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Menstrual cycle effects on sympathetic neural responses to upright

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					J Physiol 587.9 (2009) pp 2019–2031                                                                                                          2019



Menstrual cycle effects on sympathetic neural responses
to upright tilt
Qi Fu1,2 , Kazunobu Okazaki1 , Shigeki Shibata1,2 , Robin P. Shook1 , Tiffany B. VanGunday1 ,
M. Melyn Galbreath1,2 , Miriam F. Reelick1 and Benjamin D. Levine1,2
1
    Institute for Exercise and Environmental Medicine, Presbyterian Hospital of Dallas, Dallas, TX, USA
2
    The University of Texas Southwestern Medical Center at Dallas, TX, USA


                 Young women are more susceptible to orthostatic intolerance than men, though the sex-specific
                 pathophysiology remains unknown. As blood pressure (BP) is regulated through the baroreflex
                 mechanism, we tested the hypothesis that baroreflex control of muscle sympathetic nerve activity
                 (MSNA) during orthostasis is impaired in women and can be affected by the menstrual cycle.
                 MSNA and haemodynamics were measured supine and during a graded upright tilt (30 deg for
                 6 min, 60 deg for 45 min or till presyncope) in 11 young men and 11 women during the early
                 follicular (EFP) and mid-luteal phase (MLP) of the menstrual cycle. Sympathetic baroreflex
                 sensitivity was quantified using the slope of the linear correlation between total activity and
                 diastolic BP during spontaneous breathing. Baroreflex function was further assessed during
                 a Valsalva manoeuvre (VM). Although MSNA burst frequency responses during tilting were
                 similar between sexes and menstrual phases, increases in total activity were lower in women
                 during EFP than MLP (P = 0.030), while total peripheral resistance and plasma noradrenaline
                 were not similarly lower; upright total activity tended to be lower in women during EFP than
                 men (P = 0.102). Sympathetic baroreflex sensitivity did not differ between sexes (P = 0.676)
                 supine (−281 ± 46 (s.e.m.) units beat−1 mmHg−1 in men vs −252 ± 52 in EFP and −272 ± 40
                 in MLP in women), at 30 deg tilt (−648 ± 129 vs −611 ± 79 and −487 ± 94), and at 60 deg tilt
                 (−792 ± 135 vs −831 ± 92 and −814 ± 142); this sensitivity was not affected by the menstrual
                 cycle (P = 0.747). Similar sympathetic baroreflex sensitivity between sexes and phases was
                 also observed during the VM. Cardiovagal baroreflex sensitivity assessed during decreasing
                 BP (i.e. early phase II of the VM) was comparable between sexes, but it was greater in men
                 than women during increasing BP (i.e. phase IV); the menstrual cycle had no influences on
                 cardiovagal baroreflex sensitivity. We conclude that the menstrual cycle affects sympathetic
                 neural responses but not sympathetic baroreflex sensitivity during orthostasis, though upright
                 vasomotor sympathetic activity is not clearly different between men and women. Not only
                 sympathetic but also cardiovagal baroreflex sensitivity is similar between sexes and menstrual
                 phases during a hypotensive stimulus. However, cardiovagal baroreflex-mediated bradycardia
                 during a hypertensive stimulus is different between sexes but not affected by the menstrual cycle.
                 Thus, other factors rather than sympathetic baroreflex control mechanisms contribute to sex
                 differences in orthostatic tolerance in young humans.
                 (Received 30 December 2008; accepted after revision 17 February 2009; first published online 23 February 2009)
                 Corresponding author Q. Fu: Institute for Exercise and Environmental Medicine, 7232 Greenville Avenue, Suite 435,
                 Dallas, TX 75231, USA. Email: qifu@texashealth.org

                 Abbreviations BP, blood pressure; EFP, early follicular phase; MLP, mid-luteal phase; MSNA, muscle sympathetic nerve
                 activity; VM, Valsalva manoeuvre.


Young women have a greater incidence of orthostatic                               cycle or differences in some hormonal levels may affect
intolerance compared with young men (Robertson, 1999;                             orthostatic blood pressure regulation.
Fu et al. 2004a, 2005a; Meendering et al. 2005), but the                            Sympathetic neural control plays a critical role
underlying mechanisms are not well understood. It is likely                       in arterial pressure maintenance mainly through
that certain sex-specific factors, such as the menstrual                           baroreflex-mediated vasoconstriction during short-term

C    2009 The Authors. Journal compilation   C   2009 The Physiological Society                                    DOI: 10.1113/jphysiol.2008.168468

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2020                                                  Q. Fu and others                                                             J Physiol 587.9


