p value Height (cm) 163.98 ± 1.65 169.29 ± 2.71 0.168 Weight (kg) * 56.53 ± 5.02 97.14 ± 5.57 < 0.001 Waist size (cm) 81.86 ± 6.9 113 ± 19.3 < 0.001 W:H* 0.81 ± 0.01 0.96 ± 0.03 0.002 BMI* 24.1 ± 0.59 33.82 ± 1.94 < 0.001 BF%* 24.47 ± 1.1 35.42 ± 1.86 0.001 Fasted glucose (mg/dl) 91.57 ± 1.71 99.9 ± 2.78 0.007 SBP (mmHg) 115 ± 3.98 119.7 ± 4.79 0.586 DBP (mmHg) 73.7 ± 2.23 77.2 ± 3.53 0.493 Total Chol mg/dL 140.0 ± 8.6 148.4 ± 11.2 0.544 HDL Chol (mg/dL) 45.83 ± 3.29 40.9 ± 2.27 0.137 Trig (mg/dL) 97.0 ± 8.4 101.8 ± 19.2 0.841 Menses E2 (pg/mL) 75.55 ± 10.02 51.86 ± 6.37 0.186 Prolif E2 (pg/mL) 301.25 ± 34.58 346.03 ± 40.4 0.609 Menses Prog (pg/mL) 106.65 ± 63.15 155.2 ± 97.17 0.332 Prolif Prog (pg/mL) 141.57 ± 78.32 141.56 ± 97.74 0.915 Menses Prog: E2 1.93 ± 1.68 4.28 ± 4.82 0.39 Prolif Prog: E2 0.74 ± 0.55 0.51 ± 0.53 0.516 Testosterone (pg/mL) 45.6 ± 5.84 42.45 ± 8.55 0.39 oxLDL (pg/mL) 98.1 + 40.6 146.06 ± 62.25 0.047 Forearm volume (ml) 791.1 ± 13.61 1021.43 ± 73.01 0.050 Restaino et al. Artery Research (2022) 28:79–88 82 centrifuged, and plasma was aliquoted stored in 1  mL in diameter changes of conduit arteries continuously as microtubes and stored at − 80  °C for future analysis of well as changes in velocity without halting the graded 11-keto-testosterone, 17-β-estradiol and Progesterone workloads until task failure. Diameter was defined as and Oxidative LDL. the distance between intima layers of the vessel walls in a longitudinal section of the brachial artery. Diam- 2.3 Visit 2 eter measurements were assessed during the final 15 s of Upon arrival, participants were asked to provide venous each set for analysis. Velocity was continuously recorded blood samples for measurement of 17-β-Estradiol and through Doppler B-mode and a custom-built interface Progesterone. This visit was scheduled during self- audio transducer unit which processed the high-resolu- reported early menses when estrogen and progesterone tion, angle corrected, intensity weighted Doppler audio levels can be expected to be at their lowest menstrual information from the ultrasound system into a lower fre- cycle concentrations. Forearm volume was measured quency velocity signal (0–20  Hz) (Herr et  al. 2010) that using water displacement with participants placing the could be sampled in real time by AcqKnowledge 4.4 data non-dominant arm into a column of water, the resulting acquisition software. Post-processing analysis using Acq- volume of overflow being measured, and volume of the Knowledge acquisition yielded mean blood velocities cal- hand being subtracted for pure forearm volume. Partici- culated as mean of the final 30 s for ever stage [20]. pants were placed in a supine position, while three lead ECG was recorded for 10  min on a Biopac MP150 data acquisition unit using AcqKnowledge 4.4 data acquisi-2.4 Visit 3 tion software (Biopac Systems Inc., Goleta, CA). Rest- This visit was scheduled 1 week after visit 2 during the ing blood pressure was recorded after ECG using an proliferative phase of the menstrual cycle. Similar to Omron Blood Pressure Monitor. Participants remained visit 2, venous plasma samples were collected again to in the supine position during the entire course of exer- measure an expected rise in estrogen concentrations cise; all participants exercised the non-dominant left and to determine if progesterone had changed sig- forearm. Exercise was completed using a custom-built nificantly. The handgrip exercise protocol of this visit handgrip dynamic ergometer with participants exercis- repeated from that executed on the second visit and ing at a cadence of 30 handgrip contractions per minute. continuous resting and exercise ECG and blood pres- Participants began graded exercise with their non-domi- sure were also recorded on this visit. nant hand with 2 min of unloaded contraction (0 Watts) followed by a ramp increase in workload of 0.25 Watts (0.5 kg resistance) every minute [6, 9]. Participants were 2.5 Artery Diameter and Blood Velocity Analysis asked to continue exercise until task failure was reached. Diameter recordings of the brachial artery collected Task failure was defined as the inability to maintain the during the handgrip exercise bouts of visits 2 and 3 proper cadence of 30 contractions per minute. During were recorded digitally and analyzed post-test using exercise, blood velocity and vessel diameter were meas- edge detection software (Brachial Analyzer 5.10.11, ured in the brachial artery of the exercising left arm using Medical Imaging Applications, Iowa City, Iowa). Aver- a linear array ultrasound probe operating at 4–7  MHz age diameter at each stage of exercise was recorded. (Phillips HDI 5000 Ultrasound System, ATL Ultrasound, Blood velocity recordings from each visit were analyzed Bothell, WA). Doppler ultrasound was used for the meas- by determining the average velocities seen at each stage urement of blood flow in during in the graded handgrip of exercise. Arterial blood pressure and heart rate were exercise as prior research groups have determined that also recorded at each stage of exercise via beat-to-beat the strain-gauge plethysmography methods give an esti- finger plethysmography and ECG respectively. Diame - mate of limb blood flow at rest during the end of exer - ter and mean velocity data were used to calculate blood cise, but not for continuous exercise in a graded dynamic flow to the forearm through the brachial artery at each exercise setting, because the participant is required to stage using the formula Q = π r *v (ml/min). Recorded stop contracting during the exercise to measure the limb beat-to-beat blood pressures were used to calculate flow changes. Additionally, as stated by Byström et  al., mean arterial pressure (1/3 Pulse Pressure + Diastolic the occlusion pressure required for obtaining the meas- Pressure) which was used to calculate forearm vascu- urement of blood flow using occlusion plethysmography lar conductance (C = Q/P; ml/min/mmHg). Forearm of the forearm causes a 28% reduction in muscle blood volumes were used to correct blood flow and vascular flow during graded handgrip exercise and significantly by conductance values per 100  mL of forearm volume for underestimating the change in flow [2]. Doppler ultra - each participant. The intra-rater reliability for repro - sound with the linear flow probe allows for detection ducibility of the Doppler ultrasound measurement was R estaino et al. Artery Research (2022) 28:79–88 83 measured by calculating the coefficient of variation on cholesterol, between overweight and control partici- a control group (n = 10) of participants. Measurements pants. However, these comparisons were not statistically were taken of the brachial artery diameter and mean significant. All ECG recordings collected at visit 2 under - arterial velocity at rest on two separate visits by the went heart rate variability analysis; statistical review of same imaging technician. the resulting data yielded no significant results between groups. 