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Menstrual Cycle Affects Renal-Adrenal and Hemodynamic

Responses During Prolonged Standing in the Postural


Orthostatic Tachycardia Syndrome
Qi Fu, Tiffany B. VanGundy, Shigeki Shibata, Richard J. Auchus,
Gordon H. Williams, Benjamin D. Levine

AbstractApproximately 500 000 American premenopausal women have the postural orthostatic tachycardia syndrome
(POTS). We tested the hypothesis that in POTS women during orthostasis, activation of the renin-angiotensin-aldoste-
rone system is greater, leading to better compensated hemodynamics in the midluteal phase (MLP) than in the early
follicular phase of the menstrual cycle. Ten POTS women and 11 healthy women (controls) consumed a constant diet
3 days before testing. Hemodynamics and renal-adrenal hormones were measured while supine and during 2-hour
standing. We found that blood pressure was similar, heart rate and total peripheral resistance were greater, and cardiac
output and stroke volume were lower in POTS subjects than in controls during 2-hour standing. In controls,
hemodynamic parameters were indistinguishable between menstrual phases. In POTS subjects, cardiac output and stroke
volume were lower and total peripheral resistance was greater in the early follicular phase than MLP after 30 minutes
of standing; however, blood pressure and heart rate were similar between phases. Plasma renin activity (96 [SD]
versus 139 ng/mL per hour; P0.04) and aldosterone (4322 versus 5525 ng/dL; P0.02) were lower in the early
follicular phase than MLP in POTS subjects after 2 hours of standing. Catecholamine responses were similar between
phases. The percentage rate of subjects having presyncope was greater in the early follicular phase than MLP for both
groups (2 P0.01). These results suggest that the menstrual cycle modulates the renin-angiotensin-aldosterone system
and affects hemodynamics during orthostasis in POTS. The high estrogen and progesterone in the MLP are associated
with greater increases in renal-adrenal hormones and presumably more volume retention, which improve late-standing
tolerance in these patients. (Hypertension. 2010;56:82-90.)
Key Words: orthostatic intolerance renin-angiotensin-aldosterone system hemodynamics sex hormones

P atients with the postural orthostatic tachycardia syndrome


(POTS; also called chronic orthostatic intolerance) are
unable to stand or remain upright for prolonged periods of
arterial pressure maintenance, results regarding the responses
of the RAAS during upright posture in POTS patients are few
and controversial; increased,5 decreased,6,7 or unchanged8
time because of intolerable palpitations, light-headedness, plasma levels of renin and/or aldosterone have been reported.
weakness, or near-syncope. This disorder affects 500 000 Although the majority of POTS patients are premenopausal
Americans,1 the majority of whom are young women. Se- women, there is no information available concerning the
verely affected patients are unable to work, attend school, or menstrual cycle effects on the RAAS in POTS. Hirshoren et
participate in recreational activities, resulting in substantial al9 observed in young healthy women that fluid-regulatory
morbidity. However, the underlying pathophysiology remains hormones, plasma renin activity, and aldosterone increased,
unclear. It has been proposed that the mechanisms for POTS are and plasma norepinephrine decreased along the luteal phase;
heterogeneous.2 We found recently that, as a group, patients with however, blood pressure, heart rate, and their responses to
POTS have a small heart coupled with reduced blood and orthostasis remained unchanged. Chidambaram et al10 dem-
plasma volume, which contributes to a small stroke volume, onstrated that the renal-adrenal response to orthostatic stress
ultimately resulting in reflex tachycardia during orthostasis.3 was significantly augmented in the luteal phase compared
The renin-angiotensin-aldosterone system (RAAS) plays with the follicular phase. These observations were made in
an important role in the neurohumoral regulation of plasma healthy euvolemic women; whether similar results are ob-
volume and hemodynamic homeostasis in humans, especially served in POTS women, who have a small heart coupled with
during long-term orthostasis.4 Despite its importance in reduced plasma volume, is uncertain.