(Wallin & Sundlof, 1982; Fu et al. 2004b) and sustained         Table 1. Subjects’ characteristics
(Fu et al. 2006) orthostasis in humans. Results regarding
                                                                                                       Women (n = 11)
sex differences in sympathetic neural control during
orthostasis are few and controversial. There are only                                                Early
two studies, with different findings, showing muscle                                                follicular         Mid-luteal         Men
sympathetic nerve activity (MSNA) responses during              Variables                            phase             phase           (n = 11)
upright posture in young men and women (Shoemaker               Age (years)                         33 ± 3              33 ± 3          32 ± 3
et al. 2001; Fu et al. 2005a). Conversely, there is             Height (cm)                        166 ± 2†            165 ± 2†        176 ± 2
no information available concerning the effects of the          Weight (kg)                         64 ± 2†             64 ± 2†         79 ± 4
menstrual cycle on MSNA responses during orthostasis            Body mass index (kg m−2 )           23 ± 1              23 ± 1          25 ± 1
in humans.                                                      Oestradiol (pg ml−1 )               32 ± 2              92 ± 14∗          —
   Minson et al. (2000a) demonstrated previously that           Progesterone (ng ml−1 )            0.9 ± 0.2          11.1 ± 1.7∗         —
sympathetic baroreflex sensitivity was influenced by              Values are presented as means ± S.E.M. ∗ P < 0.05 compared with
hormonal fluctuations during the normal menstrual cycle          the early follicular phase in women. †P < 0.05 compared with
in healthy women. One recent study by Tank et al.               men.
(2005) showed that baroreflex regulation of MSNA was
not different between young men and women. However,
the sensitivity of the sympathetic baroreflex was assessed
                                                                history, physical examination and electrocardiogram.
during pharmacological changes in blood pressure in
                                                                Individuals with a history of fainting or neurally mediated
both of these two studies. Hogarth et al. (2007) reported
                                                                syncope were excluded. All subjects were informed of the
recently that women had a greater sympathetic baroreflex
                                                                purpose and procedures used in the study and gave their
sensitivity than men as assessed during a Valsalva
                                                                written informed consent to a protocol approved by the
manoeuvre. Whether similar results can be obtained
                                                                Institutional Review Boards of the University of Texas
during physiological modulation of blood pressure, such
                                                                Southwestern Medical Center and Presbyterian Hospital
as changes in posture (when the syndrome of orthostatic
                                                                of Dallas. The study followed guidelines set forth in the
intolerance is manifest) needs to be determined.
                                                                Declaration of Helsinki. A summary of the descriptive data
   Since young women are more susceptible to orthostatic
                                                                for the subjects in both groups is presented in Table 1.
intolerance, we speculated that their sympathetic
baroreflex sensitivity would be lower compared with
young men, especially when they are confronted with
orthostatic challenges. Based on the findings of Minson          Measurements
et al. (2000a), we further speculated that sympathetic
baroreflex sensitivity would be different between different      MSNA. MSNA signals were obtained with the micro-
menstrual phases in women, which may also contribute            neurographic technique (Vallbo et al. 1979). Briefly, a
to their susceptibility to orthostatic intolerance. Thus,       recording electrode was placed in the peroneal nerve at
the purpose of this study was to test the hypothesis            the popliteal fossa, and a reference electrode was placed
that baroreflex control of MSNA during upright post-             subcutaneously 2–3 cm from the recording electrode.
ure is impaired in women and can be affected by                 The nerve signals were amplified (gain 70 000–160 000),
the menstrual cycle. Sympathetic baroreflex sensitivity          band-pass filtered (700–2000 Hz), full-wave rectified, and
was evaluated during spontaneous breathing (Fu et al.           integrated with a resistance-capacitance circuit (time
2006). Baroreflex function was further assessed during the       constant 0.1 s). Criteria for adequate MSNA recording
Valsalva manoeuvre.                                             included: (1) pulse synchrony, (2) facilitation during
                                                                the hypotensive phase of the Valsalva manoeuvre, and
                                                                suppression during the hypertensive overshoot after
Methods                                                         release, (3) increases in response to breath holding, and
                                                                (4) insensitivity to emotional stimuli (Vallbo et al. 1979).
Subjects
Eleven healthy young men and eleven age-matched                 Heart rate and blood pressure. Heart rate was
pre-menopausal women were studied. No subject smoked,           determined from the electrocardiogram, and beat-to-beat
used recreational drugs, or had significant medical              arterial pressure was measured non-invasively from
problems. None was an endurance-trained athlete (Levine         the middle finger using photoplethysmography
et al. 1991). All women had self-reported regular               (Portapres, TNO Institute of Applied Physics Biomedical
menstrual cycles of ∼28 days, and had never taken or            Instrumentation, the Netherlands). Cuff blood
had not taken oral contraceptives for ≥ 6 months (Minson        pressure was measured by electrosphygmomanometry
et al. 2000b). Subjects were screened with a careful medical    (model 4240, SunTech Medical Instruments Inc., Raleigh,

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J Physiol 587.9                                                 Neural control and sex hormones                                           2021

