© 1995 American Heart Association, Inc.
Articles |
Association of Hormone Replacement Therapy With Hemostatic and Other Cardiovascular Risk Factors
The FINRISK Hemostasis Study
From the Department of Epidemiology and Health Promotion (V.S., E. Vartianen, J.T.) and the Department of Biochemistry (M.J., C.E.), National Public Health Institute, and the Department of Hemostasis, Finnish Red Cross Blood Transfusion Service (V.R., E. Vahtera, G.M.), Helsinki, and the Department of Environmental Epidemiology, National Public Health Institute (J.P.), Kuopio, Finland.
Correspondence to Dr V. Salomaa, National Public Health Institute, Department of Epidemiology and Health Promotion, Mannerheimintie 166, FIN-00300 Helsinki, Finland. E-mail veikko.salomaa@ktl.fi.
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Abstract |
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Abstract The risk of cardiovascular diseases in women is small until menopause but increases considerably afterwards. When all age groups are considered, cardiovascular diseases are responsible for approximately half of the total mortality in women. It has been suggested that hormone replacement therapy (HRT) in perimenopausal and postmenopausal women could be useful in the prevention of cardiovascular diseases, but its effects are insufficiently known. We performed a cross-sectional study on the associations of menopause and HRT with cardiovascular risk factors, in particular with hemostatic factors, on female participants of the FINRISK Hemostasis Study. The participants, aged 45 to 64 years, were recruited from the Finnish population register by random sampling from three geographically defined areas. The participation rate of women was 83.2%. Of the 1202 women included in the study, 29.2% were current users of HRT. Differences in cardiovascular risk factors by menopausal status and by HRT use were examined after adjustment for age, study area, current smoking, body mass index, self-reported diabetes, and years of education. Postmenopausal women not using exogenous sex hormones had on average a total cholesterol level 0.5 mmol/L (8.9%) higher and an LDL cholesterol level 0.4 mmol/L (11.4%) higher than premenopausal women. Women reporting irregular menstruation (presumably due to perimenopause) had higher adjusted plasma fibrinogen, factor VII coagulant activity, and factor VII antigen than women with regular menstruation or no menstrual periods. HRT users had an adjusted total cholesterol level 0.28 mmol/L (5%) lower (P<.0001) and an adjusted LDL cholesterol level 0.3 mmol/L (7%) (P<.0001) lower than nonusers. The data also suggested that HRT attenuated the age-dependent difference in total and LDL cholesterol (P=.01 for age by HRT interaction). HRT users had lower adjusted insulin and glucose values than nonusers. When the hemostatic factors were studied, the users were seen to have lower adjusted fibrinogen (P<.0001) but higher factor VII antigen (P=.007) and plasminogen levels (P<.0001) than nonusers. No difference was found in factor VII coagulant activity or in Lp(a). In conclusion, HRT users have clearly more favorable lipid profiles as well as insulin and glucose values compared with nonusers. Accordingly, HRT can be a potentially useful adjunct to the prevention of cardiovascular disease. Its effects on hemostatic factors are, however, mixed and of unclear clinical significance at the moment. More prospective studies on the effects of HRT on hemostasis are therefore needed before it can be recommended for the prevention of cardiovascular diseases.
Key Words: hormone replacement therapy • estrogen • hemostatic factors
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Introduction |
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CHD is relatively uncommon among women before menopause but becomes more frequent afterwards. As a whole, cardiovascular diseases, CHD and cerebrovascular diseases in particular, are important causes of mortality and morbidity among women. In 1992, cardiovascular diseases were responsible for 51% of the total mortality of women in Finland.1 Furthermore, the proportion of elderly women is rapidly increasing in the Finnish population, as in most other Western populations, and hospitalizations of women due to CHD almost doubled during the 1980s.2 Accordingly, the reduction of cardiovascular disease risk among postmenopausal women would be of considerable public health significance.