Received February 12, 2010; first decision March 10, 2010; revision accepted April 19, 2010.
From the Institute for Exercise and Environmental Medicine (Q.F., T.B.V., S.S., B.D.L.), Texas Health Presbyterian Hospital Dallas, Dallas, Tex;
University of Texas Southwestern Medical Center at Dallas (Q.F., S.S., R.J.A., B.D.L.), Dallas, Tex; Brigham and Womens Hospital (G.H.W.), Harvard
Medical School, Boston, Mass.
Correspondence to Qi Fu, Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, 7232 Greenville Ave, Suite
435, Dallas, TX 75231. E-mail QiFu@TexasHealth.org
2010 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.110.151787

82
Fu et al Sex Hormones and RAAS in POTS 83

Table. Physical Characteristics in POTS Women and Controls


POTS Women (n10) Controls (n11)

Variables EFP MLP EFP MLP


Age, y 279 3310
Height, cm 1676 1666
Weight, kg 6712 6612 637 648
BMI, kg/m2 244 244 232 232
Menstrual cycle day, d 4.00.4 20.90.9* 3.90.5 21.50.7*
Estradiol, pg/mL 33.98.3 94.654.6* 32.48.9 91.846.7*
Progesterone, ng/mL 0.80.5 7.26.1* 0.90.5 11.15.7*
Plasma volume, mL/kg 415 417 465 465
Blood volume, mL/kg 638 629 687 687
Blood pH 7.390.01 7.380.01 7.420.02 7.410.01
Na, mmol/L 1391 1381 1381 1380.4
K, mmol/L 4.20.1 4.30.1 4.20.1 4.30.1
Ca, mmol/L 1.170.02 1.150.02 1.110.02 1.150.02
24-h urine output, mL 2390900 26931174 2059860 2338799
Osmolality, mosmol/kg 296121 344231 36693 360105
pH 6.70.2 6.60.2 6.50.2 6.40.2
Na, mmol/24 h 185.948.6 196.072.2 148.253.7 169.448.8
K, mmol/24 h 65.632.2 64.226.4 52.420.6 56.717.5
Ca, mmol/24 h 2.01.2 2.11.5 1.30.7 1.70.9
Values are meanSD. Mosmol indicates milliosmol; BMI, body mass index.
*P0.05 vs EFP within the same group.
P0.05 vs controls during the same menstrual phase.

The primary objective of this study was to test the Texas Health Presbyterian Hospital Dallas. A summary of the descrip-
hypothesis that, in POTS women during orthostasis, activa- tive data for POTS women and controls is presented in the Table.
tion of the RAAS is greater, leading to better compensated
hemodynamics in the midluteal phase (MLP) than in the early
Hemodynamic Measurements
follicular phase (EFP) of the menstrual cycle. To accomplish Heart Rate and Blood Pressure
this objective, we evaluated comprehensively renal-adrenal Heart rate was monitored from the ECG (Hewlett-Packard), and
beat-to-beat arterial pressure was derived by finger photoplethys-
and hemodynamic responses during prolonged standing in mography (Portapres). Arm-cuff blood pressure was measured by
normally menstruating POTS women during the EFP (1 to 4 electrosphygmomanometry (SunTech), with a microphone placed
days after the onset of menstruation when both estrogen and over the brachial artery to detect Korotkoff sounds. Respiratory
progesterone are low) and during the MLP (19 to 22 days, excursions were detected by a nasal cannula.
when both hormones are high). Cardiac Output
Cardiac output was measured with the acetylene rebreathing tech-
Methods nique,14 from the disappearance rate of acetylene in expired air,
measured with a mass spectrometer (Marquette), after adequate
Participants mixing in the lung has been confirmed by a stable helium concen-
The patient population consisted of 54 consecutive patients referred tration. This method has been validated against standard invasive
to our tertiary Autonomic Function Clinic between December 2004 techniques, including thermodilution and direct Fick.15,16
and April 2008. Forty-six of these patients were screened, 28 Stroke volume was calculated from cardiac output and the heart rate
ultimately were enrolled, and 10 normally menstruating POTS measured during rebreathing. Total peripheral resistance was calculated
women agreed to participate in all phases of this study. All of the as the quotient of mean arterial pressure and cardiac output, multiplied
patients met the inclusion criteria for POTS11 and had a heart rate by 80 (expressed as dynes second centimeter5). Mean arterial pres-
rise 30 bpm or a rate that exceeded 120 bpm that occurred after 10 sure was calculated as [(systolic pressurediastolic pressure)/3]
minutes of standing without any evidence of orthostatic hypoten- diastolic pressure.
sion.8 Eleven age-matched healthy women (controls) were also
enrolled. All had self-reported regular menstrual cycles of 28 days Experimental Protocol
and had never taken or had not taken oral contraceptives for 6 All of the subjects were studied twice, once during the EFP and once
months.12 All were nonsmokers. None was an endurance-trained during the MLP, with the order counterbalanced. Cycle phase was
athlete.13 All were screened with a careful medical history, physical determined by the onset of menstruation and by the detection of the
examination, 12-lead ECG, and a 10-minute stand test. Patients had luteinizing hormone surge by an ovulation prediction kit (OvuQuick)
stopped taking medications that could affect the autonomic nervous and was verified by circulating estradiol and progesterone concen-
system 2 weeks before screening and testing. All were informed of trations on each study day. Luteal phase progesterone 2 ng/mL was
the purpose and procedures used in the study and gave their written confirmed in all but 1 control and 3 POTS women. Subjects were on
informed consent to a protocol approved by the institutional review an isocaloric diet consisting of 200 mEq of sodium, 100 mEq of
boards of the University of Texas Southwestern Medical Center and potassium, and 1000 mg of calcium. Fluid intake was ad libitum 3
84 Hypertension July 2010