NC, USA) with a microphone placed over the brachial                              subject stood on a plate at the end of the tilt bed on one leg,
artery to detect Korotkoff sounds. Respiratory excursions                        allowing the other leg to be relaxed for microneurography.
were detected by a nasal cannula (model 1265, Respironics                        After that, the subject was returned to supine for recovery.
California Inc., Carlsbad, CA, USA).                                                 Heart rate, blood pressure, respiratory waveforms, and
                                                                                 MSNA were recorded continuously. Cardiac output was
                                                                                 measured while supine, after 5 min of 30 deg tilt, and after
Cardiac output. Cardiac output was measured with
                                                                                 5, 10, 20, 30 and 40 min of 60 deg upright tilt. Blood
the acetylene rebreathing technique (model MGA1100,
                                                                                 samples were taken in the supine position, after 5 and
Marquette, Milwaukee, WI, USA) (Triebwasser et al.
                                                                                 20 min of 60 deg tilt, and immediately after returning to
1977). Cardiac index was derived from cardiac output
                                                                                 supine because either the subject completed 45 min of
divided by body surface area. Stroke volume was calculated
                                                                                 tilting or developed presyncope.
from cardiac output and heart rate, and was normalized
to body surface area as stroke index. Total peripheral
resistance was calculated as the quotient of mean arterial
pressure and cardiac output, multiplied by 80 (expressed
as dyne s cm−5 ). Mean arterial pressure was calculated                          Data analysis
as (systolic pressure − diastolic pressure)/3 + diastolic
                                                                                 Sympathetic bursts were identified by a computer program
pressure, where blood pressure was measured by arm cuff
                                                                                 (Cui et al. 2001), and then were confirmed by an
during the rebreathing.
                                                                                 experienced microneurographer. The integrated neuro-
                                                                                 gram was normalized by assigning a value of 100 to
                                                                                 the largest amplitude of a sympathetic burst during the
Protocol
                                                                                 6 min supine baseline. All bursts for that trial were then
Women were studied twice, once during the early follicular                       normalized against that value (Halliwill, 2000). Burst areas
phase (1–4 days after the onset of menstruation when both                        of the integrated neurogram, systolic and diastolic pre-
oestrogen and progesterone are low), and once during                             ssures, and R-R interval were measured simultaneously on
the mid-luteal phase (19 to 22 days after the onset of                           a beat-to-beat basis. Total activity of the burst was defined
menstruation when both hormones are high), with the                              as the burst area of the rectified and integrated neurogram.
order counterbalanced. Cycle phase was determined by                             The number of bursts per minute (burst frequency), the
the onset of menstruation and by the detection of the                            number of bursts per 100 heart beats (burst incidence),
luteinizing hormone surge by an ovulation prediction                             and total activity were used as quantitative indexes.
kit (OvuQuick, Quidel Corp., San Deigo, CA, USA). It
was verified by circulating oestradiol and progesterone
concentrations on each study day. Men were studied only
once. All subjects were on an isocaloric constant diet                           Assessments of sympathetic baroreflex sensitivity
consisting of 200 mEq sodium, 100 mEq potassium, and
                                                                                 during spontaneous breathing
1000 mg calcium, while fluid intake was ad libitum 2 days
prior to testing. Women took a pregnancy test and showed                         Baroreflex control of MSNA was assessed by using the
negative results on each study day.                                              slope of the linear correlation between total activity and
   The experiment was performed in the morning or after-                         diastolic pressure during spontaneous breathing in the
noon ≥ 2 h after a light breakfast or lunch, and ≥ 48 h                          supine position and during upright tilt as previously
after the last caffeinated or alcoholic beverage in a quiet,                     described (Fu et al. 2006). To perform a linear regression,
environmentally controlled laboratory with an ambient                            values for total activity were averaged over a 3 mmHg
temperature of ∼25◦ C. The subject was placed in the                             diastolic pressure bin. A statistical weighting procedure
supine position, and an intravenous catheter was inserted                        was adopted; each data point was entered once for each
into an antecubital vein of the left arm for blood samples.                      heart beat in the bin, and total activity was expressed as
At least 10 min after an acceptable nerve recording site had                     arbitrary units per heart beat (i.e. units beat−1 ) (Kienbaum
been found, baseline data were collected for 6 min. All sub-                     et al. 2001; Fu et al. 2006).
jects were then asked to perform two Valsalva manoeuvres                            Additionally, we used the MSNA and stroke index
at 40 mmHg for 20 s after a normal inspiration, separated                        relationship to further evaluate sympathetic baroreflex
by a 2 min recovery period. After sufficient recovery, the                        control for each subject during changes in posture and
subject was tilted passively to 30 deg upright for 6 min, and                    during sustained upright tilt, since MSNA has been
then 60 deg for 45 min or till presyncope. A belt was placed                     demonstrated to be related to the change in stroke volume
across the subject’s waist to make sure he/she would not                         in the supine position (Charkoudian et al. 2005) and
fall. A bicycle saddle was used to support approximately                         during orthostasis (Levine et al. 2002; Convertino et al.
two-thirds of the body weight during tilting, while the                          2004; Fu et al. 2005a, 2006).

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Assessments of baroreflex function during                                                        30 deg upright tilt, data were collected and averaged from
the Valsalva manoeuvre                                                                          the 2nd to 5th min (30 deg Tilt). During 60 deg upright
                                                                                                tilt, data were averaged from the 2nd to 5th min (Tilt5),
Sympathetic baroreflex function was assessed by relating                                         7th to 10th min (Tilt10), 17th to 20th min (Tilt20), 26th
all sympathetic bursts occurring during the 20 s straining                                      to 29th min (Tilt30), 36th to 39th min (Tilt40), and 42nd
period of the Valsalva manoeuvre to the maximum fall                                            to 45th min (Tilt45). Since some subjects had presyncope
of diastolic pressure as measured from the highest level                                        during 45 min of 60 deg upright tilt and the tilt test was
just after the beginning of straining (phase I) to its nadir                                    terminated at different time points, we used the ‘last stable
(Fu et al. 2005b). Cardiovagal baroreflex sensitivity was                                        data carry forward’ method for imputing with missing
assessed during early phase II (i.e. a hypotensive stimulus)                                    values (Ali & Talukder, 2005). Data were also averaged in
and phase IV (i.e. a hypertensive stimulus) (Fu et al.                                          20 s intervals over the last 3 min prior to presyncope in
2005b). The slope of the linear relationship between                                            presyncopal subjects, and from the 42nd to 45th min
changes in systolic pressure and the corresponding changes                                      in non-presyncopal subjects.
in R-R interval was estimated to evaluate cardiovagal                                               Supine baseline values and baroreflex sensitivity
baroreflex sensitivity.                                                                          assessed during the Valsalva manoeuvre between
Statistical analysis
                                                                                                menstrual phases were compared using Wilcoxon’s
                                                                                                signed rank tests, and between sexes were compared
Data are expressed as means ± S.E.M. Supine MSNA, blood                                         with Mann–Whitney rank sum tests. MSNA and
pressure, and heart rate were averaged for 6 min. During                                        haemodynamic responses during upright tilt between
                                                                                                sexes and phases were analysed using two-way repeated
                                                                                                measures analysis of variance (ANOVA) with factors for
      A                                                                                         sex/phase, posture, and the interaction between sex/phase
                              60           Men
                                                                                                and posture. The Bonferroni–Holm method was used
                                           Mid-luteal Phase (MLP)
                              50                                                                post hoc for multiple comparisons. The relationship
                                           Early Follicular Phase (EFP)
                                                                                                between total activity and diastolic pressure during
         MSNA (bursts/min)




                              40                                                                spontaneous breathing in the supine position and during
                                                                                                sustained upright tilt was determined for each subject
                              30                                                                by least-squares linear regression analysis, and the slopes
                                                                                                were also compared using two-way repeated measures
                              20                                                                ANOVA. The correlation between MSNA and stroke index
                                                                     P = 0.182 for sex (EFP)
                                                                     P = 0.681 for sex (MLP)    during changes in posture was determined by least-squares
                              10                                     P = 0.179 for phase
                                                                     P < 0.001 for protocol
                                                                                                linear regression for each subject, while the slopes between
                               0                                                                phases were compared using Wilcoxon’s signed rank tests,
      B                                                                                         and between sexes were compared using Mann–Whitney
                             1600                                                               rank sum tests. All statistical analyses were performed with
                                                                                                a personal computer-based analysis program (SigmaStat
                             1400
                                                                                                (Systat Software Inc., San Jose, CA, USA), SPSS (SPSS Inc.,
Total Activity (units/min)