Recent literature suggests that HRT could reduce the CHD risk in postmenopausal women almost by half3 4 and increase life expectancy, particularly for women who already have CHD.5 The mechanisms are, however, insufficiently understood. HRT is commonly considered to have a favorable effect on the serum lipid profile, but its effects on blood coagulation have been more controversial. In the Coronary Drug Project, estrogen treatment was given to men to prevent CHD, but it resulted in a clearly increased risk of cardiovascular complications.6 There are also several reports showing activated coagulation with estrogen-containing oral contraceptives.7 8 The doses and types of estrogens and progestins used for HRT are, however, different and more physiological than those used in oral contraceptives. It is therefore plausible that the effects on cardiovascular risk factors may also differ.
We have carried out a cross-sectional population-based study among a large number of women aged between 45 and 64 years to (1) examine the association of menopause with cardiovascular risk factors among women not using exogenous sex hormones and (2) compare cardiovascular risk factor levels in users and nonusers of HRT. In both cases the main emphasis was on hemostatic factors.
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Methods |
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Participants and methods of the FINRISK Hemostasis Study have been recently described.9 10 The sample consisted of 3000 individuals, aged between 45 and 64 years, randomly drawn from the Finnish population register for three geographically defined areas (North Karelia in eastern Finland, the capital [Helsinki] area in the southern part of the country, and the Turku/Loimaa area in southwest Finland). The sample was stratified so that the cell size was 250 for each sex, area, and 10-year age group. The participation rate of women was 83.2%.
The fieldwork was carried out in February and March of 1992. The participants were examined according to a standardized protocol between 11:00 AM and 06:00 PM. They were instructed to avoid fatty meals earlier during the day and to fast totally for 4 hours before the examination and blood sampling. The length of fast and type of previous meal were recorded. These data indicated good compliance with the instructions and were not correlated with the concentrations of hemostatic factors. Weight and height were measured while each subject was wearing light clothing and no shoes. Blood pressure was measured on the right arm, with each participant in a seated position, after a 5-minute rest by use of a standard mercury sphygmomanometer. The measurement was repeated and the mean of two measurements was used in the analyses. A self-administered questionnaire was used to record smoking habits, alcohol consumption, years of education, menopausal status, and the use of HRT. Menopausal status was determined with the question "Do you still have menstrual periods?" The answer alternatives were (1) Yes, regularly; (2) Yes, irregularly; and (3) No. The use of HRT was determined with the question "Have you used hormone replacement therapy (estrogen) during the past month because of menopause?" The possible answers were (1) Yes and (2) No. Alcohol consumption was assessed by a series of 10 questions. The average consumption per week was used in the analyses. Smoking was dichotomized (current smokers versus current nonsmokers). The questionnaire was checked by a nurse together with the patient and completed if necessary.
The blood samples were drawn from the antecubital vein of each seated participant with minimum stasis by use of a 20-gauge needle. The two citrate vacuum tubes (Vacutainer, Becton-Dickinson) used to determine levels of fibrinogen, factor VII:C, factor VII:Ag, and plasminogen were taken as the second and third tubes of the blood sampling. The blood was carefully mixed with anticoagulant. The tubes were centrifuged at room temperature at 1400g for 30 minutes. Plasma was then collected with a plastic pipette and divided into 0.5-mL aliquots for freezing and storage. The plasma samples were snap-frozen within 2 hours after the venipuncture in a mixture of dry ice and alcohol. They were stored at -70°C until being analyzed within 8 months after sampling.
The participants were also asked to attend the local health center on a convenient morning after a fast of 12 hours for a 2-hour glucose tolerance test. The test was carried out according to the recommendations of the World Health Organization.11 Persons with previously known diabetes were not invited to participate in the test. Fasting samples for glucose and insulin determinations were obtained from 80.8% of the female participants of the main survey, and 2-hour samples were obtained from 77.8%.
Laboratory Methods
Determination of hemostatic factors was carried out in the
Department of Hemostasis of the Finnish Red Cross Blood Transfusion
Service, Helsinki. Fibrinogen was measured with an ACL 300 R
coagulometer (Instrumentation Laboratory) from the light scattered by
the clot during the prothrombin time assay (PT-Fibrinogen,
Instrumentation Laboratory).12 The intra-assay CV in
our laboratory was 3.6% and the interassay CV was 2.3%. The samples
were measured in duplicate and had to be within 10% of their mean or
the analysis was repeated with a split sample. Two percent of
the samples were rejected because of persistently unacceptable
differences between the duplicates or because the sample was otherwise
deemed unacceptable for analysis.