A POTS Controls
120 EFP 120
MLP
115 115
SBP (mmHg)

110 110

105 105

100 100

95 95
P = 0.767 for phase and 0.037 for position
90 90 P = 0.834 for phase and 0.010 for position
P = 0.568 (EFP) and 0.750 (MLP) vs controls
0 0

B 85 85

80 80
Figure 1. Systolic blood pressure
DBP (mmHg)

75 75 (SBP; A), diastolic blood pressure


(DBP; B), and heart rate (HR; C)
70 70
responses during 2-hour standing in
65 65 the EFP (open symbols) and MLP
(closed symbols) of the menstrual
60 60 cycle in POTS women and controls. S
indicates supine. Values are expressed
P = 0.708 for phase and <0.001 for position
55 P = 0.755 and 0.861 vs controls 55 P = 0.978 for phase and <0.001 for position as meanSE.
0 0

C 140 140
130 130
120 120 P = 0.925 for phase and <0.001 for position
HR (bpm)

110 110
100 100
90 90
80 80
P = 0.978 for phase and <0.001 for position
70 P < 0.001 vs controls 70
0 0
S 35 65 95 115 S 35 65 95 115

Standing (min) Standing (min)

days before testing and assessed by 24-hour urine output the day Statistical Analysis
before testing to verify dietary compliance. Subjects were required Data are expressed as meanSD unless otherwise noted. Physical
not to exercise 24 hours before testing. They took a pregnancy test characteristics between groups were compared using Mann-
and showed negative results on each study day. Whitney rank-sum tests and between menstrual phases within
The experiment was performed in the morning or afternoon 2 groups were compared using Wilcoxon signed-rank tests. Hemo-
hours after a light breakfast or lunch and 72 hours after the last
dynamic and renal-adrenal responses during 2-hour standing
caffeinated or alcoholic beverage in a quiet, environmentally con-
between phases and between groups were analyzed using 2-way
trolled laboratory with an ambient temperature of 25C. The
subject was placed in the supine position, and an intravenous catheter repeated-measures ANOVA, and the Holm-Sidak method was
was inserted into an antecubital vein for blood samples. Hemody- used post hoc for multiple comparisons. The percentage rate of
namic variables were measured after 30 minutes in the supine subjects having presyncope between menstrual phases and groups
position and every 10 minutes after the subject began 2-hour was compared using 2 tests. All of the statistical analyses were
standing. Blood samples were collected after 1 hour in the supine performed with a personal computer-based analysis program
position and after 30 minutes and 1 and 2 hours of standing. Because (SigmaStat, SPSS). A P value of 0.05 was considered statisti-
Jacob et al17 found previously that neurohumoral responses did not cally significant.
reach a plateau after 1 hour of standing, we implemented more
prolonged (ie, 2-hour) standing in this study. Estradiol, progesterone,
plasma renin activity, vasopressin, and aldosterone were measured
Results
by radioimmunoassay techniques,18 whereas plasma catecholamines POTS Versus Controls
were measured by high-performance liquid chromatography.19
POTS women and controls were not different in age, height,
Plasma volume was measured by a modified carbon monoxide
rebreathing technique (please see the online Data Supplement at weight, or body mass index (Table). Blood electrolytes,
http://hyper.ahajournals.org for details).20,21 24-hour urine output, osmolality, and urine electrolytes did
Fu et al Sex Hormones and RAAS in POTS 85