                             1200                                                               Chicago, IL, USA). A P value of < 0.05 was considered
                             1000                                                               statistically significant.
                             800

                             600                                                                Results
                             400                                     P = 0.102 for sex (EFP)    Supine MSNA and haemodynamics
                                                                     P = 0.684 for sex (MLP)
                                                                     P = 0.030 for phase
                             200                                     P < 0.001 for protocol     Supine MSNA and plasma catecholamine concentrations
                               0
                                                                                                were not different between sexes (Fig. 1 and Table 2).
                                    Supine 30°Tilt Tilt5 Tilt10 Tilt20 Tilt30 Tilt40 Tilt45     Systolic pressure was greater in men than women, which
                                                                                                was attributable to greater cardiac output and stroke
                                                                     60°
                                                                                                volume; however, diastolic pressure, heart rate, stroke
Figure 1. Muscle sympathetic nerve activity (MSNA) burst                                        index, cardiac index, and total peripheral resistance did
frequency (A) and total activity (B) responses during a graded                                  not differ between the groups (Fig. 2).
upright tilt in men and women during the early follicular phase
                                                                                                  Even though oestradiol and progesterone were
(when both oestrogen and progesterone are low) and the
mid-luteal phase (when both sex hormones are high)                                              markedly greater in the mid-luteal phase than the
Values are means ± S.E.M. Tilt5, Tilt10, Tilt20, Tilt30, Tilt40 and Tilt45,                     early follicular phase in women, supine MSNA, plasma
5, 10, 20, 30, 40 and 45 min after 60 deg upright tilt.                                         catecholamine concentrations, and haemodynamic

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                         Table 2. Plasma catecholamine responses to upright tilt in men and women during the two
                         different menstrual phases

                                                                                        Women (n = 11)

                                                                                     Early           Mid-
                                                                                   follicular       luteal          Men
                         Variables                                                   phase          phase         (n = 11)

                         Noradrenaline (pg ml−1 )                 Supine          176 ± 16        201 ± 13       207 ± 20
                                                                  60 deg Tilt5    372 ± 32∗       371 ± 28∗      338 ± 49∗
                                                                  60 deg Tilt20   447 ± 39∗       482 ± 46∗      409 ± 52∗
                         Adrenaline (pg ml−1 )                    Supine           29 ± 5          26 ± 7         29 ± 5
                                                                  60 deg Tilt5     51 ± 12         35 ± 6         52 ± 18
                                                                  60 deg Tilt20    57 ± 12∗        54 ± 12∗       99 ± 22∗
                         Values are presented as means ± S.E.M. ∗ P < 0.05 compared with supine within the group and
                         the same menstrual phase in women.

variables were not different between the two different                            representative subject. The sensitivity increased at 30 deg,
menstrual phases (Tables 1 and 2, Figs 1 and 2).                                  further increased at 60 deg tilt, and remained elevated
                                                                                  during sustained upright tilt; the responses were not
                                                                                  different between sexes and the menstrual phases
Responses during upright tilt                                                     (Fig. 4).
                                                                                     Changes in MSNA were associated with changes in
MSNA burst frequency increased at 30 deg, further
                                                                                  stroke index during changes in posture, while the slopes
increased at 60 deg tilt, and remained elevated throughout
                                                                                  of the line relating these two variables were not different
45 min of tilting; these responses were not different
                                                                                  between sexes (−1.05 ± 0.16 bursts min−1 ml−1 m–2 in
between sexes and menstrual phases (Fig. 1A). However,
                                                                                  men vs −0.72 ± 0.11 in the early-follicular phase and
women during the early follicular phase had less increases
                                                                                  −0.92 ± 0.10 in the mid-luteal phase in women; P = 0.264
in total activity during upright tilt compared with
                                                                                  and 0.768), and the menstrual phases (P = 0.765).
the mid-luteal phase (Fig. 1B, P = 0.030). Upright total
                                                                                     The time to presyncope during the 45 min 60 deg
activity tended to be lower in women during the early
                                                                                  upright tilt did not differ between sexes and phases in
follicular phase than men (Fig. 1B, P = 0.102).
                                                                                  the present study (Fig. 5). Figure 6 depicts MSNA and
   Systolic pressure was stable in men, but decreased
                                                                                  blood pressure responses prior to presyncope in men and
progressively in women during sustained upright tilt; it
                                                                                  women during the two different menstrual phases. Mean
was greater in men compared with women (Fig. 2A).
                                                                                  arterial pressure started to fall approximately 120 s before
Diastolic pressure increased during upright tilt, and was
                                                                                  the onset of presyncope, while MSNA burst frequency
not different between sexes (Fig. 2B). Heart rate increased
                                                                                  decreased rapidly about 20 s prior to presyncope; these
progressively during graded upright tilt, and tended to
                                                                                  responses seemed to be similar between sexes and phases.
be greater in women than men (Fig. 2C). Total peri-
                                                                                  This earliest drop in blood pressure may be due to a
pheral resistance increased progressively during graded
                                                                                  reduction in cardiac output (Jardine et al. 2002) and/or
upright tilt, and the responses were similar between
                                                                                  active vasodilatation unrelated to sympathetic withdrawal.
sexes (Fig. 2D). Both stroke volume and cardiac output
decreased gradually during sustained upright tilt, and
were greater in men than women (Fig. 2E and G).
However, both stroke index and cardiac index were                                 Baroreflex sensitivity during the Valsalva manoeuvre
not different between sexes during tilting (Fig. 2F and
                                                                                  Sympathetic baroreflex sensitivity, as assessed by relating
H). The menstrual cycle had no significant impacts on
                                                                                  all sympathetic bursts occurring during the 20 s straining
haemodynamic responses during upright tilt in women,
                                                                                  period of the Valsalva manoeuvre to the maximum fall in
with similar total peripheral resistance and plasma
                                                                                  diastolic pressure (Fig. 7A), did not differ between sexes
noradrenaline concentration despite the differences in
                                                                                  and was not affected by the menstrual cycle in women
total activity (Figs 1 and 2, Table 2).
                                                                                  (Fig. 7B). Figure 8A and B depicts assessments of cardio-
                                                                                  vagal baroreflex sensitivity during the Valsalva manoeuvre.
                                                                                  The sensitivity during decreasing blood pressure (i.e.
Sympathetic baroreflex sensitivity during tilting
                                                                                  early phase II) was comparable between sexes and phases
Figure 3 depicts the assessment of sympathetic baroreflex                          (Fig. 8C). However, the sensitivity during increasing blood
sensitivity during spontaneous breathing from one                                 pressure (i.e. phase IV) was significantly greater in men

