Modulation of coronary artery disease risk factors by menopausal status:
A population based study among Iranian women (KERCADRStudy)
(1)
(2)
(3)
Gholamreza Yousefzadeh , Fatemeh Mahdavi-Jafari , Mostafa Shokoohi ,
(4)
(5)
(6)
Hamid Najafipour , Ali-Akbar Haghdoost , Vida Modares-Nejad
Original Article
Abstract
BACKGROUND: Menopause is now viewed as a risk factor for coronary heart diseases (CHD).
There is a scarcity of evidence concerning the effects of menopause on coronary artery disease
(CAD) risk factors. The present study aimed to evaluate the effects of menopausal status on CAD
risk factors.
METHODS: The present study was designed as part of the Kerman coronary artery disease risk
study (KERCADRS) that was a population-based study among a cohort of 6000 individuals aged
15 to 75 years in Kerman, Iran. Only women aged 35 to 60 years were enrolled. Participants
were categorized according to reproductive age into the three groups of premenopausal,
perimenopausal, and postmenopausal states.
RESULTS: The premenopausal status was accompanied with lower levels of triglyceride (TG),
cholesterol, fasting plasma glucose (FPG), and blood pressure compared with the other two
groups (P < 0.001). In addition, women in the postmenopausal group had higher levels of
low-density lipoprotein (LDL) in comparison with the other two groups (P < 0.001). After
adjusting for age, total cholesterol and LDL levels were significantly higher in the
postmenopausal group compared with the other two groups (P < 0.05). In addition, total
cholesterol and LDL levels, and systolic blood pressure were statistically different according to
menopausal status after adjustment for both age and body mass index (P < 0.05).
CONCLUSION: The increased risk of cardiovascular disease in postmenopausal period can be
explained by elevated levels of lipid profile and increased systolic blood pressure, regardless of
effects of advanced age or other anthropometric parameters.
Keywords: CAD Risk Factors, Women, Premenopause, Perimenopause, Postmenopause
Date of submission: 20 Apr 2013, Date of acceptance: 20 Jul 2013
Introduction
Menopause is now accepted as a risk factor for
coronary heart diseases (CHD) and its occurrence
results in increased risk of coronary artery disease
(CAD) in women.1 This increased risk can be
caused not only by estrogen deprivation, but also by
its effect on lipid profile, which is likely to occur in
the perimenopause period.2 Some studies have
suggested a central role for insulin in increasing
CAD risk factors.3 Moreover, menopause can be
associated with the aggravation of multiple
cardiovascular risk factors. These deleterious factors
can be indirectly affected by treatment with
estrogen and progestin combination.4 Besides, the
pointed probable mechanisms, an increase in the
prevalence of CAD risk factors at the time of
menopause has also been shown to be a potential
risk factor for increasing CAD risk. Some studies
have found high total cholesterol level, high lowdensity lipoprotein (LDL) cholesterol level, and
high triglyceride level to be associated with
menopausal status.4-6 In addition, menopause-
1- Assistant Professor, Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran
2- Resident, Clinical Research Center, Afzalipour Hospital, Kerman University of Medical Sciences, Kerman, Iran
3- Lecturer, Research Center for Modeling in Health, Institute for Futures Studies in Health, Kerman University of Medical Sciences,
Kerman, Iran
4- Professor, Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran
5- Professor, Research Center for Modeling in Health, Institute for Futures Studies in Health, Kerman University of Medical Sciences,
Kerman, Iran
6- Department of Obstetrics and Gynecology, Kerman University of Medical Sciences, Kerman, Iran
Correspondence to: Mostafa Shokoohi, Email: shokouhi.mostafa@gmail.com
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Yousefzadeh, et al.
associated differences in plasma LDL cholesterol
levels have been attributed to the effect of sex
hormones on LDL metabolism.7,8 However, little
information is available on the effects of menopause
on CAD risk factors, especially lipid levels, in large
populations. The present study aimed to clarify the
effects of menopausal status on various CAD risk
factors and determine the situation of these risk
factors in different age groups of women around
menopause.