A 7
POTS
7
Controls
MLP
EFP
6 6
P = 0.019 for phase and <0.001 for position
CO (L/min) 5
P = 0.003 (EFP) and 0.003 (MLP) vs controls
5

4 4

3 3
P = 0.674 for phase and <0.001 for position
0 0

B 110 110
100 100
90 P = 0.003 for phase and <0.001 for position 90
80 P < 0.001 vs controls 80
SV (mL)

70 70
60 60
50 50
40 40
30 30
20 20
P = 0.697 for phase and <0.001 for position
0 0

C 3000 3000
TPR (dyn scm -5)

2500 2500

2000 2000

1500 1500

1000 P = 0.029 for phase and <0.001 for position 1000


P = 0.008 and 0.002 vs controls P = 0.432 for phase and <0.001 for position
0 0
S 35 65 95 115 S 35 65 95 115
Standing (min) Standing (min)
Figure 2. Cardiac output (CO; A), stroke volume (SV; B), and total peripheral resistance (TPR; C) during 2-hour standing in the EFP
(open symbols) and MLP (closed symbols) of the menstrual cycle in POTS women and controls. S indicates supine. Values are
expressed as meanSE.

not differ between groups (Table). Plasma volume was lower Plasma renin activity increased progressively during
in POTS women than in controls (Table; P0.04). 2-hour standing and was greater in POTS women compared
Systolic pressure remained stable, and diastolic pressure with controls (Figure 3A). This cannot be explained by
increased during 2-hour standing; these responses were not different sodium intakes, because the urine sodium excretion
different between groups (Figure 1A and 1B). Heart rate was greater, although not significantly so, in POTS women
increased during 2-hour standing and was much greater in than in controls (Table). Rather, a reduced plasma volume in
POTS women compared with controls (Figure 1C). Both POTS women may be responsible for the greater increases in
cardiac output and stroke volume decreased during 2-hour plasma renin activity during standing. Aldosterone also in-
standing and were much lower in POTS women (Figure 2A creased gradually during 2-hour standing but did not differ
and 2B). Total peripheral resistance increased during 2-hour between groups (Figure 3B). As a consequence, the aldoste-
standing and was much greater in POTS women than in rone:renin ratio was lower in POTS women than in controls
controls (Figure 2C). Both heart rate and total peripheral after 2 hours of standing (5.52.7 versus 14.07.2 during
resistance were negatively correlated with stroke volume, the MLP; P0.01). Vasopressin increased after 1 and 2 hours
indicating that tachycardia and strong vasoconstriction were of standing in POTS women during the EFP, which was
functions of a lower stroke volume in POTS women (Figure associated with presyncope (Figure 3C). Hematocrit in-
S1 in the online Data Supplement). creased during 2-hour standing and tended to be greater in
86 Hypertension July 2010

A 16 POTS 16
Controls
MLP
14 EFP 14
PRA (ng/mL/h)

12 12
10 * 10
8 8 P = 0.029 for phase and <0.001 for position

6 6
4 P = 0.128 for phase and 4
<0.001 for position
2 P = 0.012 (EFP) and 2 *
0
0.018 (MLP) vs controls
0 * *
B 80 80
70 P
Aldosterone (ng/dL)

= 0.057 for phase and <0.001 for position


P = 0.315 and 0.542 vs controls
70
60 60
Figure 3. Plasma renin activity (PRA; A),
50 50
* aldosterone (B), and vasopressin (C)
40 * 40 responses during 2-hour standing in the
EFP (open symbols) and MLP (closed
30 30 symbols) of the menstrual cycle in
20 20 POTS women and controls. S indicates
supine. Values are meanSE. *P0.05
10 10 P = 0.205 for phase and <0.001 for position EFP vs MLP within the group.
0 0