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2024                                                                            Q. Fu and others                                                                                   J Physiol 587.9


than women, but was not affected by the menstrual cycle                                      tilt were similar between sexes and were not affected
(Fig. 8D).                                                                                   by the menstrual cycle; (2) upright total activity was
                                                                                             lower in women during the early follicular phase than
Discussion                                                                                   the mid-luteal phase, with similar increases in total
                                                                                             activity during tilting compared with men; (3) despite
The major findings from this study are that (1) MSNA                                          this difference, plasma noradrenaline concentration was
burst frequency responses during sustained upright                                           not affected by the sex or the menstrual cycle, and

                                                 Men

                A                      135
                                                 Mid-luteal Phase (MLP)                     B                       85
                                                 Early Follicular Phase (EFP)
                                       130
                                                                                                                    80
                    SBP (mmHg)




                                                                                                       DBP (mmHg)
                                       125
                                       120                                                                          75

                                       115                                                                          70
                                       110
                                                                                                                    65                    P = 0.223 for sex
                                       105     P < 0.001 for sex                                                                          P = 0.376 for phase
                                               P = 0.501 for phase                                                                        P < 0.001 for protocol
                                       100     P < 0.05 for protocol                                                60
               C                       100                                               D                  1800

                                       90                                                                   1600
                                                                                         TPR (dyn⋅s⋅cm–5)
                      HR (beats/min)




                                                                                                            1400
                                       80
                                                                                                            1200
                                       70
                                                             P = 0.099 for sex                              1000                            P = 0.212 for sex
                                       60                    P = 0.894 for phase                                                            P = 0.707 for phase
                                                             P < 0.001 for protocol                                 800                     P < 0.001 for protocol

                                       50                                                                           600

               E                       140                                                  F                        70
                                                           P = 0.011 for sex                                                                P = 0.260 for sex
                                       120                 P = 0.987 for phase                                       60                     P = 0.903 for phase
                                                           P < 0.001 for protocol                                                           P < 0.001 for protocol
                                                                                                    SI (ml/m2)




                                       100                                                                           50
                     SV (ml)




                                        80                                                                           40

                                        60                                                                           30

                                        40                                                                           20
               G                       9.0                 P = 0.010 for sex                H                       5.0                       P = 0.502 for sex
                                                           P = 0.876 for phase
                                                                                                                                              P = 0.911 for phase
                                                           P < 0.001 for protocol                                   4.5                       P < 0.001 for protocol
                                       7.5
                                                                                                  CI (l/min/m2)




                                                                                                                    4.0
                      CO (l/min)




                                       6.0                                                                          3.5
                                                                                                                    3.0
                                       4.5
                                                                                                                    2.5
                                       3.0                                                                          2.0
                                             Sup 30°Tilt T5 T10 T20 T30 T40                                                   Sup 30°Tilt T5 T10 T20 T30 T40
                                                                       60°                                                                             60°

             Figure 2. Systolic blood pressure (SBP, A), diastolic blood pressure (DBP, B), heart rate (HR, C), total
             peripheral resistance (TPR, D), stroke volume (SV, E), stroke index (SI, F), cardiac output (CO, G), and
             cardiac index (CI, H) responses during a graded upright tilt in men and women during the two different
             menstrual phases
             Values are means ± S.E.M. Sup, supine; T5, T10, T20, T30 and T40, 5, 10, 20, 30 and 40 min after 60 deg upright
             tilt.


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J Physiol 587.9                                                                    Neural control and sex hormones                                                                                      2025

                                                                                                                            120           downstream vasoconstriction was also similar; (4)
A                                                                                                                                         sympathetic baroreflex sensitivity was comparable
                 BP
               (mmHg)
                                                                                                                                          between sexes and menstrual phases during orthostasis;
                                                                                                                                 60
                                                                                                                                          and (5) cardiovagal baroreflex sensitivity during a hypo-
                                                                                                                                          tensive stimulus was similar between sexes and phases;
                                                                                                                                          however, the sensitivity was significantly greater in men
                                  ECG
                                                                                                                                          than women during a hypertensive stimulus.
                                                                                                                                             These results suggest that even though vasomotor
                                                                                                                                          sympathetic activity during orthostasis can be affected
                                                                                                                                          by the menstrual cycle, it is not clearly different between
                                                                                                                                          sexes. Sympathetic baroreflex sensitivity remains stable
                         MSNA
                                                                                                                                          in women during the two different menstrual phases
                                                                                                                                          and is not different from men. Thus, other factors (i.e.
                                                                                                                                          stroke volume and cardiac output) rather than neural
                                                                                        15 s
                                                                                                                                          control mechanisms may contribute to sex differences in
B                                                                                                                                         orthostatic tolerance in young healthy humans.
                                  16000
                                  14000
    Total Activity (units/beat)