2.6 Biomarker Analysis Plasma samples from each participant were used to 3.2 Vascular Responses to Exercise measure oxidative stress in an oxidized LDL (oxLDL) Percent dilation was calculated as the change from resting assay (Cell Biolabs, Inc., San Diego, CA). Additionally, diameter to end of the 1.5 Watt stage of exercise divided 11-keto-testosterone, 17-β-estradiol, and Progesterone by resting diameter × 100. The 1.5 Watt stage was deter - was also measured from the plasma samples collected mined as the common end point among participants. The from each participant using associated EIA kits (Caymen overall change in diameter of the brachial artery from rest Chemical Company, Ann Arbor, MI).; absorbance was to 1.5 Watts was not significantly different in either of the read at 412, 420, and 450 nm, respectively. experimental groups from early menses to the prolifera- tive phase. This change in dilation was slightly, though not significantly, different between groups (Fig.  2). Per- 2.7 Statistical Analysis cent dilation in the control group was not different dur - Within group statistical variance between time points ing the proliferative phase (12.951% ± 7.4) as compared to was assessed with a repeated-measure ANOVA with a that seen in early menses (13.5 ± 6.34). This relationship Tukey’s post hoc analysis comparing percent dilation was not seen in the abdominal obese group. In addition, from rest to 1.5 Watts (3 kg resistance), which was a com- percent dilation in the AO group during the proliferative mon end point across participants and groups. Similar phase was greater (12.37 ± 3.52) than that seen in the AO analysis assessed differences in flow and conductance group during early menses phase (10.4 ± 7.86) although corrected for forearm volume, along with mean arterial not statistically different. (Fig.  2). However, these differ - pressure. An unpaired T test was used to compare differ - ences yielded no statistical significance (p = 0.868 and ences between groups including estrogen, progesterone, 0.74, respectively). There was no statistical difference in and testosterone concentrations. The potential rise in resting diameter between groups or between time points estrogen between these two menstrual phases was cal- within the two groups. culated as the percent difference; the change from early Systolic and diastolic blood pressure was assessed menses to the proliferative phase over the average of the throughout the handgrip exercise and used to calculate two concentrations. Variation in the percent difference was assessed by an unpaired T test. P < 0.05 was consid- ered significant. To determine if the change in estrogen Percent Dilation of the Brachial Artery (Rest to 1.5 Watts) between the menses and proliferative time period had an altered effect on working muscle vascular conductance in the AO women as compared to the healthy control a Early Menses Proliferative Phase 2 × 2 mixed ANOVA was compared. Data are resented as means ± SD. 3 Results 3.1 P hysical Measurements and Functional Analysis Comparison of the anthropometric data gathered from each group yielded significant difference between control participants and AO participants. Physical measurements revealed the AO participants had significantly (P < 0.05) ControlAO waist circumference, higher body fat percentages (BF%), Groups and body mass indices (BMI) as well as significantly Fig. 2 Percent dilation during exercise within each group, comparing higher fasted blood glucose, weights and waist-to-hip dilatory responses seen during early menses (low estrogen) and ratios, oxLDL, and Forearm Volume; see Table  1. Meas- during the proliferative phase (high estrogen). Control percent urements also revealed differences in triglycerides, total dilation p = 0.868. Between group comparison at proliferative phase p = 0.433 cholesterol, systolic and diastolic blood pressures, HDL % Dilation Restaino et al. Artery Research (2022) 28:79–88 84 Control Mean Arterial Pressure, Control Mean Blood Velocity, Early Menses vs Proliferative Phase Early Menses vs. Proliferative Phase 90 15 Early Menses Proliferative Phase 10 Early Menses Rest 00.5 11.5 Proliferative Phase Workload (Watts) Rest 00.5 11.5 Abdominal Obese Mean Arterial Pressure, Workload (Watts) Early Menses vs. Proliferative Phase Abdominal Obese M ean Blood Velocity, Early Menses vs. Proliferative Phase ** ** ** Early Menses Early Menses Proliferative Phase Proliferative Phase Rest 00.5 11.5 Rest 00.5 11.5 Workload (Watts) Workload (Watts) Fig. 3 Mean arterial pressure in control and overweight participants Fig. 4 Mean blood velocity in the brachial artery during isotonic during dynamic handgrip exercise, rest to 1.5 Watts, *indicates a graded handgrip exercise in control and overweight participants, rest significant difference between the groups during the Early Menses to 1.5 watts phase (p < 0.05). **indicates a significant difference in the AO group between Early Menses and the Proliferative Phase there was no pressure differences between the groups at any point of the exercise. During the early menses exercise period in the AO group, the mean blood veloc- mean arterial pressure (MAP). During the Early Menses ity measurements were lower compared with the pro- period, there was a significantly higher MAP in the AO liferative phase in the AO participants when although group during rest, unloaded, and 0.5- and 1.0-Watts no statistical difference was found at any workload. No workloads compared to the Proliferative Phase (Fig.  3). difference was seen in blood velocity during exercise in MAP in Control participants from rest to the 1.5 Watts control participants and no statistical differences were workload stage was not seen to be significantly different present between the groups (Fig. 4). between experimental stages of the menstrual cycle, Vascular conductance of the brachial artery was cal- from early menses to the proliferative phase (Fig.  3). culated at each workload during exercise. No significant When comparing the control to the AO groups, the differences were observed within either group when con - MAP was significantly lower in the Early Menses period ductance was compared between experimental menstrual (83.1 ± 7.1 vs 91.4 ± 7.7  mmHg , p = 0.045) at rest and cycle phases. In a comparison of conductance responses the unloaded movement but was no longer significant; during early menses when estrogen concentrations were during the graded exercise, the MAP differences when lowest, AO participants presented with lower vascular estrogen was elevated; during the Proliferative Phase, MAP (mmHg) MAP (mmHg) Velocity (cm/sec) Velocity (cm/s) R estaino et al. Artery Research (2022) 28:79–88 85 Conductance responses were calculated per 100  mL Vascular Conductance during Early Menses, of forearm volume. Comparison of forearm volumes Contol vs Abdominal Obese revealed that AO participants had significantly higher forearm volumes compared to controls (Table  1). The 0.22 coefficient of variation for participants during a time 0.20 † control for the measures of resting brachial diameter 0.18 and mean blood velocity using the Doppler ultrasound 0.16 method were 1.9% and 3.4% respectively. 0.14 Plasma samples were assayed, and estrogen concen- 0.12 trations were measured for both early menses and the 0.10 proliferative phase in both control and AO groups. In 0.08 both experimental groups, a rise in estrogen was meas- 0.06 ured in pg/mL from early menses to the proliferative Control 0.04 phase. Estrogen concentrations were slightly higher Abdominal Obese in the control group as compared to the AO group 0.02 Rest 00.5 11.5 at early menses (control = 67.15  pg/mL ± 13.4; over- Worload (Watts) weight = 51.86 ± 9.005; p = 0.556); this relationship was reversed at the proliferative phase as the AO presented Vascular Conductance during Proliferative Phase, Control vs Abdominal Obese higher estrogen concentrations (control = 319.12 ± 40.6; 0.22 AO = 346.03 ± 70.21; p = 0.664), although these concen- 0.20 trations were not significantly different. Progesterone 0.18 plasma concentrations were also measured and calcu- 0.16 lated into pg/mL. The concentration from early menses 0.14 to the proliferative phase in both groups determined no statistically significant change and remained well within 0.12 the same range (control p = 0.455; AO p = 0.65). Tes- 0.10 tosterone concentrations were measured in plasma and 0.08 compared between groups; no significant difference 0.06 was seen. There was a significant difference between the Control 0.04 Abdominal Obese measurements of oxLDL (pg/mL) with the AO group 0.02 Rest 00.5 11.5 having a larger plasma concentration (146.1 ± 62.25  pg/ Workload (Watts) mL) compared to the control group (98.1 ± 40.6  pg/mL) Fig. 5 Vascular conductance of the brachial artery during handgrip as measured during the early menses stage (Table 1). exercise compared between groups during early menses, *p < 0.05, †p < 0.1. During the Early Menses period, the comparison between 4 Discussion the groups were significantly different (+ , p = 0.016) for the delta between rest and peak conductance at 1.5-Watt workload The major finding of the present study is that the over - weight abdominal obese pre-menopausal women exhibit a lowered brachial conductance response to dynamic graded small muscle exercise during the early menses conductance responses compared