Hypercapnic blood pressure response is greater
during the luteal phase of the menstrual cycle
N. EDWARDS, I. WILCOX, O. J. POLO, AND C. E. SULLIVAN
Department of Medicine, University of Sydney, Sydney 2006; and Centre for Respiratory Failure
and Sleep Disorders, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia
follicular phase; progesterone; hypercapnic ventilatory response
RESTING VENTILATION (23) and ventilatory responses to
hypercapnia (13) vary throughout the normal menstrual cycle in response to varying levels of serum
progesterone, with an increase in both during the luteal
phase. In addition, resting oxygen consumption has
been shown to be significantly greater during the luteal
phase of the menstrual cycle (1).
Blood pressure is known to be more reactive to
physical pressor-inducing stimuli such as the handgrip test and the cold-pressor test during the luteal
phase of the menstrual cycle (19). The pressor response
to cocaine is enhanced in ewes after administration of
concentrations of progesterone similar to those found
during pregnancy (9). The reasons for the increased
pressor response are unclear; however, there are a
number of studies that link high serum progesterone
concentrations and increased sympathetically mediated responses (8, 9, 20).
In men, acute hypercapnia leads to a pressor response in the systemic circulation (14, 15, 17), which is
at least partially mediated via an increased sympathetic tone (17), but this response has not been reported
in female subjects. The purpose of this study was to
2142
investigate the pressor effect of acute hyperoxic hypercapnia during the normal menstrual cycle.
METHODS
Subjects. Eleven healthy Caucasian women, aged 25 6 1
(SE) yr (range 22–36 yr), all with normal menstrual cycles,
were included in the study. None of the subjects had clinical
evidence of a sleep disorder. All subjects had normal spirometry; none was taking any regular medication, and none was
overweight (body mass index , 26 kg/m2 ).
Protocol. The subjects were studied on at least two occasions, once during the follicular phase (days 2–14) and at
least once during the luteal phase of the cycle (days 15–27).
The average day (absolute) on which the women were studied
during the follicular phase was day 8 of the menstrual cycle,
and the average day on which the study was performed
during the luteal phase was day 23. The average cycle length
for the group was 30 days. The phase of the cycle in which the
first study was performed was chosen arbitrarily; in seven
subjects, the first study was in the follicular phase and in four
the luteal phase (P 5 not significant). All tests were performed at the same time of day. Venous blood was drawn on
each occasion before ventilatory-response testing for analysis
of serum estradiol and progesterone (CLIA-chemiluminescent immunoassay on immulite). The intra- and interassay
coefficients of variation for estradiol were 15 and 16%,
respectively, and for progesterone 13 and 13%, respectively.
Two subjects had anovulatory cycles (indicated by an absence
of an increase in progesterone), and their tests were repeated
during the luteal phase of their next menstrual cycle.
The effect of acute hyperoxic hypercapnia on arterial blood
pressure and ventilation was measured with a modification of
the Read (11) rebreathing method while the subjects were
sitting awake and relaxed with background music playing.
Caffeine was withheld for at least 4 h, and consumption of
food was restricted for 2 h before each test.
The apparatus used for the studies consisted of a completely closed 6-liter biased-flow circuit comprising a 4-liter
flow-through bag, variable-bypass soda lime absorber, and
fixed-speed blower. The subjects were connected to the circuit,
which was filled with 100% O2, via a mouthpiece with the
nose occluded. Hypercapnia was induced by the addition of a
bolus of CO2, and the subjects were asked to take three deep
breaths to equilibrate the contents of the bag with the lungs.
If a plateau in inspired and expired CO2 was reached within
six breaths [indicating that the mixed venous, and thus brain,
PCO2 was near the expired PCO2 (12)], the soda lime absorber
was disconnected and the subject was allowed to rebreathe
her own expired CO2. In the first test on each subject,
rebreathing was sustained for 4 min or until the subject could
no longer tolerate further increases in end-tidal PCO2
(PETCO2). On subsequent tests, subjects rebreathed until their
maximum PETCO2 matched that obtained on the first test.
