From the IRCCS "S. Lucia," Rome (M.M., E.T., C.C.), and
Clinic of Neurology, "Tor Vergata" University of Rome (B.C.M.,
C.C., M.S.) (Italy).
Correspondence to Dr Mauro Silvestrini, Clinica Neurologica, Universita' di Roma "Tor Vergata," Ospedale S. Eugenio, P. le dell'Umanesimo 10, 00144 Rome, Italy.
Methods—Using transcranial Doppler
ultrasonography, we studied the changes of flow velocity after
hypercapnia in the middle cerebral arteries of 45 healthy premenopausal
women (mean age, 32.3 years; range, 20 to 47 years) and 40
postmenopausal women (mean age, 54.4 years; range, 48 to 64 years). The
same measurements were recorded in two groups of healthy male
subjects age matched with premenopausal (45 subjects) and
postmenopausal women (40 subjects). Moreover, a subgroup of
postmenopausal women aged 48 to 53 years (15 subjects) were compared
with a group of 15 premenopausal women of the same age. We obtained
hypercapnia with breath holding and evaluated cerebrovascular
reactivity with the breath-holding index (BHI).
Results—BHI was significantly lower in postmenopausal women
(0.89±0.3) than in premenopausal women (1.59±0.3;
P<0.0001) and in young (1.34±0.5;
P<0.001) and old men (1.20±0.4;
P<0.04). In the latter group, BHI was significantly
lower than in premenopausal women (P<.0001). BHI values
were also significantly lower in postmenopausal than in premenopausal
women of the same age (0.81±0.1 versus 1.34±0.1;
P<0.0001).
Conclusions—These findings suggest that the large reduction of
cerebrovascular reactivity in postmenopausal women cannot be considered
a simple factor related to aging but is probably influenced by hormonal
changes. The alteration in cerebrovascular regulation could be involved
in the increase of cerebrovascular disease in postmenopausal women.
Epidemiological data show that there are distinctive features of
cerebrovascular disease in men and women probably connected to their
different patterns of sex hormones. In particular, the incidence of
atherosclerotic vascular disease in premenopausal women is less than in
men, but this difference disappears after
menopause.12 13 14 15
Experimental studies have shown that female gerbils sustain less
neuronal damage after focal ischemia than their male
counterparts16 and that chronic estradiol
treatment can improve regional cerebral blood flow in female rabbits
during incomplete global ischemia and early
reperfusion.17
Because sex hormones, in particular estrogens, have well-known
vasoactive properties18 19 and their level
decreases after menopause, we aimed to assess whether changes in
cerebral vasomotor reactivity occur after menopause and to verify the
possible existence of sexual hemodynamic
differences.
Rigid exclusion criteria were established to avoid any bias by an
unbalanced distribution of concomitant diseases or drug therapy:
subjects with hypertension, diabetes mellitus, obesity, congestive
heart failure (greater than New York Heart Association grade I),
chronic obstructive lung disease, cerebrovascular disease (transient
ischemic attack, stroke, carotid artery stenoses
>30%, and intracranial stenosis evaluated by cervical
Doppler sonography and TCD), hematologic disease, and cancer were
excluded from the study, as well as patients being treated with
hormonal substances, nitrates, ß-blocking agents, calcium channel
blockers, anticoagulants, and vasodilatory drugs. The female group
included 6 premenopausal and 4 postmenopausal smokers. Hyperlipemia
(cholesterol >200 mg/dL) was present in 2
postmenopausal women. The male group comprised 12 smokers: 7 in the
younger group and 5 in the older group. In a second study, to compare
premenopausal and postmenopausal women of similar age, a subgroup of
postmenopausal subjects aged 48 to 53 years (15 subjects) was matched
with 15 premenopausal women, each coupled with a postmenopausal woman
of the closest age with similar weight and height.
Informed consent was obtained according to the declaration of Helsinki.
The study was approved by the local ethics committee.
The subjects were studied in the morning in a supine resting state with
their eyes closed. Twenty-two premenopausal women were recorded
during the follicular phase (days 3 to 8 of the menstrual cycle), that
is, estrogen dominant with high concentrations of estrogen and low
progesterone levels, and 23 during the luteal phase (days 18 to 23 of
the menstrual cycle) when progesterone levels rise to the point at
which neither hormone is dominant. The phase of the menstrual cycle was
established by considering the interval between two consecutive menses.
