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(Circulation. 2000;101:2572.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Hormone Replacement Therapy and Incidence of Acute Myocardial Infarction
A Population-Based Nested Case-Control Study
From Global Epidemiology, Development, Novartis Farmacéutica, S.A. Barcelona, Spain (C.V.-L., S.P.-G., A.D.-O.); and Centro Español de Investigación Farmacoepidemiológica (CEIFE), Madrid, Spain (L.A.G.-R.).
Correspondence to Dr Cristina Varas-Lorenzo, Novartis Farmacéutica, S.A., Development, Global Epidemiology, Gran Via de les Corts Catalanes, 764, 08013 Barcelona, Spain. E-mail cristina.varas{at}pharma.novartis.com
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Abstract |
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Background—Epidemiological studies suggest a decreased risk of coronary heart disease (CHD) in healthy women taking hormonal replacement therapy (HRT). Whether this effect is shared by oral and transdermal preparations is unknown.
Methods and Results—We conducted a population-based case-control study nested in a cohort of women 50 to 74 years of age without cardiovascular disease history in the United Kingdom. Among 164 769 women from the General Practice Research Database (January 1, 1991, to December 31, 1995), we identified 1242 first acute myocardial infarctions (AMI) and confirmed 1013 after medical record review. We randomly selected 5000 age-frequency–matched control subjects. AMI incidence was 1.6 per 1000 person-years; 13% and 17% of cases and control subjects used HRT within 6 months before the index date. Risk factor and comorbidity–adjusted OR of AMI for current-recent HRT users compared with nonusers was 0.72 (95% CI 0.59 to 0.89). The OR was similar within 30 days before the index date. The beneficial effect was present after 1 year of use (OR 0. 68; 95% CI 0.53 to 0.86), with no increase in risk within the first year. ORs for unopposed and opposed therapy were 0.52 (95% CI 0.35 to 0.78) and 0.79 (95% CI 0.59 to 1.08); 79% and 21% used oral and transdermal therapy. The protective effect was present at medium-high doses of estrogens with ORs for oral and transdermal therapy of 0.63 (95% CI 0.46 to 0.86) and 0.62 (95% CI 0.37 to 1.06) and ceased after 2 to 3 years since stopping HRT.
Conclusions—Results are consistent with those previously reported in women without CHD who were taking oral HRT and, although based on few users, suggest that transdermal therapy might have similar cardioprotective effects.
Key Words: hormones • myocardial infarction • epidemiology • prevention • women
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Introduction |
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Aconsistent male-to-female ratio for coronary heart disease (CHD) death rates ranging from 2 to 5 in populations with very different heart disease rates and lifestyles has suggested that either sex or endogenous hormones have a significant influence on the vasculature.1 2 The apparent loss of this female advantage on CHD risk in women who had a premature menopause led early on to the hypothesis that endogenous estrogens are cardioprotective. There is now considerable evidence that estrogens exert indirect and direct antiatherogenic effects.3
Evidence from multiple observational studies suggested a marked reduction in the risk of CHD associated with postmenopausal estrogen use in primary prevention. A similar effect was observed when estrogens were opposed with progestins. Although several potential sources of bias might account for part of this beneficial effect, the latest meta-analysis of published studies suggested 30% and 34% reduction in the risk among ever-users of unopposed and opposed therapy, respectively, compared with never-users.4 However, all these studies were conducted in populations taking oral preparations, many of them from the US population. No studies have provided data on the effects of the transdermal route on the risk of CHD.
As part of a study on the effects of hormone replacement therapy (HRT) in postmenopausal women, we conducted a population-based cohort study with a nested case-control analysis to evaluate the association between HRT use and the incidence of first myocardial infarction in a European population taking oral and transdermal estrogens.5 Estimates of this association by duration, dose, regimen, and route were also calculated.
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Methods |
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Study Population
A cohort of women, 50 to 74 years of age, from the general population in the United Kingdom, was identified through registration status in the General Practice Research Database between January 1, 1991, and December 31, 1995. Women with a history of cardiovascular and cerebrovascular diseases, neoplasms, coagulopathies, vasculitis, and alcohol-related diseases were excluded. The resulting study cohort consisted of 164 769 women who were followed until the occurrence of the first recorded code of myocardial infarction, any of the exclusion criteria as listed above, reaching 75 years of age, death, or to December 31, 1995, whichever occurred first.