Airflow was measured with a pneumotachograph and differential pressure transducer (DP45-14, Validyne, Northbridge,
CA). Tidal volume was calculated by digitally integrating the
airflow signal, and minute ventilation (V̇I) was calcu-
0161-7567/96 $5.00 Copyright r 1996 the American Physiological Society
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Edwards, N., I. Wilcox, O. J. Polo, and C. E. Sullivan.
Hypercapnic blood pressure response is greater during the
luteal phase of the menstrual cycle. J. Appl. Physiol. 81(5):
2142–2146, 1996.—We investigated the cardiovascular responses to acute hypercapnia during the menstrual cycle.
Eleven female subjects with regular menstrual cycles performed hypercapnic rebreathing tests during the follicular
and luteal phases of their menstrual cycles. Ventilatory and
cardiovascular variables were recorded breath by breath.
Serum progesterone and estradiol were measured on each
occasion. Serum progesterone was higher during the luteal
[50.4 6 9.6 (SE) nmol/l] than during the follicular phase
(2.1 6 0.7 nmol/l; P , 0.001), but serum estradiol did not
differ (follicular phase, 324 6 101 pmol/l; luteal phase, 162 6
71 pmol/l; P 5 0.61). The systolic blood pressure responses
during hypercapnia were 2.0 6 0.3 and 4.0 6 0.5 mmHg/Torr
(1 Torr 5 1 mmHg rise in end-tidal PCO2) during the follicular
and luteal phases, respectively, of the menstrual cycle (P ,
0.01). The diastolic blood pressure responses were 1.1 6 0.2
and 2.1 6 0.3 mmHg/Torr during the follicular and luteal
phases, respectively (P , 0.002). Heart rate responses did not
differ during the luteal (1.7 6 0.3 beats · min21 · Torr21 ) and
follicular phases (1.4 6 0.3 beats · min21 · Torr21; P 5 0.59).
These data demonstrate a greater pressor response during
the luteal phase of the menstrual cycle that may be related to
higher serum progesterone concentrations.
HYPERCAPNIC PRESSOR RESPONSES DURING THE MENSTRUAL CYCLE
RESULTS
Serum hormone concentrations. Serum estradiol concentration (Table 1) was not significantly different
during the luteal and follicular phases. Estradiol concentration ranged from 45 to 1,089 pmol/l in the follicular
phase and from 78 to 885 pmol/l in the luteal phase.
Serum progesterone concentration (Table 1) was found
to be greater during the luteal phase of the cycle, with
Table 1. Mean baseline ventilatory
and cardiovascular recordings
Progesterone, nmol/l
Estradiol, pmol/l
V̇I, l/min
PETCO2 , Torr
SBP, mmHg
DBP, mmHg
MAP, mmHg
HR, beats/min
Follicular
Phase
(Days 2–14)
Luteal Phase
(Days 15–28)
P Value
2.1 6 0.7
324 6 101
6.8 6 0.3
40.7 6 2.9
125 6 1.6
73 6 4.0
92 6 3.3
73 6 3.1
50.4 6 9.6
416 6 71
7.2 6 0.4
36.6 6 0.9
123 6 3.3
66 6 3.6
85 6 2.9
75 6 3.8
,0.001
NS
NS
0.09
NS
0.09
0.07
NS
Values are means 6 SE from baseline recordings; n 5 11 subjects.
V̇I, minute ventilation; PETCO2 , end-tidal PCO2 ; SBP, DBP, and MAP,
systolic, diastolic, and mean arterial blood pressure, respectively;
HR, heart rate. Venous blood for mean progesterone and estradiol
concentration was drawn before onset of baseline recording. P values
were calculated with paired 2-tailed t-tests. NS, not significant. P
values are .0.1.
the range in the follicular phase being 0.7–2.7 nmol/l
and during the luteal phase 8.6–108 nmol/l.