to healthy controls of the menstrual cycle follicular phase. This attenuated all workloads (Fig.  5). The group difference in the high vascular response was also resolved equal to the age- estrogen period of the proliferative phase was attenuated matched health controls upon increases in Estrogen dur- at the AO group presented with an increase in conduct- ing the menstrual proliferative phase prior to ovulation. ance response although not significantly difference from Previous studies have described a potential facilitating Early Menses and the control group at the same period. effect of estrogen on increases in vascular conductance When comparison of the delta from rest to the 1.5-Watt during exercise [4], 5, 12]. Overall, the data in this study workload using a 2 × 2 ANOVA, the difference in the indicate that in young women, normally considered vas- mean values among the different levels of weight group cularly healthy can present with the characteristics of is greater than would be expected by chance after allow- vascular deficiencies not presumed to be detrimental. ing for effects of differences in ovarian phase. There is a We found the MAP when compared between phases statistically significant difference (+ in Fig.  5, P = 0.016). of the menstrual cycle within the control group exhib- However, there is not a statistically significant interaction ited no differences in MAP between early menses and between Ovarian Phase and Weight group (P = 0.778). Conductance (ml/min/mmHg/100mL forearm vol) Conductance (mL/min/mmHg/100 mL forearm vol) Restaino et al. Artery Research (2022) 28:79–88 86 the proliferative phase; however, MAP in the AO women increase in Progesterone in the Early Menses Phase of the was higher during early menses than that seen during the AO group, there was not a significant difference either proliferative phase (Fig.  3). MAP within the AO women between the control groups and overweight at either during the proliferative phase was returned to levels time point; neither was there a progesterone to estrogen consistent with those seen in the healthy control group ratio significance difference (Table  1). However, as indi- (Fig.  3). This difference in arterial pressure during exer - cated by Limberg et al., the increase in Progesterone dur- cise at the two menstrual cycle time points could poten- ing the follicular phase of the menstrual cycle in healthy tially serve as the cause for the difference in conductance controls and overweight abdominal obese women could during early menses in AO women when compared potentially attenuate the benefits that estrogen may pro - to controls. Vascular function assessed in the forearm vide for vascular function [12]. The AO group exhibit a of women across the menopausal transition in seden- reduced conductance during exercise similar to that seen tary women suggests functional lost with the loss ovar- in post-menopausal women, but only during the Early ian function [16, 17]. However, the ovarian functional Menses phase of the cycle. This reduced response is only changes to the vascular blood flow in sedentary over - reversed with increases in endogenous estrogen, similar weight women at various stages of the menstrual cycle to that seen in post-menopausal women after exogenous have not been demonstrated, although obesity is highly estrogen treatment [5]. Removal of estrogen through linked to hypertension and sympathetic reflex abnormali - menopause in overweight women would leave no means ties [8, 11]. Additionally, abdominal obesity is highly cor- of maintaining relative cardiovascular health. Reduced related to higher Pulse Wave Velocity in women which function is expected with aging (Parker et al. 2008),how- could also indicate stiffer arteries causing elevated blood ever, this reduced function is already present in young pressure and diminished flow (van den [27]. The rela - pre-menopausal women. Further endothelial dysfunc- tionship between abdominal obesity and PWV during tion could potentially increase with the advancement of the menstrual cycle phases was not accessed during this associated insulin resistance and diabetes, and worsen study. Although blood pressures were higher in the early beyond even normal aging. As previously demonstrated, menses phase for the overweight group during the exer- sedentary practices also have deleterious effects on vas - cise, an alternative approach is needed for the role of cen- cular function [1], [22, 23, 18] Though exercise-induced tral and peripheral arterial stiffness during these different shear stress can restore normal function in response to phases of the menstrual cycle in both groups. an acute sedentary period and even prevent it [22, 18], The significance difference in vascular conductance such benefits may not be fully realized in young over - seems to be mostly weighted in the changes in MAP and weight females. The present results indicate an impor - resulting changes in vascular conductance in the AO tant link between menstrual hormone concentrations women. Our results indicate that AO pre-menopausal and exercise-stimulated blood flow, and the attenuation women have reduced vascular conductance during early of this dynamic in the presence of poor metabolic health. menses when estrogen concentrations are lowest, only to A sedentary lifestyle can lead to excess weight gain and return to within a normal healthy range during the pro- metabolic dysfunction, both impairing vascular functions liferative phase when endogenous estrogen is increased. systemically. Though physical activity has the capability This significant rise in vascular conductance between of maintaining vascular health, it is evident that the pres- early menses and the proliferative was not seen in the ence of estrogen in females is of equal importance. healthy control group; MAP and vascular conductance This experiment faced some potential limitations such as remained relatively similar between menstrual phases assessment of neural activity during exercise and compari- within this group (Figs.  3, 4, 5). Taking these results into son of the activity of other hormones. Neural control of the consideration, estrogen could potentially play a more vasculature from the sympathetic nervous system during drastic cardiovascular protective role in abdominal obese exercise was not measured in participants. Increased sym- pre-menopausal women compared to healthy weight pre- pathetic activity would increase heart rate and decrease menopausal women. However, as seen in Table  1, there artery diameter during exercise, a response that is abolished was not a significant difference in the overall Estradiol by the presence of estrogen [4, 5]. Future investigations (E2) content between the groups during the Early Men- should measure concentrations of norepinephrine spillo- ses and Proliferative Phase. Additionally, in the study, ver or Muscle Sympathetic Nerve Activity (MSNA) during analysis using the 2 × 2 ANOVA comparing the groups exercise to determine if overweight women have higher by weight, and menstrual cycle phase on the outcomes of levels of sympathetic activity compared to healthy controls. vascular conductance indicated these was changes within This increased sympathetic activity could potentially drive the groups but not between the groups when comparing down vascular conductance. Concentrations of 11-keto-tes- the menstrual cycle phase. Although there is an initial tosterone were measured to determine potential hormone R estaino et al. Artery Research (2022) 28:79–88 87 Author details imbalances within the overweight women,however, no Department of Biology, Eastern New Mexico University, Station 33, 1500 S. imbalance was seen. Future investigations should consider Ave K, Portales, NM 88130, USA. Biology Division, Trocaire College, Buffalo, NY the role of insulin as a growth factor or the activity of other 14220, USA. hormones such as leptin on the vasculature. Increased Received: 19 January 2022 Accepted: 3 May 2022 leptin has been associated with hyperinsulinemia, insulin Published online: 27 May 2022 resistance, and obesity [29],these heightened leptin concen- trations have led to coronary endothelial dysfunction in rat and dog models [10]. Further investigation should consider References metabolic regulation in overweight abdominal obese pre- 1. 