C 12 12
P = 0.286 for phase and 0.037 for position
Vasopressin (pg/mL)

10 P = 0.266 and 0.076 vs controls 10

8 8
P = 0.270 for phase and 0.273 for position
6 6

4 * 4
*
2 2

0 0

-2 -2
S 30 60 120 S 30 60 120

Standing (min) Standing (min)

POTS women during the MLP (Figure 4A). Plasma norepi- The menstrual cycle did not influence supine hemodynamics
nephrine increased progressively during 2-hour standing and in POTS women and controls (Figure 1 and 2 and Table S1).
tended to be greater in POTS women during the EFP Supine plasma renin activity was greater in the MLP than in
compared with controls (Figure 4B). Plasma epinephrine the EFP for both groups, and supine aldosterone was greater in
increased during 2-hour standing and did not differ between the MLP in POTS women only (Figure 3 and Table S1). The
groups (Figure 4C). menstrual cycle did not affect blood pressure and heart rate
Both plasma renin activity and hematocrit were negatively responses during 2-hour standing in both groups (Figure 1). In
correlated with stroke volume, suggesting that a greater reduc- controls, hemodynamic parameters were indistinguishable be-
tion in central blood volume can cause a lower strove volume tween phases. Interestingly, in POTS women during the initial
and, thereafter, a greater activation of the renal system during 30 minutes of standing, cardiac output, stroke volume, and total
prolonged standing in POTS women (Figure S2). peripheral resistance responses were not different between
phases; however, cardiac output and stroke volume were lower,
EFP Versus MLP whereas total peripheral resistance was greater in the EFP than in
Circulating levels of estradiol and progesterone were greater the MLP after 30 minutes of standing (Figure 2; all P0.05).
in the MLP than in EFP for both groups (Table; both Plasma renin activity was lower in the EFP than in the MLP
P0.01). During the MLP, progesterone was lower in POTS in both groups after 2 hours of standing (Figure 3A). Aldoste-
women than in controls (P0.04), although menstrual cycle rone was lower in the EFP than in the MLP in POTS women
days did not differ between groups. Plasma volume and blood after 1 and 2 hours of standing, and it trended similarly in controls
volume were not affected significantly by the menstrual cycle (Figure 3B). Plasma catecholamine concentrations were not af-
in both groups (Table). fected by the menstrual cycle in both groups (Figure 4B and 4C).
Fu et al Sex Hormones and RAAS in POTS 87

A 46
POTS 46
Controls
MLP
EFP
44 44

Hematocrit (%)
42 42

40 40

38 38

36 36
P = 0.593 for phase and <0.001 for position
P = 0.137 (EFP) and 0.057 (MLP) vs controls P = 0.846 for phase and <0.001 for position
0 0
B
1000 1000
Norepinephrine (pg/mL)

900 900
800 800
700 700
600 600
500 500
400 400
300 300
200 200
100 P = 0.598 for phase and <0.001 for position 100
P = 0.062 and 0.457 vs controls P = 0.167 for phase and <0.001 for position
0 0

C 100 100
90 90
Epinephrine (pg/mL)

80 80
70 70
P = 0.725 for phase and 0.001 for position
60 P = 0.336 and 0.393 vs controls 60
50 50
40 40
30 30
20 20
10 10 P = 0.568 for phase and 0.001 for position
0 0
S 30 60 120 S 30 60 120
Standing (min) Standing (min)
Figure 4. Hematocrit (A), plasma norepinephrine concentration (B), and plasma epinephrine concentration (C) responses during 2-hour
standing in the EFP (open symbols) and MLP (closed symbols) of the menstrual cycle in POTS women and controls. S indicates
supine. Values are meanSE.