Baseline recordings. During baseline recordings
(Table 1), there was no significant difference in ventilatory and cardiovascular variables between the follicular and luteal phases. However, there was a trend
toward PETCO2 being lower during the luteal phase
of the menstrual cycle, but this did not reach the
stipulated level of significance. Similarly, diastolic and
mean arterial blood pressures tended toward being
lower during the follicular phase of the menstrual
cycle; however, these also did not reach significance.
Ventilatory responses. As previously reported, the
ventilatory responses during the luteal phase of the
menstrual cycle were significantly higher than during
the follicular phase (Fig. 1). The mean ventilatory
responses for the group during the follicular and luteal
phases of the menstrual cycle were 2.43 6 0.28
l · min21 · Torr21 (range 0.6–4.6 l · min21 · Torr21 ) and
3.81 6 0.49 l · min21 · Torr21 (range 1.3–6.2 l · min21 ·
Torr21 ), respectively (Table 2).
Blood pressure responses. There was a high variation
in the systolic blood pressure response among the
subjects; however, the slope for each subject was always
higher during the luteal phase of their ovulatory cycles
than during the follicular phase. The range of systolic
blood pressure responses during the follicular phase
was 0.2–4.2 mmHg/Torr and during the luteal phase
was 1.2–7.6 mmHg/Torr (Fig. 2). The range of diastolic
blood pressure responses during the follicular phase
was 0.1–2.9 mmHg/Torr and during the luteal phase
was 0.7–3.1 mmHg/Torr (Fig. 2). The average mean
arterial blood pressure responses during the follicular
and luteal phases of the menstrual cycle were 1.35 and
2.71 mmHg/Torr, respectively (P , 0.005).
The systolic blood pressures during the follicular and
luteal phases of the menstrual cycle at the onset of
hypercapnia were 132 and 126 mmHg, respectively
(P 5 0.39) and at the conclusion of hypercapnia were
140 and 162 mmHg, respectively (P , 0.02). The
diastolic blood pressures for the follicular and luteal
phases at the onset of hypercapnia were 74 and 74
mmHg, respectively (P 5 0.95). At the conclusion of
hypercapnia, the diastolic blood pressures for the follicular and luteal phases of the menstrual cycle were 76
and 96 mmHg, respectively (P , 0.01).
In the two subjects who had anovulatory cycles, there
was little difference in the blood pressure responses
during the two different phases of the menstrual cycle.
The systolic blood pressure responses for these two
subjects were 2.17 and 2.07 mmHg/Torr during the
follicular phase and 2.18 and 1.25 mmHg/Torr during
the luteal phase.
Heart rate responses. The mean heart rate responses
were similar during the follicular (1.4 6 0.6
beats · min21 · Torr21 ) and luteal phases (1.7 6 0.3
beats · min21 · Torr21; P 5 0.57) of the menstrual cycle.
The range of heart rate responses in the follicular and
luteal phases were 0.0–3.3 and 0.2–4.6 beats ·
min21 · Torr21, respectively.
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lated. PETCO2 was measured at the mouth with a capnometer
(HP-47210A, Hewlett-Packard, Waltham, MA). Arterial oxyhemoglobin saturation (SaO2) and heart rate were measured
transcutaneously from the ear lobe with a pulse oximeter
(Biox 3700E, Ohmeda, Englewood, CO). Arterial blood pressure was measured noninvasively with a self-calibrating
finger photoplethysmograph (Finapres, Ohmeda, Englewood,
CO). PETCO2, SaO2, blood pressure (systolic, diastolic, and
mean arterial), heart rate, and V̇I were analyzed breath by
breath with customized software (Laboratory Software, Leonay, Australia). The ventilatory and blood pressure responses to hypercapnia were calculated from the slope of the
regression line plotted against PETCO2 and expressed as the
change in V̇I (in l/min) and blood pressure [systolic, diastolic,
and mean arterial; in mmHg/Torr (1 Torr 5 1 mmHg rise in
PETCO2)].