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Augmented sympathetic vasoconstriction in exercising forearms results have uncovered this condition at an early time point of postmenopausal women is reversed by oestrogen therapy. J Physiol. where simple changes in lifestyle may be all that is required 2004;561(Pt 3):893–901. https:// doi. org/ 10. 1113/ jphys iol. 2004. 073619. 6. Gonzales JU, Thompson BC, Thistlethwaite JR, Harper AJ, Scheuermann to improve vascular function. This experiment provides BW. Forearm blood flow follows work rate during submaximal dynamic a potential mechanistic target in vascular dysfunction in forearm exercise independent of sex. J Appl Physiol. 2007;103(6):1950–7. young overweight women at a time when complications https:// doi. org/ 10. 1152/ jappl physi ol. 00452. 2007. 7. Gonzales JU, Thistlethwaite JR, Thompson BC, Scheuermann BW. Exercise- can be rectified. induced shear stress is associated with changes in plasma von Willebrand factor in older humans. Eur J Appl Physiol. 2009;106(5):779–84. https:// doi. org/ 10. 1007/ s00421- 009- 1074-x. Abbreviations 8. Grassi G, Seravalle G, Dell’Oro R, Turri C, Bolla GB, Mancia G. Adrenergic AO: Abdominal obese; eNOS: Endothelial nitric oxide synthase; NO: Nitric and reflex abnormalities in obesity-related hypertension. Hypertension. oxide; HDL: High-density lipoprotein; BMI: Body mass index; BF%: Body fat 2000;36(4):538–42. https:// doi. org/ 10. 1161/ 01. hyp. 36.4. 538. percentage; ECG: Electrocardiogram; oxLDL: Oxidative low-density lipoprotein; 9. Gupta A, Gupta V. Metabolic syndrome: what are the risks for humans? MAP: Mean arterial pressure. Biosci Trends. 2010;4(5):204–12. 10. Knudson JD, Dincer UD, Zhang C, Swafford AN Jr, Koshida R, Picchi A, Author contributions Focardi M, Dick GM, Tune JD. Leptin receptors are expressed in coronary RMR and MAB conceived and designed research; RMR and MAB performed arteries, and hyperleptinemia causes significant coronary endothelial experiments; RMR analyzed data; MAB interpreted results of experiments; dysfunction. Am J Physiol Heart Circ Physiol. 2005;289(1):H48–56. https:// RMR and MAB prepared figures; RMR and MAB drafted manuscript; edited and doi. org/ 10. 1152/ ajphe art. 01159. 2004. revised manuscript; RMR, KC, and MAB approved final version of manuscript. 11. Lambert E, Straznicky N, Eikelis N, Esler M, Dawood T, Masuo K, Schlaich M, Lambert G. Gender differences in sympathetic nervous activity: influ- Funding ence of body mass and blood pressure. J Hypertens. 2007;25(7):1411–9. Research reported in this publication was supported by an Institutional Devel- https:// doi. org/ 10. 1097/ HJH. 0b013 e3281 053af4. opment Award (IDeA) from the National Institute of General Medical Sciences 12. 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Ability of physical activity to predict Conflict of interests cardiovascular disease beyond commonly evaluated cardiometabolic The authors declare that they have no competing interests. Consent for publication Not Applicable. Restaino et al. Artery Research (2022) 28:79–88 88 risk factors. Am J Cardiol. 2009;104(11):1522–6. https:// doi. org/ 10. 1016/j. amjca rd. 2009. 07. 023. 15. Moore DJ, Barlow MA, Gonzales JU, McGowan CL, Pawelczyk JA, Proctor DN. Evidence for the emergence of leg sympathetic vasoconstrictor tone with age in healthy women. Physiol Rep. 2015;3(1):e12275. https:// doi. org/ 10. 14814/ phy2. 12275. 16. Moreau KL, Donato AJ, Tanaka H, Jones PP, Gates PE, Seals DR. Basal leg blood flow in healthy women is related to age and hormone replace - ment therapy status. J Physiol. 2003;547(Pt 1):309–16. https:// doi. org/ 10. 1113/ jphys iol. 2002. 032524. 17. Moreau KL, Hildreth KL, Meditz AL, Deane KD, Kohrt WM. 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Pinola P, Lashen H, Bloigu A, Puukka K, Ulmanen M, Ruokonen A, Marti- kainen H, Pouta A, Franks S, Hartikainen AL, Järvelin MR, Morin-Papunen L. Menstrual disorders in adolescence: a marker for hyperandrogenaemia and increased metabolic risks in later life? Finnish general population- based birth cohort study. Hum Reprod. 2012;27(11):3279–86. https:// doi. org/ 10. 1093/ humrep/ des309. 22. Restaino RM, Holwerda SW, Credeur DP, Fadel PJ, Padilla J. Impact of pro- longed sitting on lower and upper limb micro- and macrovascular dilator function. Exp Physiol. 2015;100(7):829–38. https:// doi. org/ 10. 1113/ EP085 23. Restaino RM, Walsh LK, Morishima T, Vranish JR, Martinez-Lemus LA, Fadel PJ, Padilla J. Endothelial dysfunction following prolonged sitting is mediated by a reduction in shear stress. Am J Physiol Heart Circ Physiol. 2016;310(5):H648–53. https:// doi. org/ 10. 1152/ ajphe art. 00943. 2015. 24. Somani YB, Moore DJ, Kim DJ, Gonzales JU, Barlow MA, Elavsky S. 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Sex differences in fat distribution influence the association between BMI and arterial stiffness. J Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : Hypertens. 2017;35(6):1219–25. https:// doi. org/ 10. 1097/ HJH. 00000 00000 fast, convenient online submission 28. Virdis A, Ghiadoni L, Pinto S, Lombardo M, Petraglia F, Gennazzani A, thorough peer review by experienced researchers in your field Buralli S, Taddei S, Salvetti A. Mechanisms responsible for endothelial dysfunction associated with acute estrogen deprivation in normotensive rapid publication on acceptance women. Circulation. 2000;101(19):2258–63. https:// doi. org/ 10. 1161/ 01. cir. support for research data, including large and complex data types 101. 19. 2258. • gold Open Access which fosters wider collaboration and increased citations 29. Widjaja A, Stratton IM, Horn R, Holman RR, Turner R, Brabant G. UKPDS 20: plasma leptin, obesity, and plasma insulin in type 2 diabetic subjects. J maximum visibility for your research: over 100M website views per year Clin Endocrinol Metab. 1997;82(2):654–7. https:// doi. org/ 10. 1210/ jcem. 82.2. 3744. At BMC, research is always in progress. 30. Yang YM, Huang A, Kaley G, Sun D. eNOS uncoupling and endothe- Learn more biomedcentral.com/submissions lial dysfunction in aged vessels. Am J Physiol Heart Circ Physiol. 2009;297(5):H1829–36. https:// doi. org/ 10. 1152/ ajphe art. 00230. 2009. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Artery Research Springer Journals

Effects of the Follicular Menstrual Phase on Forearm Vascular Conductance in Abdominal Obese Premenopausal Women During Graded Handgrip Exercise

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10.1007/s44200-022-00017-x
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Abstract

Purpose: Previous studies have reported a sympatholytic action of estrogen on the vasculature in response to increased sympathetic outflow, an effect most notable during exercise, providing for necessary increases in blood flow to working muscle. In contrast, elevated concentrations of progesterone can inhibit this action of estrogen, impairing increases in blood flow. We hypothesize that the peak concentration of estrogen during the proliferative portion of the follicular phase of the menstrual cycle in female humans will increase vascular conductance during exercise when the effects of progesterone are negligible. In addition, we hypothesize that overweight abdominally obese females will have an attenuated conductance response to dynamic exercise during the same menstrual phase. Methods: Participants engaged in graded forearm exercise using an isotonic handgrip dynometer with sequential increases in resistance at a cadence of 30 contractions/minute until task failure. They performed exercise at time points of the menstrual cycle corresponding to low concentrations of both sex hormones and elevated estrogen, while progesterone remained low. Blood flow and vascular conductance were measured using Doppler ultrasound. Results: This revealed a trend that abdominal obese women during a phase of low estrogen had a lower overall blood flow and vascular conductance response than healthy controls at matching resistance stages during rest