FVII:C was measured by use of the one-stage method13 with rabbit brain thromboplastin (Thromboplastin IS, Baxter Dade) and human immunodepleted factor VII–deficient plasma (Behring). This assay was also carried out with an ACL 300 R coagulometer. A lyophilized plasma pool was used as a standard. It was calibrated with a frozen plasma pool from 44 normal donors and taken as 100%. The interassay CV in our laboratory was 2.4% and the intra-assay CV was 3.9%. Some samples (1.5%) were rejected either because the sample was unacceptable or because the participant was receiving ongoing oral anticoagulant therapy. FVII:Ag was measured by use of an ELISA technique with an Asserachrom FVII:Ag kit (Diagnostica Stago) according to the manufacturer's instructions. A frozen plasma pool (as for FVII:C) was used as a standard and taken as 100%. The intra-assay CV was 5.0% and the interassay CV was 10.9%. The samples were tested in duplicate, and the measurements had to be within 16% of their mean or the analysis was repeated with a split sample. A small fraction (1.5%) of the samples were rejected because of an unacceptable sample or test result or because the participant was receiving oral anticoagulant therapy.
Plasminogen was measured with a Coamate Plasminogen kit (Chromogenix AB) according to the manufacturer's instructions. This method was found to be independent of the fibrinogen concentration of the sample at the usual fibrinogen levels. The intra-assay CV in our laboratory was 3.2% and the interassay CV was 2.9%. Some of the samples (1.8%) were rejected as being unacceptable for the analysis.
Serum lipids, Lp(a), and plasma insulin and glucose were determined in the Department of Biochemistry, National Public Health Institute, Helsinki. Lp(a) was determined by use of an immunoradiometric assay (IRMA, Pharmacia Diagnostics) as described.14 Total cholesterol and triglycerides were determined with enzymatic assays (Boehringer Mannheim, GmbH Diagnostics). HDL cholesterol was determined after precipitation of apoB-containing lipoproteins with dextran sulfate and MgCl2. LDL cholesterol was calculated as described by Friedewald et al.14 Participants with triglyceride levels greater than 4 mmol/L (n=25) were excluded from the calculation of LDL cholesterol.
Plasma glucose was determined enzymatically by use of the glucose dehydrogenase method (Roche). The assay was carried out with a Cobas Mira Plus analyzer. The interassay CV was 1.9% at the level of 5.1 mmol/L of glucose. The method was also validated by the laboratory's participation in the LABQUALITY External Quality Control program 12 times a year. Plasma insulin was measured with a Phadeseph Insulin RIA kit (Pharmacia) according to the manufacturer's instructions. This method is based on the double-antibody solid-phase technique. Effective measuring range was 3 to 240 mU/L. Samples having values higher than 240 mU/L were diluted with 0.9% NaCl. The radioactivity was measured with a Wizard gamma counter (Wallac). The intra-assay CV was 5.3% at the level of 20.1 mU/L, 9.4% at the level of 42.6 mU/L, and 4.6% at the level of 78.7 mU/L. Interassay CVs for the samples with the same levels of insulin (20.1, 42.6, and 78.7 mU/L) were 7.6%, 9.8%, and 5.8%, respectively.
Statistical Methods
Women for whom information on menstrual status or HRT use was
missing (n=4) were excluded from the analyses. Also excluded
were women using hormonal contraception (n=15) or lipid-lowering
medication (n=22). Fibrinogen, FVII:C, FVII:Ag, and
plasminogen were approximately normally distributed.