A 5-min control period was recorded during quiet breathing
to provide a baseline measurement of systemic blood pressure, heart rate, PETCO2, and V̇I. During the control period, all
expired CO2 was absorbed by the soda lime and SaO2 was
maintained by computer-controlled addition of O2 to the
rebreathing circuit. Values obtained during the control period
for all subjects are expressed as means of the 5-min recordings.
Of 11 subjects, 9 had 1 pair of studies with 1 data set
obtained in the follicular phase and another in the luteal
phase. The remaining two subjects had anovulatory cycles
(their serum progesterone concentration in the luteal phase
being ,2 nmol/l), and these subjects were restudied in the
luteal phase of their next menstrual cycle.
All values are expressed as means 6 SE for the group.
Within-group comparisons between the follicular and luteal
phases were made with a paired Student’s t-test. A two-tailed
P value , 0.05 was considered significant. P values . 0.1 are
reported as not significant.
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HYPERCAPNIC PRESSOR RESPONSES DURING THE MENSTRUAL CYCLE
DISCUSSION
This study has demonstrated that the systemic arterial blood pressure response to acute hyperoxic hypercapnia is greater during the luteal phase of the menTable 2. Ventilatory, MAP, and HR response slopes
during follicular and luteal phases
Ventilatory response,
l · min21 · Torr21
MAP response, mmHg/Torr
HR response,
beats · min21 · Torr21
Follicular
Phase
(Days 2–14)
Luteal Phase
(Days 15–28)
P Value
2.4 6 0.3
1.4 6 0.2
3.8 6 0.5
2.7 6 0.3
,0.02
,0.005
1.4 6 0.3
1.7 6 0.3
NS
Values are means 6 SE for each mmHg change in PETCO2 (Torr); n 5
11 subjects. P values were calculated with paired 2-tailed t-tests.
strual cycle. Furthermore, we have shown that the
heart rate response to hypercapnia is unchanged between the two phases of the menstrual cycle.
The phase of the menstrual cycle during which the
first study was conducted was chosen arbitrarily and
was equally liable to have been performed in either of
the phases of the cycle, making it unlikely that an order
effect influenced our findings.
Previous studies have shown that anovulatory menstrual cycles are common in normal premenopausal
women who report regular menstrual cycles (22). For
this reason, it was important, even in subjects reporting regular menstrual cycles, to confirm ovulation by
the measurement of serum concentrations of progesterone and estradiol. The importance of this was demonstrated during the protocol when two of the women
studied had anovulatory cycles. Notably, these two
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Fig. 1. Blood pressure waveform trace (BP; from Finapres), arterial oxyhemoglobin saturation (SaO2), end-tidal
PCO2 (CO2 ), and tidal volume (VT ) during 5 min of baseline recording and then during acute hyperoxic hypercapnia
in 2 different phases of menstrual cycle of 1 subject. Arrows, time at which the 3 breaths were taken at onset of
rebreathing test. Note that BP decreases, as expected, during the 3 deep inspirations. A: recording during follicular
phase of menstrual cycle when serum estradiol concentration was 67 pmol/l and serum progesterone concentration
was 1.4 nmol/l. Ventilatory response to hypercapnia during this test was 2.4 l · min21 · Torr21 (1 Torr 5 1 mmHg rise
in end-tidal PCO2), and the systolic and diastolic blood pressure responses were 2.7 and 1.8 mmHg/Torr, respectively.