and exercise. This group difference was attenuated during the proliferative phase with elevated circulating estrogen. There is not a statistically significant interaction between Ovarian Phase and Weight group (P = 0.778). Conclusion: The results indicate that overweight women are at a disadvantage during exercise in increasing blood flow to working muscles, which can be detrimental to overall fitness improvement during the early and potentially late follicular phase of the menstrual cycle. Keywords: Abdominal obese, Pre-menopausal females, Brachial artery exercise, Blood flow, Menstrual cycle During exercise, estrogen can facilitate increased blood 1 Introduction flow to working muscles through endothelial-depend - Estrogen provides a protective role in maintaining proper ent dilation via activation of endothelial nitric oxide endothelial function in pre-menopausal women [28]. synthase (eNOS). This action of estrogen proves to be sympatholytic as it occurs with increased sympathetic *Correspondence: matthew.barlow@enmu.edu outflow via activation of the exercise pressor reflex. In contrast, progesterone can act to block this sympatho- Department of Biology, Eastern New Mexico University, Station 33, 1500 S. Ave K, Portales, NM 88130, USA lytic mechanism of estrogen limiting increases in blood Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Restaino et al. Artery Research (2022) 28:79–88 80 flow during exercise [4]. In healthy women, this bal - follicular phase of the menstrual cycle in female humans ance in hemodynamic effects of sex hormones serves to will increase vascular conductance during exercise when regulate increases in blood flow and vascular conduct - the effects of progesterone are negligible. In addition, we ance. Overweight and abdominal obese conditions, how- hypothesize that overweight abdominal obese females ever, correlate to disturbances in the menstrual cycle. will have an attenuated conductance response to graded These menstrual disturbances could potentially lead to isotonic handgrip exercise during the same menstrual decreases in estrogen production and an increased level phase. of androgens in young women who are overweight [21]. Potentially, the hormonal imbalance could leave over-2 Methods weight women at a disadvantage during exercise due 2.1 Participants to decreased blood flow and conductance to working 20 women (11 controls and 9 abdominal obese) aged muscle. 25 ± 1.29  years were examined in this study. All partici- Excessive body weight in young women can poten- pants were volunteers and were non-smokers, sedentary tially intensify the advancement of peripheral vascular (30  min of moderate exercise less than 4 times a week), dysfunction and cardiovascular disease similar to that and not on any form of birth control as determined by seen in normal aging. Impairment in eNOS activity and a physical examination form and a personal question- blunted production of the vasodilator nitric oxide (NO) naire. Participants were screened and separated into has been demonstrated to be the underlying cause of two groups based on physical characteristics: healthy vascular dysfunction with exercise in the elderly with sedentary control and sedentary abdominal obese (AO) evidence in both the arms and legs [26, 19, 20]). Other (having at least two but not ≥ 3 criteria of the NCEP III characteristics and risk factors that arise from being categorization of the Metabolic Syndrome including a overweight are analogous to those seen in an aging popu- waist circumference > 96  cm) [9]. On study days, partici- lation, and specifically in conduit artery sheer stress post- pants refrained from caffeine, aspirin, or ibuprofen inges - menopausal women [24]. Increased oxidative stress and tion 12  h prior to arrival. Participation took place over reduced antioxidant capacity, factors seen in both over- the course of three separate visits. All participants were weight and elderly individuals, impair endothelial func- recruited locally and gave written informed consent prior tion through oxidation of NO and uncoupling of eNOS to any action taken in the laboratory. A schematic of the [15], Hashimoto et  al. 1995, Kawano et  al. 1995 [3, 30]. study design is presented in Fig. 1. All experimental pro- Estrogen may have antioxidant effects at the cellular cedures and protocols conformed to the Declaration of level, protecting young healthy women from dysfunction Helsinki and the study was approved by the Human Sub- [16]. However, young overweight women with poten- jects Committee Institutional Review Board at Eastern tially impaired effects of estrogen could be at a similarly New Mexico University. elevated risk as post-menopausal women. [25, 24]. Fur- ther investigation is necessary to decipher the potential 2.2 Visit 1 disruption of normal vascular physiology during exercise Classification of participants to study groups was based in overweight young women statistically associated with on physical characteristics (BMI, body fat percentage, lower levels of cardiovascular fitness [13, 14]. waist/hip ratio, resting blood pressure, fasted blood glu- The aim of this study is to determine if elevated cose, triglycerides, total cholesterol, and HDL). Group endogenous estrogen has an altered effect on working characteristics are reported in Table  1. All participants muscle vascular conductance in overweight women as were asked to refrain from alcohol, exercise, caffeine, compared to healthy control individuals. Limberg et  al. aspirin, and ibuprofen, for at least 12  h prior to all test- [12] concluded there is a facilitating effect of estrogen on ing. We recorded anthropometric measurements at this increases in vascular conductance with reduced alpha2- physical screening visit with participants arriving fasted aderenergic vasoconstriction during isometric handgrip 10–12 h prior to arrival. BMI and percent body fat were exercise. However, there was no significant difference measured through bioimpedance using an Omron Fat between the male group and early follicular phase. The Loss Monitor (HBF-306C). Triglycerides, HDL, total lack of change between the Early Follicular Menses cholesterol, and fasted blood glucose were measured phase and the luteal phase could have been from vascu- from capillary blood sample obtained through finger lar antagonist effects of the rise in progesterone during prick (CardioChek Portable Blood Test System, PTS this phase, although Limberg et  al. unfortunately lacked Panels, for cholesterol; OneTouch Ultra 2 Blood Glucose the plasma measurement of estrogen and progesterone Monitoring System for glucose measurement). Two 6 mL in the study. We hypothesize that the peak concentra- venous blood samples were collected in 10.8  mg EDTA- tion of estrogen during the proliferative portion of the treated 6  mL vacutainers (BD, Franklin Lakes, NJ) and R estaino et al. Artery Research (2022) 28:79–88 81 Plasma collecon for hormone analysis Visit 1: Physical Measurements, Familiarizaon 10 minute resng ECG and Blood Pressure No specific me interval Visit 2: Experimental visit, Exercise bout I, Exercise Protocol Early Menses 7 days between 30 seconds 2 minutes Increase in Visit 2 and Visit 3 Rest unloaded workload, 0.25 contracons Was/minute Visit 3: Experimental visit, Exercise bout II, Brachial artery diameter and blood velocity Proliferave Phase recorded throughout exercise Fig. 1 A Overall schematic of participation in study; B, description of experimental visits and exercise protocol Table 1 Physical characteristics of overall experimental groups displayed as averages ± SD; categories statistically different between groups are marked by * (W:H waist-to-hip ratio, BMI Body Mass Index, BF% percent Body Fat) Control/healthy (n = 11) Abdominal obese (n = 10) p value Height (cm) 163.98 ± 1.65 169.29 ± 2.71 0.168 Weight (kg) * 56.53 ± 5.02 97.14 ± 5.57 < 0.001 Waist size (cm) 81.86 ± 6.9 113 ± 19.3 < 0.001 W:H* 0.81 ± 0.01 0.96 ± 0.03 0.002 BMI* 24.1 ± 0.59 33.82 ± 1.94 < 0.001 BF%* 24.47 ± 1.1 35.42 ± 1.86 0.001 Fasted glucose (mg/dl) 91.57 ± 1.71 99.9 ± 2.78 0.007 SBP (mmHg) 115 ± 3.98 119.7 ± 4.79 0.586 DBP (mmHg) 73.7 ± 2.23 77.2 ± 3.53 0.493 Total Chol mg/dL 140.0 ± 8.6 