Triglycerides, glucose, insulin, and Lp(a) were skewed and
were therefore log transformed for the analyses. In the tables,
however, they are presented as back transformed to the
geometric means. ANOVA was used to compare the means of hemostatic and
other cardiovascular risk factors between women with
regular, irregular, or no menstruation as well as between users and
nonusers of HRT. The main models included age, study area,
current smoking, BMI, self-reported diabetes, and years of
education as covariates. The covariates were also compared between
users and nonusers of HRT as well as between women with
regular, irregular, or no menstruation using ANOVA or
2 tests. The interactions of HRT with relevant
factors such as age, smoking, BMI, and alcohol consumption were also
tested. The analyses were carried out with the Statistical
Analysis System (SAS).16
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Results |
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In all, 1202 women were included in the study. Of these, 351 (29.2%) reported current use of HRT, and 353 (29.4%) reported having regular menstrual periods, 110 (9.2%) reported irregular periods, and 739 (61.5%) had no menstruation. The main covariates by use of HRT are presented in Table 1
. The users were slightly
older, somewhat leaner, and more educated than nonusers. No
difference was observed in alcohol consumption or in the prevalence of
smoking. The same variables among nonusers of HRT are given
by menstrual status in Table 2. As expected, women with
no menstruation were older than those with regular or irregular
menstrual periods. BMI differed similarly with age. Younger women with
regular or irregular menses were more educated than the older women
with no menses. They also consumed more alcohol, and a greater
proportion of them were current smokers.
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Data for serum lipids and blood pressure, as well as those for plasma
insulin, glucose, and hemostatic factors in women not using HRT or
other exogenous sex hormones, are presented by menstrual status
in Table 3. After adjustment for age, study area,
current smoking, BMI, self-reported diabetes, and years of
education, women with no menstruation had total cholesterol
levels 0.5 mmol/L (8.9%) higher and LDL cholesterol levels
0.4 mmol/L (11.4%) higher than women with regular menstruation. No
significant differences were observed in HDL cholesterol,
triglycerides, systolic or diastolic blood
pressure, or fasting or 2-hour insulin or glucose. Women with irregular
menstruation (presumably perimenopausal in this age range) had higher
adjusted plasma fibrinogen levels and FVII:C, and also tended to have
higher FVII:Ag than the other women. No difference was observed in
plasminogen or Lp(a).
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Women using HRT had, on average, adjusted total cholesterol
levels 0.3 mmol/L (5%) lower (P<.0001) and adjusted LDL
cholesterol levels 0.3 mmol/L (7%) lower
(P<.0001) than women not using HRT (Table 4). They also had slightly higher adjusted HDL
cholesterol levels (a difference of 0.04 mmol/L [3%];
P=.03), but triglyceride concentrations were not
significantly different. However, because triglycerides are
strongly correlated with BMI, the analysis was repeated after
BMI was removed from the covariates. In this analysis, HRT
users had significantly lower triglyceride concentrations
compared with nonusers (1.37 versus 1.48 mmol/L,
P=.006). HRT users also had significantly lower adjusted
fasting and 2-hour insulin and fasting blood glucose levels compared
with nonusers. No difference was observed in systolic or
diastolic blood pressure or in 2-hour blood glucose
level.
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Adjusted plasma fibrinogen was on average 0.21 g/L lower
(P<.0001) in HRT users than in nonusers (Table 4
).
Adjusted FVII:Ag was significantly higher (P=.007) in HRT
users than in nonusers. However, there was no difference in
adjusted FVII:C. Adjusted plasminogen was higher
(P<.0001) in users compared with nonusers, but no
difference was observed in Lp(a). The proportion of women with high
Lp(a) (>250 mg/L) was also examined, but still no difference was
observed.
In this cross-sectional analysis, the difference in
adjusted LDL cholesterol by age was significantly greater
among nonusers of HRT than among users (P=.01 for
age by HRT interaction; Fig 1). In contrast, fibrinogen
was consistently lower in all age groups among users of HRT
than among nonusers (Fig 2). HRT showed no
interactions with smoking, BMI, or alcohol intake regarding any of the
cardiovascular risk factors measured.