Materials and Methods
The present study was designed as a part of The
Kerman coronary artery disease risk study
(KERCADRS-No. 88/110).9 The KERCADRS was
a population-based, epidemiological research among
a cohort of 6000 individuals aged 15 to 75 years and
residences of Kerman city, Iran. The study
addressed the epidemiological data regarding
various coronary artery disease risk factors and
menopausal status. All subjects with a history of
metabolic disorders or using antilipidemic drugs
were not included into the study. A well-validated
questionnaire
regarding risk
profile
was
administered by trained and certified medical staff.
Participants also underwent a clinical examination
that included measurement of height, weight, and
arterial blood pressure (mean of two measurements
performed with a standard sphygmomanometer in a
sitting position after a 5-min rest) according to
standardized protocols. Furthermore, blood samples
were taken after at least 12 h of overnight fasting
and hemoglobin A1c (HbA1c), fasting plasma
glucose (FPG), serum triglyceride (TG), and total
cholesterol, and high-density lipoprotein (HDL)
cholesterol were measured. LDL cholesterol was
also calculated using the Friedewald formula. In this
study, only women aged 35 to 60 years were
enrolled. Participants were categorized according to
their reproductive age into three groups of
postmenopausal group (with an amenorrhea for at
least 12 months),2,10 perimenopausal group (with an
amenorrhea for 6 to 12 months, or older than 40
years old with irregular bleeding, and/or older than
40 years old with regular bleeding using
progesterone medication), premenopausal group
(age less than 40 years with regular bleeding, or age
more than 40 years with regular bleeding without
using progesterone drugs, or age less than 40 years
with irregular bleeding).
Lipid-lowering therapy was defined as the daily
intake within the previous 15 days of at least one
lipid-lowering drug among those defined by the
National Guide Drug Prescription used at the time
of the study.11 Similar definitions of treatments were
used for diabetes mellitus and antihypertensive
treatments.2 Hormonal treatments were defined as
the daily intake of contraceptive drugs or hormone
replacement therapy. Women with a history of
hysterectomy were excluded. The study protocol
was approved by the research and ethics
committees of the Kerman University of Medical
Sciences, and informed consents were obtained
from all participants.
Statistical analysis
Results were presented as mean ± standard
deviation (SD) for quantitative variables and were
summarized by absolute and relative frequencies for
categorical variables. Categorical variables were
compared using chi-square test or Fisher's exact
test. Quantitative variables were also compared
using ANOVA, and Tukey's post-hoc analysis was
used to elicit pairwise difference between means
where significant differences were found. The
analysis of factors associated with coronary risk
factors was conducted with multivariable logistic
modeling. Age and body mass index were
considered as potential confounding factors.
Statistical significance was determined as a P value
of ≤ 0.05. All statistical analysis was performed
using SPSS for Windows (version 18; SPSS Inc.,
Chicago, IL, USA).
Results
The mean age of the whole sample was 49.25 ± 4.61
years. Among the 1538 women, 21.0% were taking
daily antihypertensive drugs, 10.9% were taking
daily diabetes mellitus medication, and 13.1% were
taking daily lipid-lowering drugs. Fifty women
(3.3%) were currently taking hormonal replacement
therapy. According to study classification, 931
women were allocated in the premenopausal group,
84 women in the perimenopausal groups, and 523
women in postmenopausal group. As presented in
table 1, except for the overall prevalence of current
smoking that was similar across the three
subgroups, other traditional cardiovascular risk
factors including family history of coronary diseases,
hypertension, hyperlipidemia, and diabetes mellitus
were more frequent in perimenopausal and
postmenopausal groups compared to others.
Systolic and diastolic blood pressures, FPG, TG,
total cholesterol, and LDL cholesterol were
associated with the menopausal status (Table 2).