148.4 ± 11.2 0.544 HDL Chol (mg/dL) 45.83 ± 3.29 40.9 ± 2.27 0.137 Trig (mg/dL) 97.0 ± 8.4 101.8 ± 19.2 0.841 Menses E2 (pg/mL) 75.55 ± 10.02 51.86 ± 6.37 0.186 Prolif E2 (pg/mL) 301.25 ± 34.58 346.03 ± 40.4 0.609 Menses Prog (pg/mL) 106.65 ± 63.15 155.2 ± 97.17 0.332 Prolif Prog (pg/mL) 141.57 ± 78.32 141.56 ± 97.74 0.915 Menses Prog: E2 1.93 ± 1.68 4.28 ± 4.82 0.39 Prolif Prog: E2 0.74 ± 0.55 0.51 ± 0.53 0.516 Testosterone (pg/mL) 45.6 ± 5.84 42.45 ± 8.55 0.39 oxLDL (pg/mL) 98.1 + 40.6 146.06 ± 62.25 0.047 Forearm volume (ml) 791.1 ± 13.61 1021.43 ± 73.01 0.050 Restaino et al. Artery Research (2022) 28:79–88 82 centrifuged, and plasma was aliquoted stored in 1  mL in diameter changes of conduit arteries continuously as microtubes and stored at − 80  °C for future analysis of well as changes in velocity without halting the graded 11-keto-testosterone, 17-β-estradiol and Progesterone workloads until task failure. Diameter was defined as and Oxidative LDL. the distance between intima layers of the vessel walls in a longitudinal section of the brachial artery. Diam- 2.3 Visit 2 eter measurements were assessed during the final 15 s of Upon arrival, participants were asked to provide venous each set for analysis. Velocity was continuously recorded blood samples for measurement of 17-β-Estradiol and through Doppler B-mode and a custom-built interface Progesterone. This visit was scheduled during self- audio transducer unit which processed the high-resolu- reported early menses when estrogen and progesterone tion, angle corrected, intensity weighted Doppler audio levels can be expected to be at their lowest menstrual information from the ultrasound system into a lower fre- cycle concentrations. Forearm volume was measured quency velocity signal (0–20  Hz) (Herr et  al. 2010) that using water displacement with participants placing the could be sampled in real time by AcqKnowledge 4.4 data non-dominant arm into a column of water, the resulting acquisition software. Post-processing analysis using Acq- volume of overflow being measured, and volume of the Knowledge acquisition yielded mean blood velocities cal- hand being subtracted for pure forearm volume. Partici- culated as mean of the final 30 s for ever stage [20]. pants were placed in a supine position, while three lead ECG was recorded for 10  min on a Biopac MP150 data acquisition unit using AcqKnowledge 4.4 data acquisi-2.4 Visit 3 tion software (Biopac Systems Inc., Goleta, CA). Rest- This visit was scheduled 1 week after visit 2 during the ing blood pressure was recorded after ECG using an proliferative phase of the menstrual cycle. Similar to Omron Blood Pressure Monitor. Participants remained visit 2, venous plasma samples were collected again to in the supine position during the entire course of exer- measure an expected rise in estrogen concentrations cise; all participants exercised the non-dominant left and to determine if progesterone had changed sig- forearm. Exercise was completed using a custom-built nificantly. The handgrip exercise protocol of this visit handgrip dynamic ergometer with participants exercis- repeated from that executed on the second visit and ing at a cadence of 30 handgrip contractions per minute. continuous resting and exercise ECG and blood pres- Participants began graded exercise with their non-domi- sure were also recorded on this visit. nant hand with 2 min of unloaded contraction (0 Watts) followed by a ramp increase in workload of 0.25 Watts (0.5 kg resistance) every minute [6, 9]. Participants were 2.5 Artery Diameter and Blood Velocity Analysis asked to continue exercise until task failure was reached. Diameter recordings of the brachial artery collected Task failure was defined as the inability to maintain the during the handgrip exercise bouts of visits 2 and 3 proper cadence of 30 contractions per minute. During were recorded digitally and analyzed post-test using exercise, blood velocity and vessel diameter were meas- edge detection software (Brachial Analyzer 5.10.11, ured in the brachial artery of the exercising left arm using Medical Imaging Applications, Iowa City, Iowa). Aver- a linear array ultrasound probe operating at 4–7  MHz age diameter at each stage of exercise was recorded. (Phillips HDI 5000 Ultrasound System, ATL Ultrasound, Blood velocity recordings from each visit were analyzed Bothell, WA). Doppler ultrasound was used for the meas- by determining the average velocities seen at each stage urement of blood flow in during in the graded handgrip of exercise. Arterial blood pressure and heart rate were exercise as prior research groups have determined that also recorded at each stage of exercise via beat-to-beat the strain-gauge plethysmography methods give an esti- finger plethysmography and ECG respectively. Diame - mate of limb blood flow at rest during the end of exer - ter and mean velocity data were used to calculate blood cise, but not for continuous exercise in a graded dynamic flow to the forearm through the brachial artery at each exercise setting, because the participant is required to stage using the formula Q = π r *v (ml/min). Recorded stop contracting during the exercise to measure the limb beat-to-beat blood pressures were used to calculate flow changes. Additionally, as stated by Byström et  al., mean arterial pressure (1/3 Pulse Pressure + Diastolic the occlusion pressure required for obtaining the meas- Pressure) which was used to calculate forearm vascu- urement of blood flow using occlusion plethysmography lar conductance (C = Q/P; ml/min/mmHg). Forearm of the forearm causes a 28% reduction in muscle blood volumes were used to correct blood flow and vascular flow during graded handgrip exercise and significantly by conductance values per 100  mL of forearm volume for underestimating the change in flow [2]. Doppler ultra - each participant. The intra-rater reliability for repro - sound with the linear flow probe allows for detection ducibility of the Doppler ultrasound measurement was R estaino et al. Artery Research (2022) 28:79–88 83 measured by calculating the coefficient of variation on cholesterol, between overweight and control partici- a control group (n = 10) of participants. Measurements pants. However, these comparisons were not statistically were taken of the brachial artery diameter and mean significant. All ECG recordings collected at visit 2 under - arterial velocity at rest on two separate visits by the went heart rate variability analysis; statistical review of same imaging technician. the resulting data yielded no significant results between groups. 2.6 Biomarker Analysis Plasma samples from each participant were used to 3.2 Vascular Responses to Exercise measure oxidative stress in an oxidized LDL (oxLDL) Percent dilation was calculated as the change from resting assay (Cell Biolabs, Inc., San Diego, CA). Additionally, diameter to end of the 1.5 Watt stage of exercise divided 11-keto-testosterone, 17-β-estradiol, and Progesterone by resting diameter × 100. The 1.5 Watt stage was deter - was also measured from the plasma samples collected mined as the common end point among participants. The from each participant using associated EIA kits (Caymen overall change in diameter of the brachial artery from rest Chemical Company, Ann Arbor, MI).; absorbance was to 1.5 Watts was not significantly different in either of the read at 412, 420, and 450 nm, respectively. experimental groups from early menses to the prolifera- tive phase. This change in dilation was slightly, though not significantly, different between groups (Fig.  2). Per- 2.7 Statistical Analysis cent dilation in the control group was not different dur - Within group statistical variance between time points ing the proliferative phase (12.951% ± 7.4) as compared to was assessed with a repeated-measure ANOVA with a that seen in early menses (13.5 ± 6.34). This relationship Tukey’s post hoc analysis comparing percent dilation was not seen in the abdominal obese group. In addition, from rest to 1.5 Watts (3 kg resistance), which was a com- percent dilation in the AO group during the proliferative mon end point across participants and groups. Similar phase was greater (12.37 ± 3.52) than