Data Source
More than 2000 general practitioners (GPs) use the
General Practice Research Database to register healthcare and medical
information about their patients in a standardized
manner.6 This research-oriented database covers a general
population exceeding 3 million residents in England and Wales. The UK
National Health System provides universal coverage, and no segment of
the population is excluded from the database. The registered
information includes demographic data, all medical diagnoses,
consultant and hospital referrals, and a record of all
prescriptions issued. Practitioners generate prescriptions
directly from the computer, ensuring its automatic recording.
Medication codes are based on the Prescription Pricing Authority. A
modification of the OXMIS code is used to record
diagnoses.7 Several validation studies have shown that
>90% of information present in the manual medical records of
the GPs, and >95% of newly prescribed drugs are recorded in the
database.8 9 The GP may also record laboratory results
and other medical data in a free text comment field.
Definition and Ascertainment of Cases
Potential cases were identified by an automated computer search
with the use of specific and nonspecific OXMIS codes for myocardial
infarction. We identified 1242 potential cases of first myocardial
infarction. For each of them, a questionnaire was sent to their
corresponding GPs requesting all available medical information related
to the acute episode, including hospital discharge letters, ECGs,
myocardial serum enzyme levels (CPKs), autopsy reports, and death
certificates.
To validate cases, we adapted the international standardized
diagnostic criteria for acute myocardial
infarction.10 11 A woman was classified as a definite case
of nonfatal acute myocardial infarction if she had 
2 of the following
criteria: characteristic chest pain, raised levels of CPKs, an ECG
consistent with the diagnosis of myocardial infarction, an
arteriogram documenting a recent coronary occlusion, or
treatment with fibrinolytic therapy. A woman was classified as possible
case of nonfatal acute myocardial infarction when this information was
not available but a consultant cardiologist confirmed the
diagnosis. The same criteria were applied to define fatal cases of
myocardial infarction. For patients who died before reaching the
hospital or for whom hospital records were not available, we used
the diagnosis recorded on autopsy reports and death certificates,
as available, to determine the cause of death. Fatal cases, whether
sudden or not, were classified as (a) definite fatal myocardial
infarction in which there was a definite myocardial infarction within
30 days of death or/and a fresh myocardial infarction and/or recent
coronary occlusion described at necropsy report or (b) possible
acute CHD death without a preceding nonfatal coronary event in
which there was no good evidence for another cause of death clinically
or at necropsy and a death certificate with acute CHD as primary code
of death cause.
After the review of all available information by 2 of the investigators independently and blinded to therapy, a total of 1013 women were confirmed with a first myocardial infarction. Overall, 229 cases were excluded because the diagnosis of myocardial infarction was not established or an exclusion criterion was identified. For each event, the index date was defined as the earliest of the date of symptoms onset, when available, the date of hospital admission or the date of death.
Selection of Control Subjects
We used a time-incidence sampling method to select control
subjects.12 A random date within the study period was
generated for each of the women of the cohort. All women with a random
date included in their person-time period of observation (from study
entry to end of follow-up) were eligible as control subjects. This
procedure takes into account the amount of person-time contributed by
each woman. Thus, we ensure that our control selection will yield a
comparison group whose relevant exposure characteristics accurately
reflect those of the source population for cases. In addition, we
introduced calendar time in the analysis to control for secular
changes in both the incidence of cases and the prevalence of exposure.
The same computer-based exclusion criteria as those for the cases were
applied to all eligible control subjects, with each woman’s random
date used as her index date. Finally, 5000 control subjects were
randomly sampled and matched by the age-frequency of cases.
Exposure and Other Risk Factor Assessment
A list of all medications containing estrogens and/or
progestogens recommended for HRT and available in the United Kingdom
during the study period was extracted from the British National
Formulary. These drugs were grouped in the following regimens: (a) oral
estrogens (76% were conjugated equine estrogens; (b) transdermal
estradiol; (c) estradiol implant; and (d) tibolone. In addition, oral
estrogens and transdermal estradiol were classified as opposed or
unopposed, depending on whether a progestogen was supplied along with
estrogens. For each woman, the date of the last issued prescription for
each of the regimens before the index date was identified. We defined a
nonuser as a woman who never had a prescription for HRT
recorded in the database, a current-recent user as a woman who used
HRT at any time in the 6-month period before the index date, and a past
user as a woman who stopped therapy >6 months before the index date.