                                  12000                                                                                                   Sex and sympathetic neural control during orthostasis
                                  10000                                                                                                   We found that MSNA responses during sustained (i.e.
                                   8000                                                                                                   45 min) upright tilt were similar between men and women
                                   6000                                                                                                   in the mid-luteal phase, which is consistent with our
                                                                                                                                          previous report in an entirely different group of subjects
                                   4000
                                                                                                                                          during acute (i.e. 6 min) upright tilt (Fu et al. 2005a).
                                   2000                                                                                                   In the previous study, we did not control menstrual
                                        0   Y = 47656 − 560X                                                                              phases in female subjects, but none of them were tested
                                            R = 0.961, P < 0.001                                                                          during menstruation (Fu et al. 2005a). The present
                                  -2000
                                       60       65      70         75        80         85                                        90      study showed that women during menstruation (i.e. the
                                                             DBP (mmHg)                                                                   early follicular phase) tended to have lower increases
                                                                                                                                          in total activity during orthostasis compared with men,
Figure 3
A, sympathetic baroreflex sensitivity assessment during spontaneous                                                                        but these differences were small and not statistically
breathing from one representative subject. B, the slope of the linear                                                                     robust. Both supine and upright sympathetic baroreflex
correlation between total activity and diastolic blood pressure (DBP)                                                                     sensitivity did not differ between men and women
indicates sympathetic baroreflex sensitivity.




                                                                                                                                                                                 60°
                                                                                                                                          Sup   30°Tilt   T5         T10   T20         T30    T40      T45
                                                                                                                                      0
                                                                                             Sympathetic BRS (units/beat/mmHg)




                                                                                                                                  -200


                                                                                                                                  -400


                                                                                                                                  -600


                                                                                                                                  -800
Figure 4. Effects of sex and the menstrual cycle on
sympathetic baroreflex sensitivity (BRS) during a
graded upright tilt in healthy humans                                                                                            -1000
Values are means ± S.E.M. Sup, supine; T5, T10, T20,                                                                                        Early Follicular Phase                      P = 0.676 for sex
T30, T40 and T45, 5, 10, 20, 30, 40 and 45 min after                                                                                        Mid-luteal Phase                            P = 0.747 for phase
                                                                                                                                            Men                                         P < 0.001 for protocol
60 deg upright tilt.                                                                                                             -1200


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2026                                                                                                 Q. Fu and others                                                                   J Physiol 587.9


                       1.0
                                                                                                               (2005) but different from that of Hogarth et al. (2007).
                                                                                                               Our results provide strong evidence that healthy young
                                                                                                               men and women have comparable sympathetic baroreflex
                       0.8                                                                                     control during orthostasis.
Survival Probability




                                                                                                                  Tank et al. (2005) evaluated sympathetic baroreflex
                       0.6                                                                                     function during pharmacological changes in blood
                                                                                                               pressure. Their finding was confirmed during physio-
                                                                                             Log-Rank Test
                                                                                                               logical modulation of blood pressure during orthostasis in
                       0.4
                                                                                               P = 0.694       our subjects. However, they showed that the sympathetic
                                                                                                               baroreflex curve was shifted toward lower systolic pressure
                       0.2                          Men                                                        values in women, even though the sensitivity was not
                                                    Early follicular phase
                                                    Mid-luteal phase                                           different between sexes. Different from their method, we
                       0.0                                                                                     used diastolic pressure (Wallin et al. 1974; Sundlof &
                                 0                    10          20          30              40        50     Wallin, 1978; Kienbaum et al. 2001) rather than systolic
                                                                     Time (min)                                pressure as an input stimulus for MSNA, since it has
Figure 5. Survival probability during sustained (i.e. 45 min)                                                  been demonstrated that when, for each cardiac cycle,
60 deg upright tilt in men and women during the two different                                                  the occurrence of a sympathetic burst is correlated with
menstrual phases                                                                                               different blood pressure parameters there is regularly a
                                                                                                               close negative correlation to diastolic pressure, a low
during the two different menstrual phases. In addition,                                                        correlation to systolic, and an intermediary negative
sympathetic baroreflex sensitivity assessed during the                                                          correlation to mean blood pressure (Sundlof & Wallin,
Valsalva manoeuvre was similar between sexes. These                                                            1978). We assessed sympathetic baroreflex sensitivity
observations are in agreement with the study of Tank et al.                                                    during spontaneous breathing. Although the entire

                                                        Early Follicular Phase                     Mid-lutealPhase                                    Men
                                             100

                                              80
                         MSNA (bursts/min)




                                              60

                                              40

                                              20

                                               0

                                             -20
                                                           Non-presyncopal    (n = 6)                                 (n = 8)                                           (n = 7)
                                                           Presyncopal        (n = 5)                                 (n = 3)                                           (n = 4)
                                             120

                                             100
                         MAP (mmHg)




                                              80


                                              60


                                              40


                                              20
                                                    S a b     180s     120s      60s    0s          S a b 180s       120s       60s   0s         S a b 180s            120s       60s     0s

                                                   Figure 6. MSNA and mean arterial pressure (MAP) responses prior to presyncope in men and women
                                                   during the two different menstrual phases
                                                   Values are means ± S.E.M. S, supine; a, 30 deg Tilt; b, between the 2nd and 5th min of 60 deg upright tilt. Data
                                                   were also averaged in 20 s intervals over the last 3 min prior to presyncope in presyncopal subjects, and from the
                                                   42nd to 45th min in non-presyncopal subjects. The vertical lines indicate the critical time point for both falls in
                                                   blood pressure and sympathetic nerve activity.
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J Physiol 587.9                                                 Neural control and sex hormones                                                                    2027