that seen in the AO analysis assessed differences in flow and conductance group during early menses phase (10.4 ± 7.86) although corrected for forearm volume, along with mean arterial not statistically different. (Fig.  2). However, these differ - pressure. An unpaired T test was used to compare differ - ences yielded no statistical significance (p = 0.868 and ences between groups including estrogen, progesterone, 0.74, respectively). There was no statistical difference in and testosterone concentrations. The potential rise in resting diameter between groups or between time points estrogen between these two menstrual phases was cal- within the two groups. culated as the percent difference; the change from early Systolic and diastolic blood pressure was assessed menses to the proliferative phase over the average of the throughout the handgrip exercise and used to calculate two concentrations. Variation in the percent difference was assessed by an unpaired T test. P < 0.05 was consid- ered significant. To determine if the change in estrogen Percent Dilation of the Brachial Artery (Rest to 1.5 Watts) between the menses and proliferative time period had an altered effect on working muscle vascular conductance in the AO women as compared to the healthy control a Early Menses Proliferative Phase 2 × 2 mixed ANOVA was compared. Data are resented as means ± SD. 3 Results 3.1 P hysical Measurements and Functional Analysis Comparison of the anthropometric data gathered from each group yielded significant difference between control participants and AO participants. Physical measurements revealed the AO participants had significantly (P < 0.05) ControlAO waist circumference, higher body fat percentages (BF%), Groups and body mass indices (BMI) as well as significantly Fig. 2 Percent dilation during exercise within each group, comparing higher fasted blood glucose, weights and waist-to-hip dilatory responses seen during early menses (low estrogen) and ratios, oxLDL, and Forearm Volume; see Table  1. Meas- during the proliferative phase (high estrogen). Control percent urements also revealed differences in triglycerides, total dilation p = 0.868. Between group comparison at proliferative phase p = 0.433 cholesterol, systolic and diastolic blood pressures, HDL % Dilation Restaino et al. Artery Research (2022) 28:79–88 84 Control Mean Arterial Pressure, Control Mean Blood Velocity, Early Menses vs Proliferative Phase Early Menses vs. Proliferative Phase 90 15 Early Menses Proliferative Phase 10 Early Menses Rest 00.5 11.5 Proliferative Phase Workload (Watts) Rest 00.5 11.5 Abdominal Obese Mean Arterial Pressure, Workload (Watts) Early Menses vs. Proliferative Phase Abdominal Obese M ean Blood Velocity, Early Menses vs. Proliferative Phase ** ** ** Early Menses Early Menses Proliferative Phase Proliferative Phase Rest 00.5 11.5 Rest 00.5 11.5 Workload (Watts) Workload (Watts) Fig. 3 Mean arterial pressure in control and overweight participants Fig. 4 Mean blood velocity in the brachial artery during isotonic during dynamic handgrip exercise, rest to 1.5 Watts, *indicates a graded handgrip exercise in control and overweight participants, rest significant difference between the groups during the Early Menses to 1.5 watts phase (p < 0.05). **indicates a significant difference in the AO group between Early Menses and the Proliferative Phase there was no pressure differences between the groups at any point of the exercise. During the early menses exercise period in the AO group, the mean blood veloc- mean arterial pressure (MAP). During the Early Menses ity measurements were lower compared with the pro- period, there was a significantly higher MAP in the AO liferative phase in the AO participants when although group during rest, unloaded, and 0.5- and 1.0-Watts no statistical difference was found at any workload. No workloads compared to the Proliferative Phase (Fig.  3). difference was seen in blood velocity during exercise in MAP in Control participants from rest to the 1.5 Watts control participants and no statistical differences were workload stage was not seen to be significantly different present between the groups (Fig. 4). between experimental stages of the menstrual cycle, Vascular conductance of the brachial artery was cal- from early menses to the proliferative phase (Fig.  3). culated at each workload during exercise. No significant When comparing the control to the AO groups, the differences were observed within either group when con - MAP was significantly lower in the Early Menses period ductance was compared between experimental menstrual (83.1 ± 7.1 vs 91.4 ± 7.7  mmHg , p = 0.045) at rest and cycle phases. In a comparison of conductance responses the unloaded movement but was no longer significant; during early menses when estrogen concentrations were during the graded exercise, the MAP differences when lowest, AO participants presented with lower vascular estrogen was elevated; during the Proliferative Phase, MAP (mmHg) MAP (mmHg) Velocity (cm/sec) Velocity (cm/s) R estaino et al. Artery Research (2022) 28:79–88 85 Conductance responses were calculated per 100  mL Vascular Conductance during Early Menses, of forearm volume. Comparison of forearm volumes Contol vs Abdominal Obese revealed that AO participants had significantly higher forearm volumes compared to controls (Table  1). The 0.22 coefficient of variation for participants during a time 0.20 † control for the measures of resting brachial diameter 0.18 and mean blood velocity using the Doppler ultrasound 0.16 method were 1.9% and 3.4% respectively. 0.14 Plasma samples were assayed, and estrogen concen- 0.12 trations were measured for both early menses and the 0.10 proliferative phase in both control and AO groups. In 0.08 both experimental groups, a rise in estrogen was meas- 0.06 ured in pg/mL from early menses to the proliferative Control 0.04 phase. Estrogen concentrations were slightly higher Abdominal Obese in the control group as compared to the AO group 0.02 Rest 00.5 11.5 at early menses (control = 67.15  pg/mL ± 13.4; over- Worload (Watts) weight = 51.86 ± 9.005; p = 0.556); this relationship was reversed at the proliferative phase as the AO presented Vascular Conductance during Proliferative Phase, Control vs Abdominal Obese higher estrogen concentrations (control = 319.12 ± 40.6; 0.22 AO = 346.03 ± 70.21; p = 0.664), although these concen- 0.20 trations were not significantly different. Progesterone 0.18 plasma concentrations were also measured and calcu- 0.16 lated into pg/mL. The concentration from early menses 0.14 to the proliferative phase in both groups determined no statistically significant change and remained well within 0.12 the same range (control p = 0.455; AO p = 0.65). Tes- 0.10 tosterone concentrations were measured in plasma and 0.08 compared between groups; no significant difference 0.06 was seen. There was a significant difference between the Control 0.04 Abdominal Obese measurements of oxLDL (pg/mL) with the AO group 0.02 Rest 00.5 11.5 having a larger plasma concentration (146.1 ± 62.25  pg/ Workload (Watts) mL) compared to the control group (98.1 ± 40.6  pg/mL) Fig. 5 Vascular conductance of the brachial artery during handgrip as measured during the early menses stage (Table 1). exercise compared between groups during early menses, *p < 0.05, †p < 0.1. During the Early Menses period, the comparison between 4 Discussion the groups were significantly different (+ , p = 0.016) for the delta between rest and peak conductance at 1.5-Watt workload The major finding of the present study is that the over - weight abdominal obese pre-menopausal women exhibit a lowered brachial conductance response to dynamic graded small muscle exercise during the early menses conductance responses compared to healthy controls of the menstrual cycle follicular phase. This attenuated all workloads (Fig.  5). The group difference in the high vascular response was also resolved equal to the age- estrogen period of the proliferative phase was attenuated matched health controls upon increases in Estrogen dur- at the AO group presented with an increase in conduct- ing the menstrual proliferative phase prior to ovulation. ance