The time of this interval ranged from 25 to 31 days, with a mean of 28
days. All subjects were drug free and had abstained from smoking,
alcohol, and caffeine-containing beverages for at least 12 hours before
the study. A routine hemogram performed at the time of TCD evaluation
showed normal hematocrit values in all the study subjects without
significant differences among groups (premenopausal women, 41±3;
postmenopausal women, 40±2; young men, 43±3; old men, 42±4; young
postmenopausal women, 41±4; premenopausal women of similar age,
41±2).
MFV of the MCA was continuously monitored by means of a Multi-Dop X/TCD
transcranial Doppler instrument (DWL Elektronische
Systeme GmbH). One dual 2-MHz transducer fitted on a headband and
placed on the temporal bone window was used to obtain continuous
measurements. The highest signal was sought at a depth ranging from 46
to 54 mm. This unit allows for continuous-wave Doppler
recording of the intracranial artery with on-line calculation
of MFV in centimeters per second. By activating the record
function, it is possible to save the Doppler spectra during the
entire period of each study. Reactivity was examined by calculating the
BHI.4 This index is obtained by dividing the
percent increase in MFV occurring during breath holding by the length
of time (seconds) that subjects hold their breath after a normal
inspiration (%MFV increase per second). The MFV at rest was obtained
by the continuous recording of a 1-minute period of normal room
air breathing. After a breath-holding period, the MFV over a 4-second
interval was recorded. A fixed period of 30 seconds for breath
holding was arbitrarily chosen. The efficacy of breath holding was
checked by means of a respiratory activity monitor (Normocap-Oxy,
Datex). With this kind of procedure, this method of induction of
hypercapnia proved to be effective and reproducible in the study of
cerebral hemodynamics.10 11 In
particular, the fact that subjects hold their breath after a normal
inspiration avoids a Valsalva phenomenon and the possible interference
of blood pressure changes with cerebral
hemodynamics.4 MBP and HR were
continuously monitored by means of a blood pressure monitor (2300
Finapress, Ohmeda).
A preliminary analysis was performed on premenopausal women to
detect whether there were differences in BHI in the follicular and
luteal phases. A one-way ANOVA was used with BHI as dependent factor
and phase of the menstrual cycle (follicular and luteal) as between
factors. Since no significant difference was detected, all values were
considered together as premenopausal values. To investigate possible
differences related to sex and age, a two-way ANOVA (BHI as dependent
factor) was performed with sex (men and women) and age (premenopausal
and postmenopausal women, men aged 47 years or younger, or men older
than 47 years) as between factors. Moreover, post hoc comparisons
(Scheffé's test) were performed when necessary. The same
analysis was used for MFV, HR, and MBP values at rest. The
comparison between BHI of the subgroup of younger postmenopausal women
and premenopausal woman of similar age was performed by means of a
one-way ANOVA with the group (postmenopausal and premenopausal women)
as between factor and BHI as dependent factor.
HR and MBP at rest were comparable in the subgroup of young
postmenopausal women and in the group of premenopausal women of similar
age (Table 2
HR and MBP during breath holding showed a slight increase. These
modifications, as shown in Tables 1
Epidemiological21 22 and
experimental16 23 studies suggest that many
different aspects must be considered in the relationship between sex
and cerebrovascular disease. There is evidence that cerebral
ischemic events have a more benign natural course in women than
in men15 and that there are sex differences in
the antithrombotic effect of aspirin.24 Moreover,
the incidence of stroke in premenopausal women is lower than in
age-matched men and, after menopause, there is a strong increase in the
incidence of vascular diseases in women.12 13 14 15
These facts suggest that the relevance of several
pathophysiological substrates involved in verifying
stroke events may not be the same in the two sexes.
Strict exclusion criteria were used in the present
investigation to eliminate any bias caused by concomitant drug therapy
or diseases or lifestyle that might influence cerebral vasomotor
reactivity. The main finding of our study was the reduction of
cerebrovascular reactivity in postmenopausal with respect to
premenopausal women. We also found that while BHI was significantly
lower in the postmenopausal women with respect to men of the same age,
the latter subjects did not differ from younger men but had a
significantly lower cerebrovascular reactivity to hypercapnia in
comparison to premenopausal women. These findings lead us to believe
that factors other than age may influence the reduction of
cerebrovascular reactivity in women at the end of the fertile period.