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Discussion |
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The first aim of our study was to examine the association of menopause with a large set of cardiovascular risk factors among women not using exogenous sex hormones. The results demonstrate a significant difference in total and LDL cholesterol with cessation of menstruation, which is in agreement with previous studies.17 18 This may for the most part explain the increase in cardiovascular disease risk seen in women after menopause. Very little data exist on glucose and insulin, but our findings suggest that there are no changes. Our data do not reveal any effect of menopause on Lp(a) in women not using exogenous sex hormones. This was contradictory to the findings in some studies, but it is in line with a recent report from the Framingham Offspring Study.19
Previous literature has shown that postmenopausal women have higher plasma levels of fibrinogen, FVII:C, and plasminogen than premenopausal women.20 21 22 23 24 We found the highest values for fibrinogen, FVII:C, and FVII:Ag in women with irregular menstruation, whereas the values in women with no menstruation were quite close to those seen in women with regular menstrual periods. This suggests that these hemostatic factors increase during perimenopause and may return to close to the original levels later on. It should be noted that most of the reports mentioned above have examined a more narrow age range (usually between 45 and 54 years) than we did and therefore may have actually examined perimenopausal women. There may of course be other possible explanations. Women with the steepest decreases of estrogen may have experienced more symptoms due to menopause and therefore started to use HRT, which may have biased the results of non-HRT users towards smaller changes. Kuller et al25 have shown that women with steep declines of estrogen levels during the menopause have more adverse changes in the lipid profile than those with more gradual declines.
An important limitation related to the first aim of the present study was that our questions about menstruation are only surrogate markers of menopause. For example, we do not know how many of our participants had undergone hysterectomy and how many had had their ovaries removed. From the literature, however, we know that among Finnish women aged between 45 and 64 years the prevalence of hysterectomy is 19% and the prevalence of bilateral oophorectomy is 5%.26 Therefore, there may be some women among our study participants who do not menstruate because they have been hysterectomized but who are still premenopausal in terms of hormonal function. The effect of this misclassification, if any, would be to reduce the differences between women with no menstruation and those with regular or irregular menstruation, thus making our results conservative.
The second aim of our study was to compare the levels of cardiovascular risk factors present in users and nonusers of HRT. We found significantly lower total and LDL cholesterol in HRT users than in nonusers. Several other cross-sectional studies have reported similar results,4 27 28 which have been confirmed in placebo-controlled clinical trials.29 30 It seems therefore likely that this is a real effect of HRT and not merely an association in a cross-sectional analysis. The suggested biological mechanism is that the estrogens increase the number of hepatic LDL receptors and thereby the clearance and catabolism of LDL particles.29 31 32 Our results further suggest that HRT attenuates the increase in total and LDL cholesterol during menopause.
Higher HDL cholesterol in HRT users compared with nonusers has been described,4 30 32 and the results of our study are in agreement with these findings. The situation with triglycerides is, however, more controversial. Estrogens are known to increase the synthesis of triglycerides and apoB,29 31 32 and accordingly higher triglyceride levels have been described in HRT users than in nonusers.4 31 In the PEPI Trial, all active treatments increased the mean triglyceride level by 0.13 to 0.15 mmol/L compared with placebo.30 The increase in triglyceride synthesis is, however, dependent on the dose of estrogen and on the possible inclusion of progestin. This may explain why we found no difference in triglyceride levels in HRT users compared with nonusers (and even lower triglyceride levels in HRT users than in nonusers if the values were not adjusted for BMI).
Three recent studies have found lower fasting glucose and insulin levels in HRT users than in nonusers.4 28 33 Our study confirms these findings and also indicates that 2-hour insulin is lower among HRT users. The findings of the PEPI Trial are, however, conflicting: Fasting glucose levels decreased significantly in all active treatment areas compared with placebo, whereas 2-hour glucose levels increased significantly. Fasting insulin also tended to decrease, whereas 2-hour insulin showed a nonsignificant increase.30 The biological mechanisms for the effects of HRT on insulin and glucose are poorly known, but altered body composition and ß-cell function have been suggested.33
The finding of lower fibrinogen in HRT users than in nonusers is potentially important, because there is prospective evidence showing that fibrinogen is as strong a risk factor for CHD in women as it is in men.34 Our finding is consistent with reports from other cross-sectional studies,4 22 28 and the difference in fibrinogen remained significant after adjustment for multiple potential confounding factors such as smoking, BMI, and years of education (as a surrogate for socioeconomic status). Recently these cross-sectional findings were confirmed by the placebo-controlled PEPI Trial, in which fibrinogen increased in the placebo group during the follow-up time of 3 years but remained nearly unchanged in the active treatment groups.30 The difference in fibrinogen between users and nonusers of HRT observed in our study (0.21 g/L) is even larger than that seen in the PEPI Trial and may be associated with a clinically significant difference in CHD risk. It should be noted, however, that the biological mechanism for the fibrinogen-lowering effect of HRT is poorly known at the moment, and some smaller trials have not observed a significant fibrinogen-lowering effect of HRT.35 36 37
Several, but not all, studies have found a higher level of FVII:C in HRT users compared with nonusers.20 28 37 In the Atherosclerosis Risk in Communities study, FVII:C was higher in women using estrogen alone but not in women using estrogen combined with progestin.4 This may explain why we found higher FVII:Ag but not higher FVII:C in HRT users compared with nonusers. Another explanation may be that the triglyceride level, which is an important determinant of FVII:C,38 39 40 did not differ between users and nonusers in our study.