sympathetic baroreflex stimulus−response curve cannot                             women. Conversely, downstream vasoconstriction during
be evaluated, our data can be used to reveal the physio-                         orthostaisis did not differ between phases. These results
logical modulation of sympathetic neural control around                          suggest that for the same degree of peripheral vaso-
the prevailing and regulated operating point in humans                           constriction, less efferent sympathetic nerve discharges
(Fu et al. 2006). Our finding was further confirmed by                             seem to be needed in the early follicular phase than
the negative linear correlation between MSNA and stroke                          the mid-luteal phase. This may be attributable to the
index during changes in posture. Since diastolic pressure                        fluctuations of female sex hormones (i.e. oestrogen and
was similar between sexes in the study of Tank et al. (2005),                    progesterone) (Minson et al. 2000a). Meyer et al. (1997)
the sympathetic baroreflex curve would have been super-                           showed that oestrogen replacement attenuated resistance
imposed in men and women if diastolic pressure had been                          artery adrenergic sensitivity via endothelial vasodilators
used in the assessment of sympathetic baroreflex function.                        such as nitric oxide and prostaglandins in female rats. It
   Hogarth et al. (2007) showed that women had a greater                         was also found that oestrogen supplementation selectively
sympathetic baroreflex sensitivity compared with men.                             attenuated vasoconstrictor responses in perimenopausal
It is of note that Hogarth et al. (2007) studied both                            women (Sudhir et al. 1997). It is likely that the low level
pre- and post-menopausal women, while we enrolled                                of oestrogen during the early follicular phase could have
only young pre-menopausal women who had regular                                  the opposite effects on adrenergic sensitivity and vaso-
menstrual cycles and did not take oral contraceptives.                           constrictor responsiveness in these women.
It has been demonstrated that MSNA increases with                                   It is evident that both oestrogen and progesterone
advancing age, and the increment is greater in women                             have significant impacts on autonomic circulatory control.
than men (Matsukawa et al. 1998; Narkiewicz et al.                               Whether these two sex hormones have counteractive
2005). It seems possible that middle-aged and/or elderly                         or additive effects is unknown. Oestrogen was reported
women may have a greater sympathetic baroreflex control                           to enhance renal and splanchnic sympathetic baroreflex
compared with their male counterparts, even in the healthy
population. This speculation needs to be tested in future
studies, especially in patients with hypertension (Fu et al.                         A
2008).                                                                                         200                                     Decrease in DBP
                                                                                               180
                                                                                  BP (mmHg)




                                                                                               160
Menstrual cycle and sympathetic baroreflex                                                      140
                                                                                               120
sensitivity during orthostasis
                                                                                               100
We found for the first time that total activity responses                                        80
during sustained upright tilt were affected by the                                                                                 MSNA Responses (bursts/20 s)
menstrual cycle. Since MSNA burst frequency during
tilting was not different between the two different
menstrual phases, it could be argued that the blunted
                                                                                              MSNA




upright total activity could be explained by displacement
of the recording electrodes during tilting. However, this
possibility seems unlikely given the low variability in
                                                                                                                                               20 s
total activity response during both phases. Moreover, we
cannot think of any reasons that the displacement only                                                                    Women-EFP       Women-MLP          Men
occurred during the early follicular phase but not the                           B                                 0.0
mid-luteal phase. It has been suggested that total activity is                                                     -0.2
                                                                                              (bursts/20 s/mmHg)




more closely related to noradrenaline spillover in humans
                                                                                               Sympathetic BRS




                                                                                                                   -0.4
compared with burst frequency (Hjemdahl et al. 1989),
                                                                                                                   -0.6
suggesting that the smaller increases in total activity during
tilting are consistent with a blunted sympathetic activation                                                       -0.8
in the early follicular phase.                                                                                     -1.0
    We did not measure noradrenaline spillover in this                                                             -1.2   P= 0.509 for sex
study; however, plasma noradrenaline concentration                                                                 -1.4
                                                                                                                          P= 0.405 for phase
during upright tilt was similar between the menstrual
                                                                                 Figure 7
phases. It is possible that body fluid retention
                                                                                 A, sympathetic baroreflex sensitivity (BRS) assessed during the Valsalva
(volume expansion) under different hormonal conditions                           manoeuvre. B, the sensitivity was not different between sexes and
(Stachenfeld & Taylor, 2004, 2005) may influence                                  menstrual phases. Values are means ± S.E.M. EFP, the early follicular
plasma concentrations of noradrenaline in these                                  phase; MLP, the mid-luteal phase.


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2028                                                                            Q. Fu and others                                                                         J Physiol 587.9


sensitivity through a central mechanism in rats (He                                         Blunted cardiovagal baroreflex-mediated bradycardia
et al. 1998). It was also found that oestrogen may                                          in women
influence nitric oxide production by increasing the enzyme
nitric oxide synthase expression (Geary et al. 2000),                                       Our finding that cardiovagal baroreflex sensitivity during
and thereby, increase vasomotor sympathetic outflow                                          the hypotensive stimulus (early phase II of the Valsalva
in humans (Skarphedinsson et al. 1997). However,                                            manoeuvre) was similar between sexes and was not
previous studies in post-menopausal women showed that                                       affected by the menstrual cycle in women is in agreement
oestrogen replacement therapy decreased (Vongpatanasin                                      with some (Minson et al. 2000a; Tank et al. 2005), but not
et al. 2001) or did not change (Hunt et al. 2001) MSNA at                                   all (Tanaka et al. 2003) previous reports. Interestingly, we
rest, suggesting that the effect of oestrogen on sympathetic                                found that cardiovagal baroreflex sensitivity during the
neural control is complex and can probably be affected by                                   hypertensive stimulus was significantly lower in women
other factors. Conversely, progesterone was found to exert                                  than men. The overshoot (phase IV) of the Valsalva
sympathoinhibitory effect and to attenuate sympathetic                                      manoeuvre, when the arterial pressure rises quickly,
baroreflex responses via a central mechanism in rats                                         represents a physiological challenge for the baroreflex.
(Heesch & Rogers, 1995). Thus, it is likely that the opposite                                  Baroreflex-mediated bradycardia involves reciprocal
impacts of oestrogen and progesterone could lead to an                                      changes in vagal activation and sympathetic activity
unaltered sympathetic neural control, and, therefore, a                                     inhibition (Coleman, 1980). It has been demonstrated
stable haemodynamic homeostasis during orthostasis in                                       that an increase in vagal tone occurs rapidly, whereas
women.                                                                                      sympathetic withdrawal happens more slowly (Katona
                                                                                            et al. 1970). Sex dimorphism in cardiovagal baroreflex