response although not significantly difference from Previous studies have described a potential facilitating Early Menses and the control group at the same period. effect of estrogen on increases in vascular conductance When comparison of the delta from rest to the 1.5-Watt during exercise [4], 5, 12]. Overall, the data in this study workload using a 2 × 2 ANOVA, the difference in the indicate that in young women, normally considered vas- mean values among the different levels of weight group cularly healthy can present with the characteristics of is greater than would be expected by chance after allow- vascular deficiencies not presumed to be detrimental. ing for effects of differences in ovarian phase. There is a We found the MAP when compared between phases statistically significant difference (+ in Fig.  5, P = 0.016). of the menstrual cycle within the control group exhib- However, there is not a statistically significant interaction ited no differences in MAP between early menses and between Ovarian Phase and Weight group (P = 0.778). Conductance (ml/min/mmHg/100mL forearm vol) Conductance (mL/min/mmHg/100 mL forearm vol) Restaino et al. Artery Research (2022) 28:79–88 86 the proliferative phase; however, MAP in the AO women increase in Progesterone in the Early Menses Phase of the was higher during early menses than that seen during the AO group, there was not a significant difference either proliferative phase (Fig.  3). MAP within the AO women between the control groups and overweight at either during the proliferative phase was returned to levels time point; neither was there a progesterone to estrogen consistent with those seen in the healthy control group ratio significance difference (Table  1). However, as indi- (Fig.  3). This difference in arterial pressure during exer - cated by Limberg et al., the increase in Progesterone dur- cise at the two menstrual cycle time points could poten- ing the follicular phase of the menstrual cycle in healthy tially serve as the cause for the difference in conductance controls and overweight abdominal obese women could during early menses in AO women when compared potentially attenuate the benefits that estrogen may pro - to controls. Vascular function assessed in the forearm vide for vascular function [12]. The AO group exhibit a of women across the menopausal transition in seden- reduced conductance during exercise similar to that seen tary women suggests functional lost with the loss ovar- in post-menopausal women, but only during the Early ian function [16, 17]. However, the ovarian functional Menses phase of the cycle. This reduced response is only changes to the vascular blood flow in sedentary over - reversed with increases in endogenous estrogen, similar weight women at various stages of the menstrual cycle to that seen in post-menopausal women after exogenous have not been demonstrated, although obesity is highly estrogen treatment [5]. Removal of estrogen through linked to hypertension and sympathetic reflex abnormali - menopause in overweight women would leave no means ties [8, 11]. Additionally, abdominal obesity is highly cor- of maintaining relative cardiovascular health. Reduced related to higher Pulse Wave Velocity in women which function is expected with aging (Parker et al. 2008),how- could also indicate stiffer arteries causing elevated blood ever, this reduced function is already present in young pressure and diminished flow (van den [27]. The rela - pre-menopausal women. Further endothelial dysfunc- tionship between abdominal obesity and PWV during tion could potentially increase with the advancement of the menstrual cycle phases was not accessed during this associated insulin resistance and diabetes, and worsen study. Although blood pressures were higher in the early beyond even normal aging. As previously demonstrated, menses phase for the overweight group during the exer- sedentary practices also have deleterious effects on vas - cise, an alternative approach is needed for the role of cen- cular function [1], [22, 23, 18] Though exercise-induced tral and peripheral arterial stiffness during these different shear stress can restore normal function in response to phases of the menstrual cycle in both groups. an acute sedentary period and even prevent it [22, 18], The significance difference in vascular conductance such benefits may not be fully realized in young over - seems to be mostly weighted in the changes in MAP and weight females. The present results indicate an impor - resulting changes in vascular conductance in the AO tant link between menstrual hormone concentrations women. Our results indicate that AO pre-menopausal and exercise-stimulated blood flow, and the attenuation women have reduced vascular conductance during early of this dynamic in the presence of poor metabolic health. menses when estrogen concentrations are lowest, only to A sedentary lifestyle can lead to excess weight gain and return to within a normal healthy range during the pro- metabolic dysfunction, both impairing vascular functions liferative phase when endogenous estrogen is increased. systemically. Though physical activity has the capability This significant rise in vascular conductance between of maintaining vascular health, it is evident that the pres- early menses and the proliferative was not seen in the ence of estrogen in females is of equal importance. healthy control group; MAP and vascular conductance This experiment faced some potential limitations such as remained relatively similar between menstrual phases assessment of neural activity during exercise and compari- within this group (Figs.  3, 4, 5). Taking these results into son of the activity of other hormones. Neural control of the consideration, estrogen could potentially play a more vasculature from the sympathetic nervous system during drastic cardiovascular protective role in abdominal obese exercise was not measured in participants. Increased sym- pre-menopausal women compared to healthy weight pre- pathetic activity would increase heart rate and decrease menopausal women. However, as seen in Table  1, there artery diameter during exercise, a response that is abolished was not a significant difference in the overall Estradiol by the presence of estrogen [4, 5]. Future investigations (E2) content between the groups during the Early Men- should measure concentrations of norepinephrine spillo- ses and Proliferative Phase. Additionally, in the study, ver or Muscle Sympathetic Nerve Activity (MSNA) during analysis using the 2 × 2 ANOVA comparing the groups exercise to determine if overweight women have higher by weight, and menstrual cycle phase on the outcomes of levels of sympathetic activity compared to healthy controls. vascular conductance indicated these was changes within This increased sympathetic activity could potentially drive the groups but not between the groups when comparing down vascular conductance. Concentrations of 11-keto-tes- the menstrual cycle phase. Although there is an initial tosterone were measured to determine potential hormone R estaino et al. Artery Research (2022) 28:79–88 87 Author details imbalances within the overweight women,however, no Department of Biology, Eastern New Mexico University, Station 33, 1500 S. imbalance was seen. Future investigations should consider Ave K, Portales, NM 88130, USA. Biology Division, Trocaire College, Buffalo, NY the role of insulin as a growth factor or the activity of other 14220, USA. hormones such as leptin on the vasculature. Increased Received: 19 January 2022 Accepted: 3 May 2022 leptin has been associated with hyperinsulinemia, insulin Published online: 27 May 2022 resistance, and obesity [29],these heightened leptin concen- trations have led to coronary endothelial dysfunction in rat and dog models [10]. Further investigation should consider References metabolic regulation in overweight abdominal obese pre- 1. 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Journal

Artery Research – Springer Journals

Published: Jun 1, 2022

Keywords: Abdominal obese; Pre-menopausal females; Brachial artery exercise; Blood flow; Menstrual cycle

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