In accordance with the results of the Healthy Women Study20 and other studies,41 we found higher plasminogen in HRT users than in nonusers. Interestingly, a recent study from Germany found a positive association between plasminogen and the extent of coronary atherosclerosis in angiography.42 Other reports have documented lower tissue plasminogen activator and plasminogen activator inhibitor 1 antigen concentrations in HRT users compared with nonusers, suggesting enhanced fibrinolytic potential (Dr E. Shahar, et al, unpublished data, 1995). The clinical significance of these findings is, however, unclear at the moment. It should also be noted that some recent reports suggest increased thrombin generation and thrombin activity after estrogen admistration to postmenopausal women.37 43 Therefore, prospective studies are needed before the net effect of HRT on coagulation is known.
According to the literature, the plasma level of Lp(a) is influenced by several hormonal factors. It is lowered by an anabolic steroid, stanozolol,44 and by estrogens45 46 and progestins.47 Therefore, it was surprising that as with the menopause, we were unable to show any effect of HRT on Lp(a). We also examined the proportions of women with high Lp(a)(>250 mg/L), as has been suggested by Kostner et al,48 but that analysis also showed no differences. Our results are, however, similar to those of the Framingham Offspring Study, which was also unable to show a significant difference in Lp(a) due to HRT.19 Given the large sample sizes of our study and the Framingham Offspring Study, the negative finding cannot be due to inadequate statistical power. One explanation may be the cross-sectional nature of our study and other limitations explained above. Alternatively, different populations may respond differently to HRT for genetic reasons, but only positive findings tend to be published.
Two important limitations related to the second aim of the present study should be mentioned. First is the cross-sectional and observational nature of our study. We cannot exclude the possibility that the HRT users are a self-selected group of health-conscious women who have low risk factor levels because of their healthy lifestyles. Our findings were, however, independent of several potential confounding factors such as age, BMI, years of education, and smoking, which speaks against this explanation. The second limitation is due to our questionnaire. We asked only whether a woman had used HRT during the past month or not. We do not know for how long she had been using it or whether she was using estrogen alone or estrogen combined with progestin. The recommended treatment in Finland is combination therapy in women who have not had a hysterectomy. In 1989, the sales figures of fixed estrogen-progestin combinations had surpassed the sales figures of preparations containing estrogen alone.49 Since then, however, estrogen patches and other new methods of HRT administration have made the situation more complex, and we cannot estimate reliably what proportion of HRT users in our study population were receiving estrogen alone and what proportion were receiving combination therapy.
In summary, the changing age structure of Western populations emphasizes the need to prevent cardiovascular disease in postmenopausal women. HRT is a potentially important adjunct in the arsenal of preventive measures. The favorable changes in serum lipid profile associated with HRT use seem to be real biological effects and are large enough to be of considerable public health significance. However, more prospective studies are needed, especially on the effects of HRT on hemostatic factors, before HRT can be widely recommended for the prevention of cardiovascular disease.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The FINRISK Haemostasis study was financially supported by a grant from the Finnish Heart Association (The Fund of February 19th).
Received May 1, 1995; accepted July 19, 1995.
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References |
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