Three POTS women and 2 controls developed presyncope the initial 30 minutes (ie, early) of standing, cardiac output,
during the EFP, whereas 1 POTS woman and no controls had stroke volume, and total peripheral resistance responses were
presyncope during the MLP. The percentage rate of subjects not different between phases; however, cardiac output and
experiencing presyncope was greater in the EFP than in the stroke volume were lower, whereas total peripheral resistance
MLP for POTS women (30% versus 10%; 2 P0.01) and was greater in the EFP than in the MLP after 30 minutes (ie,
controls (9% versus 0%; 2 P0.01), suggesting a role for late) of standing; and (4) the percentage rate of subjects
both estrogen and progesterone in promoting orthostatic having presyncope was greater in the EFP than in the MLP
tolerance in women. The rate was not different between for both POTS and healthy women.
groups (2 P0.22). These results suggest that the menstrual cycle modulates
the RAAS and affects hemodynamics during prolonged
Discussion standing in POTS women. The high estrogen and progester-
Our major findings are as follows: (1) plasma renin activity one in the MLP are associated with greater increases in
increases were greater in POTS women than in controls renal-adrenal hormones and presumably more volume reten-
during 2-hour standing, presumably because of a reduced tion, which improve late-standing tolerance in these patients.
plasma volume in POTS; however, aldosterone responses did
not differ between groups; (2) both plasma renin activity and RAAS Responses in POTS
aldosterone were lower in the EFP than in the MLP in POTS We found that standing plasma renin activity was markedly
women during 2-hour standing; (3) in POTS women during greater in POTS women than in controls, whereas standing
88 Hypertension July 2010

BP

PRA CO TPR
Presyncope
POTS ALDO SV HR

P
BP

EF
BP Figure 5. Possible mechanisms for plasma renin
activity (PRA), aldosterone (ALDO), and hemodynam-
CO TPR Orthostasis Poor compensation
ics including cardiac output (CO), stroke volume
SV HR
(SV), total peripheral resistance (TPR), heart rate
(HR), and blood pressure (BP) responses during pro-
BP longed standing in POTS women during the EFP and
ML

BP
MLP of the menstrual cycle.
P

Compensated

PRA CO TPR
ALDO SV HR
+
Vasodilation
BP
Better compensation

aldosterone did not differ between groups. These observa- low-salt diet28 and a greater increase in plasma norepineph-
tions are consistent in part with some5,6 but not all8 previous rine concentration during standing compared with modulating
studies. The reasons for these conflicting results are unclear, hypertensive patients.29 Whether abnormalities in the RAAS
although timing of hormonal measurements obviously con- contribute to POTS or whether the reduced aldosterone:renin
tributes. In addition, differences in salt intake (ie, 150 mEq of ratio is a result of POTS (ie, deconditioning) needs to be
sodium per day in previous studies versus 200 in our study) determined.
may be one potential explanation, because it has been
demonstrated that dietary sodium can modulate the responses Menstrual Cycle Effects in POTS Women
of the RAAS in humans.22,23 We used the relatively high-salt Consistent with previous findings in healthy women,10,30,31
diet because many patients had already been requested by we observed that plasma renin activity and aldosterone
their physicians to increase dietary salt intake or to take salt increases during 2-hour standing were greater in the MLP
tablets; moreover, the high-salt diet would allow us to detect than in the EFP in POTS women. Studies using oral estrogen
a greater RAAS response during prolonged standing. The and progesterone in postmenopausal women have demon-
second possible explanation may be the influences of the strated that both hormones can activate the RAAS.32,33
menstrual cycle. It has been shown that the fluctuations of However, other data suggest that only progesterone activates
estrogen and progesterone during the menstrual cycle affect the RAAS, whereas estrogen might inhibit the activation of
plasma renin activity and aldosterone in healthy women.9,10,23 this system.34,35 Szmuilowicz et al23 showed that progesterone
All of the previous studies did not control for or standardize may directly contribute to increased luteal phase aldosterone
phase of the menstrual cycle in POTS women.5,6,8 In contrast, production independent of the RAAS.
our study was well controlled not only for the diet but also for Activation of the RAAS can lead not only to salt and water
the menstrual cycle. retention but also to vasoconstriction. Given the higher
However, one observation is common in the current study plasma renin activity and aldosterone, we would predict
and all previous studies, namely that POTS patients had a greater cardiac output, stroke volume, and total peripheral
reduced aldosterone:renin ratio. Raj et al8 termed this dys- resistance during 2-hour standing in the MLP compared with
regulation in POTS the renin-aldosterone paradox. It might the EFP in POTS women. However, standing total peripheral
be possible that the levels of aldosterone are so high in the resistance was actually lower in the MLP, although standing
upright posture that the aldosterone response has reached a cardiac output and stroke volume were indeed greater. There
physiological maximum in POTS women. Interestingly, a are several possibilities for the lower standing total peripheral
similar reduced aldosterone:renin ratio was also observed in resistance during the MLP in POTS women. First, Chapman
healthy individuals after a period of bed rest (ie, simulated et al30 found that the hormonal changes in the luteal phase had
microgravity exposure), in which deconditioning (ie, car- a specific renal vasodilating effect, overriding secondary
diac atrophy and hypovolemia) occurs.24 26 Numerous studies activation of other renal vasoconstricting systems, such as the
have shown that real or simulated microgravity exposure can RAAS. Second, animal and human studies showed that
elicit a POTS-like syndrome even in healthy fit people. estrogen could upregulate NO and stimulate an increase in
Conversely, a blunted adrenal response to angiotensin II or endothelial NO synthesis,36,37 producing a direct vasodilatory
renin has been found in 40% of patients with essential effect.38 In addition, NO can downregulate angiotensin II type
hypertension, and the concept of nonmodulating hypertension 1 receptors in vascular tissue39 and adrenal glands40 and
is based on this theory.27 It has also been found that mitigate the actions of angiotensin II. Third, standing cardiac
nonmodulating hypertensive patients have a greater decrease output and stroke volume were greater in the MLP in POTS
in plasma volume when shifted from a high-salt diet to a women, which, in turn, could attenuate the increase in total
Fu et al Sex Hormones and RAAS in POTS 89