         A                                     Early Phase II               Phase IV            C
                                 160                                                                                           10
                                 140                                                                                                         P = 0.596 for sex
             BP (mmHg)




                                                                                                     Decreasing BP (ms/mmHg)
                                                                                                      Cardiovagal BRS During




                                 120                                                                                                         P = 0.146 for phase
                                                                                                                                8
                                 100
                                  80
                                                                                                                                6
                                  60
                                  40
                                                                                                                                4
                                 100
             HR (beats/min)




                                  90
                                  80                                                                                            2
                                  70
                                  60                                                                                            0
                                  50
                                  40                         20s

         B                                                                                      D                              25
                                           Early Phase II                    Phase IV
                                 800                            1100
                                                                                                     Increasing BP (ms/mmHg)
                                                                                                      Cardiovagal BRS During




                                 780                                                                                           20
                                                                1000
                                          r =0.97
                                                7                                4
                                                                           r =0.93                                                        P = 0.025 for sex
             R-R Interval (ms)




                                 760                             900                                                           15         P = 0.151 for phase
                                 740
                                                                 800
                                 720                                                                                           10
                                                                 700
                                 700
                                                                                                                                5
                                 680                             600

                                 660                      500                                                                   0
                                   100 110 120 130 140 150 110 120 130 140 150 160                                                  EFP           ML P             Men
                                         SBP (mmHg)              SBP (mmHg)                                                               Women

                                 Figure 8
                                 A, cardiovagal baroreflex sensitivity (BRS) assessed during early phase II and phase IV of the Valsalva manoeuvre.
                                 B, the slope of the linear relationship between R-R interval and systolic BP indicates cardiovagal BRS. C, the
                                 sensitivity during decreasing BP was not different between sexes and phases. D, however, it was greater in men
                                 than women of both phases during increasing BP. Values are means ± S.E.M. EFP, the early follicular phase; MLP,
                                 the mid-luteal phase.


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J Physiol 587.9                                                 Neural control and sex hormones                                            2029

sensitivity has been proposed, at least partly, from a                           invasive pharmacological manipulation. Therefore the
smaller increase in vagal outflow to the heart in response                        entire baroreflex stimulus–response curve cannot be
to baroreceptor activation (Abdel-Rahman, 1999). This                            evaluated. Consequently, we cannot determine whether
notion is supported by the findings from one previous                             the operating point on this stimulus–response curve has
study in anaesthetized humans (under the condition of                            simply shifted to a steeper part of the curve during
parasympathetic nervous system activation) showing that                          upright posture or whether an entirely new relationship
baroreflex sensitivity assessed by the pharmacological                            is achieved. Additionally, spontaneous variations in
method in men was significantly greater than women                                blood pressure and sympathetic activity may be in
(Tanaka et al. 2004). Abdel-Rahman et al. (1994) showed                          part due to the baroreflex, but in part due to other
that the relatively depressed baroreflex control of heart                         influences. However, our results were confirmed by other
rate in women was almost entirely dependent on the                               non-invasive approaches (i.e. the Valsalva manoeuvre, and
pattern of blood pressure elevation, brief versus sustained.                     the correlation between MSNA and stroke volume/index).
It is possible that an adaptive response can occur within                        Second, the initial premise that women would have greater
the central nervous system (Kunze, 1986). On the other                           orthostatic intolerance than men was not duplicated in
hand, it was reported that women had lower carotid                               this study, simply because we applied upright tilt for
artery distensibility compared with men (Hayward & Kelly,                        a fixed time period (i.e. 60 deg for 45 min) and did
1997). Carotid distensibility was found to be associated                         not bring every subject to presyncope. More prolonged
with cardiovagal baroreflex sensitivity (Bonyhay et al.                           and/or intensive orthostatic challenges would be needed
1996). The lower levels of carotid artery distensibility in                      to confirm this observation. Third, all our subjects were
women would result in a smaller mechanical transduction                          healthy individuals with no previous history of syncope.
of arterial pressure into barosensory stretch. This, in                          Still, about 40% of them had presyncope during tilting,
turn, would result in an attenuated cardiovagal baroreflex                        which is actually common in both healthy individuals and
response. Even though cardiovagal baroreflex sensitivity                          syncopal patients (Mosqueda-Garcia et al. 1997; Jardine
was reduced in women, the baroreflex threshold and                                et al. 2002; Fu et al. 2006; Ichinose et al. 2006).
saturation, operating range, or operating point were found                          In summary, we found in this study that the menstrual
to be similar between sexes (Beske et al. 2001).                                 cycle affected vasomotor sympathetic responses but not
                                                                                 sympathetic baroreflex sensitivity during orthostasis.
                                                                                 Not only sympathetic but also cardiovagal baroreflex
Orthostatic tolerance
                                                                                 sensitivity was similar between sexes and menstrual phases
In the present study, we found that five out of the 11 women                      during the hypotensive stimulus. However, cardiovagal
had presyncope in the early-follicular phase, while three                        baroreflex-mediated bradycardia during the hypertensive
of them had presyncope in the mid-luteal phase of their                          stimulus was different between sexes but not affected by
menstrual cycles. Surprisingly, the survival probability                         the menstrual cycle. Thus, other factors (i.e. stroke volume
during sustained (i.e. 45 min) upright tilt was not different                    and cardiac output) rather than sympathetic baroreflex
between men and women, as well as between the menstrual                          control mechanisms may contribute to sex differences in
phases. However, these observations do not allow us to                           orthostatic tolerance in humans.
conclude that there are no sex and/or menstrual phase
differences in orthostatic tolerance in humans. Since not
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  norepinephrine spillover in perimenopausal women.                              The time and effort put forth by the subjects is greatly
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  vasomotor tone in women and men. Hypertension 45,
  1159–1164.                                                                     The authors have no conflicts to disclose.




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