This is also confirmed by the fact that we found a significantly lower
cerebrovascular reactivity in young postmenopausal women with respect
to premenopausal women of similar age. At present, the mechanisms
of the decrease of vasomotor reactivity in women after menopause and
the pathophysiological significance of this
phenomenon cannot be completely defined. At menopause, levels of
estradiol, primarily produced by the ovarium, fall, and this hormone is
replaced by estrone, a less active estrogen, produced mainly by
conversion of androstenedione in adipose tissue. After menopause there
is little further decrease in endogenous estrogens with
advancing age.25 The low cerebrovascular
reactivity in postmenopausal women could be connected with these
changes, but further studies comparing changes in concentrations of
specific sex hormones with changes in cerebral
hemodynamics are needed before we can state this with
certainty.
From a clinical point of view, estrogen administration in
postmenopausal women has been associated with a significant reduction
in the development of clinical manifestations of coronary
artery disease and stroke.26 27 These
observations have been interpreted as probable evidence that female
reproductive hormones provide vascular protection in
ischemic heart disease and stroke. However, it is unclear
whether estrogens per se are critical for modulating the risk of stroke
or which mechanism provides protection. Although estrogens have been
shown to favorably alter the lipid profile12 and
inhibit endothelial
hyperplasia,28 these effects do not fully account
for the degree of clinical benefit attributed to estrogen therapy in
postmenopausal women. Another mechanism proposed for the vascular
protective effect of estrogens is favorable modulation of
vasoreactivity. In fact, estrogens are well known for their systemic
vasoactivity.18 19 Intravenous
administration of ethinyl estradiol in postmenopausal women produces an
increase in coronary flow and cross-sectional area and a
decrease in resistance of coronary
arteries.29 Several studies have demonstrated
that estrogens improve vascular flow and arterial
pulsatility.30 31 32 A recent TCD
study33 has shown an increase of flow resistance
of the internal carotid artery and MCA during postmenopausal years,
suggesting that this effect may be one of the mechanisms by which
menopause is associated with the increased risk of vascular
disease.
The mechanism for the estrogen-related arterial
vasodilatation and improved pulsatility is most likely mediated through
increased production of prostacyclin34 or
enhanced release and/or activity of nitric
oxide.35 The possibility of a direct effect of
estrogens on the arterial wall must also be considered,
because estrogens influence artery wall metabolism, as
suggested by the presence of estrogen receptors in the
arterial wall.36
The possible pathophysiological significance
of reduced cerebral reactivity to hypercapnia in postmenopausal women
does not necessarily imply that cerebrovascular disorders after
menopause should be considered predominantly on a
hemodynamic basis, excluding other well-known
mechanisms of ischemic events. However, there is evidence that
in areas of the brain where there is limited capacity for further
capillary vasodilatation, susceptibility to ischemic damage is
increased.37 For this reason, altered cerebral
hemodynamics can be considered a sign of increased risk
of cerebrovascular events. This seems confirmed by several
investigations showing an association between risk factors for stroke
such as smoking10 or carotid
lesions8 9 11 and the presence of a reduced
cerebrovascular reserve capacity. Our finding that cerebrovascular
reactivity to hypercapnia in the postmenopausal women was significantly
lower than that of age-matched men is difficult to explain, but it
furthermore suggests the existence of differences in the pathogenesis
of stroke in the two sexes. This is also confirmed by the fact that
atherosclerotic vascular lesions are more severe in men than in women
of similar age.38 39 On the basis of our data we
hypothesize that impaired cerebral hemodynamics,
probably related to low levels of estrogen, may be particularly
important in the pathophysiology of cerebrovascular disease in
postmenopausal women. Further studies, also associated with measures of
sex hormonal levels, are needed to confirm our data and to determine
whether estrogen replacement therapy is able to bring about an
improvement in cerebrovascular reactivity.
Received September 30, 1997;
revision received February 10, 1998;
accepted February 10, 1998.
© 1998 American Heart Association, Inc.
Original Contributions
Age and Sex Differences in Cerebral Hemodynamics
A Transcranial Doppler Study
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and
Purpose—Hemodynamic factors seem to play an
important role in the pathogenesis of cerebral ischemic events.
The aim of this study was to evaluate whether changes in
cerebrovascular reactivity occur in women after menopause.