peripheral resistance during upright posture via the baroreflex ioral modification during the EFP. Although POTS women
mechanism. demonstrated the anticipated changes in the RAAS during the
In POTS women during early standing, cardiac output, menstrual cycle, namely, greater plasma renin activity and
stroke volume, and total peripheral resistance responses were aldosterone increases during prolonged standing in the MLP
not different between phases; however, cardiac output and compared with the EFP, the aldosterone:renin ratio was lower
stroke volume were lower, whereas total peripheral resistance in these patients compared with healthy women. This obser-
was greater in the EFP compared with the MLP after 30 vation could suggest a rationale for the common use of
minutes of standing. These results suggest that a lower fludrocortisone in such patients, although the optimal timing
activation of the RAAS in the EFP, rather than any funda- and dose of this medication are unclear. Whether the blunted
mental difference in the gravitationally mediated hemody- adrenal response is a consequence or signature of POTS or
namics of the upright posture, or intrinsic impairment of whether abnormalities in the RAAS contribute to this syn-
baroreflex function may account for the different responses drome needs to be determined in future studies.
during different menstrual phases. The menstrual cycle mod-
ulated renal-adrenal increases during 2-hour standing in both Acknowledgments
POTS and healthy women, but it affected hemodynamics in The time and effort put forth by the subjects is greatly appreciated. We
POTS women only. It is possible that the vasodilatory effects thank Robin P. Shook, Kazunobu Okazaki, Jeffrey L. Hastings, M.
Dean Palmer, Daniel L. Creson, Colin L. Conner, Diane Bedenkop, and
of sex hormones may depend on the degree of vasoconstric- Peggy Fowler for their valuable laboratory assistance.
tion. POTS women had greater vasoconstriction in response
to upright posture compared with controls, and, thus, the Sources of Funding
vasodilatory effects of estrogen and progesterone were This study was supported by a National Institutes of Health K23
greater in these patients. It is also possible that the sensitivity grant (HL075283), a National Space Biomedical Research Institute
or density of estrogen and progesterone receptors on the grant (CA00701), and a Clinical and Translational Research Center
blood vessels may be greater in POTS women than in (formerly the General Clinical Research Center) grant (RR00633).
controls. However, blood pressure and heart rate responses
Disclosures
during prolonged standing in POTS women did not vary
None.
during the menstrual cycle, suggesting that POTS, per se, is
not caused by the fluctuations of sex hormones but rather that References
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