Baseline end-tidal PCO2, minute ventilation, and BP were 39 Torr, 7.8 l/min, and 120/60 mmHg, respectively. B:
recording during luteal phase of menstrual cycle when serum estradiol concentration was 514 pmol/l and serum
progesterone concentration was 48.3 nmol/l. Ventilatory response was 5.0 l · min21 · Torr21, and the systolic and
diastolic blood pressure responses were 5.9 and 2.9 mmHg/Torr, respectively. Baseline end-tidal PCO2, minute
ventilation, and BP were 36 Torr, 8.1 l/min, and 119/74 mmHg, respectively. Follicular phase of menstrual cycle was
1st study to be conducted in this patient, and level of CO2 reached was determined by length of time taken for the
test (4 min, as stipulated in METHODS ). During luteal phase of test, study was continued until end-tidal PCO2 reached
that of the 1st study. Time taken for each test differed because of the markedly higher ventilatory response in luteal
phase causing an increased production of CO2.
HYPERCAPNIC PRESSOR RESPONSES DURING THE MENSTRUAL CYCLE
subjects had no change in their pressor response between the two phases.
The Finapres device that was used for recording
arterial blood pressure during these studies is a commonly used noninvasive method of accurately recording arterial blood pressure. The device has been correlated with the intra-arterial ipsilateral blood pressure
recordings in both the steady-state and dynamic blood
pressure systems. Even for rapidly dynamic blood
pressure recordings (in a range of 86–266 mmHg), the
measurements obtained by the device correlate closely
with intra-arterial recordings. The correlation coefficients for systolic, diastolic, and mean arterial blood
pressures in this study were 0.97, 0.93, and 0.97,
respectively (4).
Progesterone is a respiratory stimulant (26) and
increases the ventilatory drive to hypercapnia (23), and
thus basal V̇I is significantly higher (18) and PETCO2
significantly lower (13) in the luteal phase of the
menstrual cycle. In the present study, basal V̇I did not
change significantly over the course of the menstrual
cycle; however, we did demonstrate a trend toward a
lower PETCO2. The principal goal of this study was to
examine ventilatory and systemic arterial blood pressure responses to hypercapnia and not specifically to
reexamine changes in baseline V̇I. Interestingly, there
was also a trend toward lower basal systolic and
diastolic blood pressure measurements during the luteal phase of the menstrual cycle. Although the aim of
this study was to measure pressor responses to hypercapnia and not basal changes in blood pressure, we
demonstrated a trend toward lower basal diastolic (P 5
0.09) and mean arterial blood pressures (P 5 0.07)
during the luteal phase of the menstrual cycle, findings
in agreement with Dunne et al. (2).
We propose that a major factor influencing the increased pressor response to hypercapnia during the
luteal phase of the menstrual cycle is the upregulation
of catecholamine receptors within the cardiovascular
system. There are a number of studies that suggest
that catecholamine receptors are upregulated in the
presence of higher levels of progesterone. The toxic
response to cocaine (a sympathomimetic) is much
greater after administration of progesterone in doses
similar to those occurring during pregnancy. Re et al.
(10) have suggested that parenteral administration of
progesterone results in increased sympathetic tone in
cardiac muscle. Both Mehta and Chakrabarty (8) and
Tollan et al. (20) showed evidence of increased sympathetic activity (increased blood pressure and increased
sweating) during the luteal phase of the menstrual
cycle. However, Tollan et al. (20) also showed that even
though blood pressure is increased in the luteal phase
of the cycle, net serum catecholamine concentrations
are reduced. Trzebski and Kubin (21) have suggested
that the pressor response to hypercapnia in male
subjects is mediated via central control mechanisms
increasing peripheral sympathetic tone. Thus it is
probable that although acute hyperoxic hypercapnia
leads to a similar increase in sympathetic output
during the two different phases of the cycle, the postulated upregulation of sympathetic receptors by progesterone during the luteal phase results in a greater
response.
Other potential mechanisms of the increased pressor
response to hypercapnia must be considered. Progesterone increases intravascular volume, and this could lead
to an increased mean circulatory filling pressure and
hence an increased cardiac output (mediated via a
greater stroke volume). Mean circulatory filling pressure increases reflexly under hypercapnic conditions
due to stimulation of aortic arch chemoreceptors (14).