Key Words: gender • ultrasonography, Doppler, transcranial • vasomotor reactivity
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Transcranial
Doppler ultrasonography permits the noninvasive measurement of
blood flow velocities in the basal brain arteries that have been found
to reliably correlate with changes in cerebral blood
flow.1 2 Cerebral vasomotor reactivity can easily
be studied by measuring changes in flow velocity in response to
vasodilatory stimuli such as CO2 inhalation,
breath holding, or acetazolamide
administration.3 4 5 The assessment of cerebral
vasoreactivity can provide information regarding the reserve capacity
of cerebral circulation, that is, the possibility of vessels to adapt
in response to systemic modification or brain metabolic
activity requiring an increase or decrease of cerebral blood
flow.6 7 Reduction of this property has been
found in association with situations predisposing toward
cerebrovascular diseases.8 9 10 11
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
After giving informed consent, 170 right-handed healthy subjects
selected from the hospital personnel (85 women and 85 men) were
admitted to the study. Each female subject was matched with a male of
the same age. The population was divided into four groups: 45
premenopausal women (mean age, 32.3 years; range, 20 to 47 years), 40
postmenopausal women (mean age, 54.4 years; range, 48 to 64 years), 45
men aged 47 years or younger (mean age, 36.5 years; range, 20 to 47
years), and 40 men older than 47 years (mean age, 56.5 years; range, 48
to 64). Postmenopausal status was defined as amenorrhea for at least 6
months, with gonadotropin and estradiol values within the
postmenopausal range. The menopausal period ranged from 43 to 46 years.
The interval from menopause to Doppler assessment ranged from 4 to
18 years (mean, 10.5 years).
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
HR and MBP at rest were comparable in the four groups considered
(Table 1
). Values of MFV at rest were
also comparable: 62.3±12.1 cm/s in premenopausal women; 59.8±9.3 cm/s
in postmenopausal women; 60.5±11.4 cm/s in men aged 47 years or
younger; and 61.6±10.2 cm/s in men older than 47 years. Regarding
cerebrovascular reactivity during apnea, the sex effect was not
significant. In fact, when all the included subjects were considered
without distinction for age, BHI was comparable in women and men (1.24
versus 1.19). The age effect was significant (F=38.9;
P<0.0001, df 1 and 166). In fact, considering
woman and men together, the BHI was significantly higher in the younger
(premenopausal women and young men) than in the older (postmenopausal
women and old men) subjects (1.47 versus 0.96). Finally, the sexxage
interaction was significant (F=16.8; P<0.0001,
df 1 and 166). Post hoc comparison (Scheffé's test)
showed that BHI was significantly lower in the postmenopausal women
with respect to premenopausal women (P<0.0001), young men
(P<0.001), and old men (P<0.04) and in old men
with respect to premenopausal women (P<0.001). These data
are shown in Table 1.
View this table:
[in a new window]
Table 1. BHI, HR, and MBP in the Four Groups of Subjects ). Values of MFV at rest were
also comparable: 60.2±8.3 cm/s in postmenopausal women and 63.1±10
cm/s in premenopausal women. Regarding BHI, the group effect was
significant (F=65.2; P<0.0001, df 1 and 28).
This was due to the fact that the BHI values were lower
(P<0.0001) in postmenopausal than in premenopausal women
(Table 2).
View this table:
[in a new window]
Table 2. BHI, HR, and MBP in the Subgroup of Young
Postmenopausal Women and in the Group of Premenopausal Women of Similar
Age 
and 2, were comparable in all
groups. For this reason, when the analysis on BHI was repeated
introducing HR and MBP changes as covariant factors, the
results remained unchanged. Changes of HR and MBP with respect to
baseline were calculated considering the values of the 4-second
interval after the breath-holding period.
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
The results of our study suggest that changes of cerebrovascular
reactivity in healthy subjects may be related to aging, but they are
probably mainly influenced by hormonal changes. The only previous TCD
study describing sex-related differences in cerebral vasomotor
reactivity has shown increased vasodilatory response to the
acetazolamide test in female compared with male
subjects.20 These data are not comparable with
ours. In fact, the study design did not permit establishing the number
of women in the fertile period and the number in the postmenopausal
period at the time of the assessment.
Selected Abbreviations and Acronyms
BHI
=
breath-holding index
HR
=
heart rate
MBP
=
mean blood pressure
MCA
=
middle cerebral artery
MFV
=
mean flow velocity
TCD
=
transcranial Doppler ultrasonography
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
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