The premenopausal status was accompanied with
lower levels of TG, total cholesterol, FPG, and
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333
Menopausal status on CAD risk factors
blood pressure compared with perimenopausal and
postmenopausal statuses (P < 0.001). Moreover,
women in the postmenopausal group had higher
levels of LDL cholesterol in comparison with
perimenopausal and premenopausal statuses
(P < 0.001). After adjusting for age variable, only total
cholesterol and LDL cholesterol were significantly
higher in postmenopausal women compared with the
other two groups. However, serum level of TG, FPG,
and systolic and diastolic blood pressures were not
statistically different in the different menopausal
statuses. In addition, serum total cholesterol and LDL
levels, and systolic blood pressure did not differ
according to menopausal status.
After further adjustment for age and body mass
index, postmenopausal women were importantly
characterized by higher total cholesterol (P < 0.001),
LDL cholesterol (P < 0.001), and systolic blood
pressure (P = 0.025) compared with others (Table 1).
Discussion
The incidence of cardiovascular diseases in
postmenopausal period has been estimated to be
higher than 50% in some observational studies.
Different physiological mechanisms are now
identified which are related to the increased risk of
cardiovascular disease in postmenopausal status.
The beneficial effects of hormone replacement
therapy on reducing risk of CAD emphasize the
role of the impairment of sex hormones in
triggering CAD and its-related risk factors. The
major part of these deleterious effects appears to be
due to an increase in total cholesterol level, LDL
cholesterol level, and reduction of HDL cholesterol.
Furthermore, deregulation of hormonal systems can
result in endothelial dysfunction predisposing to the
appearance and progression of CAD.12,13 Besides,
some other studies have shown mechanisms by
which estrogen might increase coagulation or
Table 1. Comparison of cardiovascular risk factors according to menopausal status
Premenopausal
Perimenopausal
Characteristics
(n = 931)
(n = 84)
*
Family history of CAD
212 (22.8)
20 (23.8)
Hypertension
89 (9.6)
15 (17.9)
Hyperlipidemia
69 (7.4)
17 (20.2)
Diabetes mellitus
14 (1.5)
3 (3.6)
Current smoking
80 (8.6)
9 (10.7)
Postmenopausal
(n = 523)
154 (29.4)
117 (22.4)
138 (26.4)
18 (3.4)
38 (7.3)
P
0.005
< 0.001
< 0.001
0.017
0.384
*N (%); Comparing was performed by the ANOVA test; CAD: Coronary artery disease
Table 2. Comparison of age-adjusted means of coronary heart diseases (CHD) risk factors according to menopausal status
Premenopausal Perimenopausal Postmenopausal Unadjusted Age-adjusted Age and BMI
adjusted
(n = 931)
(n = 84)
(n = 523)
P
P
P
*
BMI (kg/m2)
27.9 ± 4.7
27.8 ± 4.6
28.5 ± 5.0
0.077
0.458
0.444
Waist
85.0 ± 11.1
88.6 ± 11.0
89.2 ± 11.7
< 0.001a,c
0.578
0.014c
circumference
(cm)
Systolic blood
112.7 ± 17.3
126.0 ± 20.8
125.7 ± 20.5
< 0.001a,c
0.070
0.025c
pressure (mmHg)
Diastolic blood
75.8 ± 9.5
80.6 ± 10.7
80.9 ± 10.8
<0.001a,c
0.186
0.073
pressure (mmHg)
Fasting glycemia
100.4 ± 34.3
113.7 ± 51.6
117.8 ± 55.2
<0.001a,c
0.504
0.478
(g/dl)
Total cholesterol
197.2 ± 37.9
209.3 ± 43.6
219.3 ± 47.2
< 0.001a,c
< 0.001a
< 0.001a
(mg/dl)
LDL cholesterol
129.1 ± 31.7
133.7 ± 32.5
144.3 ± 39.4
< 0.001a,b
< 0.001a
< 0.001a
HDL cholesterol
39.9 ± 10.9
39.6 ± 10.6
40.4 ± 9.2
0.663
0.791
0.788
Triglycerides
143.7 ± 79.1
167.7 ± 79.9
170.5 ± 87.9
< 0.001a,c
0.166
0.110
* Mean ± SD, a: P < 0.05 for postmenopausal vs. premenopausal; b: P < 0.05 for postmenopausal vs. perimenopausal; c: P < 0.05 for
perimenopausal vs. premenopausal; Comparisons were performed by ANOVA test followed by Tukay’s post-hoc analysis; CHD:
Coronary heart diseases; BMI: Body Mass Index; LDL: Low density lipoprotein; HDL: High density lipoprotein
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Yousefzadeh, et al.