Under these circumstances, the pressor effect of hypercapnia would be increased in the presence of a greater
intravascular volume. It is unlikely that alterations in
parasympathetic tone contributed to the increased
pressor response to hypercapnia, because parasympathetic function is believed to be unaltered by the phase
of the menstrual cycle (8).
It is clear from the results of this study that the
menstrual cycle is an important factor in determining
the blood pressure response to hypercapnia. There are
a number of implications of these findings when considered in conjunction with other studies reporting greater
systemic blood pressure responses to a variety of pressor-inducing stimuli during the luteal phase of the
menstrual cycle. Importantly, these results suggest an
increased risk of cardiovascular accidents during pressor-inducing activities in the luteal phase of the menstrual cycle. However, obstructive sleep apnea (OSA) in
premenopausal women may be another very important
public health issue when considered in the context of
the results reported in the present study. Blood pressure increases acutely in response to apnea in men with
OSA (16). One mechanism that may be involved in the
acute pressor response after apnea is the transient increase in PETCO2. Although OSA is classically reported
to occur predominantly in men and postmenopausal
women (24), there is increasing evidence that OSA also
occurs commonly in premenopausal women, with one
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Fig. 2. Systolic and diastolic blood pressure responses to hypercapnia for the 11 subjects during follicular (open bars) and luteal phases
(solid bars) of menstrual cycle. Values are means 6 SE. Systolic blood
pressure responses during follicular and luteal phases of menstrual
cycle are 2.0 6 0.3 and 4.0 6 0.5 mHg/Torr, respectively. Diastolic
blood pressure responses during follicular and luteal phases of
menstrual cycle were 1.1 6 0.2 and 2.1 6 0.3 mmHg/Torr, respectively. ** Paired 2-tailed P values . 0.01.
2145
2146
HYPERCAPNIC PRESSOR RESPONSES DURING THE MENSTRUAL CYCLE
The authors gratefully acknowledge the assistance of Dr. Thomas
Wessendorf and Dr. Heinrich Becker for taking venous blood samples,
the Royal Prince Alfred Hospital (Camperdown, Australia) Endocrinology Laboratory for analyzing serum hormone concentrations,
Monique Aarts for assistance in performing tests, and Gunnar Ungar
for technical expertise in keeping the ventilatory-response circuit
working and for providing technical information on the components
involved in the circuit.
N. Edwards was supported by the David Read Scholarship.
Address for reprint requests: C. E. Sullivan, Dept. of Medicine,
Blackburn Bldg. (D06), Univ. of Sydney, Sydney, New South Wales
2006, Australia.
Received 23 October 1995; accepted in final form 10 April 1996.
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epidemiological study suggesting that 4.9% of women
aged 30–49 yr have significant OSA (25). According to
the data presented here, premenopausal women may
have an enhanced pressor response to apnea during the
luteal phase of each menstrual cycle. Male sleep apneics often present with daytime hypertension (3), and
OSA is suggested to be a major risk factor for the
development of hypertension (3, 6, 7, 17). The risk of
stroke and acute myocardial infarct are also increased
in men with OSA (5). No similar data on cardiovascular
morbidity and mortality in OSA exist for premenopausal women. However, if the pressor response to
obstructive sleep apnea is enhanced in premenopausal
women during the luteal phase of the menstrual cycle,
then the occurence of OSA may pose an even greater
risk for the development of hypertension and vascular
disease in these women.
In conclusion, this study has demonstrated an increased pressor response to acute hyperoxic hypercapnia during the luteal phase of the menstrual cycle. This
effect is associated with higher serum progesterone
concentrations, which may either modify the sympathetic response to hypercapnia by upregulation of sympathetic adrenoceptors at the level of the heart and
blood vessels or increase intravascular volume. The
results suggest a profound influence of the menstrual
cycle on cardiovascular control in premenopausal
women with OSA.