inflammation, which trigger coronary events in
advanced lesions.14 Animal studies have also
suggested that hormones might retard early
atherosclerosis, while both animal studies and
human angiographic trials are conclusive that
hormones do not retard progression of raised
lesions.15 It seems that these conflicting results can
be caused by the different changes in the situations
of CAD risk factors in postmenopausal period.
Although it has been found that after adjustment
for initial potential cofounders, the trend of these
changes is discrepant.
In the present study on the situations of CAD
risk factors in different menopausal-related periods,
most of the CAD risk factors were considerably
more prevalent in postmenopausal status than
premenopausal and perimenopausal periods, when
unadjusted for potential cofounders such as age and
body mass index. However, after adjustment for
these confounding indicators, the condition of some
risk profiles such as anthropometric parameters,
fasting blood sugar, and blood pressure changed
significantly. On the other hand, regardless of the
effects of age or body mass index, postmenopausal
status is associated with increased levels of total
serum and LDL cholesterol. Some previous studies
found similar findings. In the study by Agrinier et al.
after adjustment of LDL cholesterol level for age
and body mass index, these parameters were still
significantly higher in postmenopausal women than
in premenopausal women, indicating that other
factors, independent of age and BMI, strongly
influence LDL cholesterol levels in women.2 The
decrease in plasma estrogen levels after menopause
might play a significant role in the reduction of the
clearance of LDL particles and subsequent increase
in LDL cholesterol level in postmenopausal women.
In this regard, estrogen replacement treatment has
been shown to markedly decrease LDL cholesterol
level in dyslipidemic postmenopausal women. In
addition, studies in animal models have indicated
that estrogen treatment is followed by a marked
increase in the number of hepatic cell surface LDL
receptors and a faster clearance of LDL particles.16
Furthermore, treatment with estrogen has been
shown to increase cholesterol excretion in humans,
and to decrease the conversion of VLDL-apoB to
LDL-apoB in rabbits.17,18 Moreover, according to our
findings, postmenopausal and perimenopausal
women suffered from increased systolic blood
pressure compared with premenopausal women even
after adjustment for confounders. Some studies
showed that elevated systolic blood pressure is a
potent risk factor in premenopausal women.19 Recent
epidemiologic and experimental evidence indicate
that estrogen deficiency may cause increases in
systolic blood pressure through impacting endothelial
vascular function and/or systemic arterial
compliance.20-23 It can be certainly intensified in
postmenopausal period because of its related
hormonal disturbances. However, these hypotheses
should be further investigated in future studies.
Conclusion
In summary, the increased risk of cardiovascular
disease in postmenopausal period can be explained
by elevated levels of lipid profile and increased
systolic blood pressure regardless of the effects of
advanced age or anthropometric parameters.
Acknowledgements
The authors would like to thank all participants who
took part in the KERCARDS. The research was a
Resident’s thesis of the second author (FMJ) and
was financially supported by the Kerman University
of Medical Sciences.
Conflict of Interests
Authors have no conflict of interests.
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How to cite this article: Yousefzadeh Gh,
Mahdavi-Jafari F, Shokoohi M, Najafipour H,
Haghdoost AA, Modares-Nejad V. Modulation of
coronary artery disease risk factors by
menopausal status: A population based study
among Iranian women (KERCADRStudy). ARYA
Atheroscler 2013; 9(6): 332-6.
ARYA Atheroscler 2013; Volume 9, Issue 6
www.mui.ac.ir
15 Nov
Hamid Najafipour