The time period corresponding to consecutive prescriptions was used to
define duration of HRT use. The daily dose of estrogens, type of
regimen, and route of administration was obtained from the last
prescription. Duration was categorized as (a) 
1 year of use; (b)
between 1 year and 3 years; and (c) >3 years. Estrogen prescribed dose
was categorized as (a) low dose: <0.625 mg of oral estrogens or 25
µg of transdermal estradiol; (b) medium dose: 0.625 mg of oral
estrogens or 50 µg of transdermal estradiol; and (c) high dose:
1.25 mg of oral estrogens or 100 µg of transdermal estradiol.
Information on coronary risk factors and drug utilization was
obtained from the database. History of hypertension, diabetes,
hypercholesterolemia, smoking, and family
history of CHD were considered present when this information was
registered in the database. Overweight was defined as recorded
history of obesity and/or individual body mass index (calculated from
recorded height and weight) over 27 kg/cm2.
Menopause was considered surgical when a bilateral oophorectomy was
recorded with or without hysterectomy. Comorbidity was assessed for
all cohort members and was present if there was 1 recorded
code at any time before the index data of a disease in the following
systems: nervous, cardiovascular, respiratory, renal,
or osteoarticular or diabetes.
Statistical Analysis
The distribution of risk factors according to HRT use was
directly standardized by age with the use of the overall age
distribution of control subjects. Person-time of follow-up was
calculated for all cohort members by age and exposure categories and
was used as the denominator to obtain incidence rates of myocardial
infarction. Age-adjusted incidence rates were obtained by the direct
method, with the overall age distribution of the cohort used as
standard.13 To evaluate the potential clinical impact of
using HRT, we calculated rate differences (the excess number of cases
on average attributable to the nonuse of hormones per 1000
person-years).14
ORs were used as the measure of association. Adjusted ORs and 95% CIs were estimated with the use of unconditional multiple logistic regression by the LOGISTIC procedure of SAS release 6.08.15 Adjusted ORs were obtained by recent HRT use compared with nonuse. The effect of duration was assessed among current-recent users. The effect of oral and transdermal therapy and unopposed and opposed therapy was assessed in current-recent users with duration >1 year compared with nonusers. The effect of estrogen dose was also assessed in long-term users of oral estrogens and transdermal estradiol, unopposed or opposed, aggregated in a single group of users.
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Results |
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Overall prevalence of HRT was 22%. Use during the last 6 months was found in 133 (13%) cases and 855 (17%) control subjects .Women who had ever used HRT tended to be younger and have a better risk profile than those women who never used the therapy, except for smoking history (Table 1
). Use of HRT was
inversely related to age. In the age group 50 to 59 years, 38% of
control subjects used the therapy in the last 6 months. Among women
60 years of age, this pattern of use was found in 15% of control
subjects.
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Among cases, 791 were nonfatal myocardial cases (525 were definite and 266 possible) and 222 were fatal cases (103 were definite fatal myocardial infarctions and 119 possible acute CHD deaths). In our cohort, the absolute risk of all these events per 1000 person-years of follow-up was 1.6. The age-adjusted incidence rates per 1000 person-years were 1.8 in women who never used hormones and 1.2 in those who used hormones in the last 6 months, resulting in an absolute risk difference of 0.6 per 1000 person-years.
Overall incidence of fatal and nonfatal myocardial infarction and acute
CHD deaths was positively associated with history of smoking, diabetes,
hypertension, hypercholesterolemia, and family
history of CHD (Table 2). The
age-adjusted OR and 95% CIs for myocardial infarction in women who
used HRT during the last 6 months, as compared with nonusers,
was 0.72 (95% CI 0.59 to 0.88) (Table 2). After adjusting for
potential confounding factors, that is, those mentioned above plus
obesity, comorbidity, prophylactic use of aspirin (defined
as current use of aspirin with duration >30 days), and surgical
menopause, the OR remained unchanged. We performed a sensitivity
analysis and estimated the OR by using different time-window
definitions within the last 6 months before the index date. Narrowing
this time period of use to 30 days before the index date yielded an OR
of 0.73 (95% CI 0.59 to 0.91).
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The protective effect was observed in users of >1 year of therapy
(long-term users) with an adjusted OR of 0.68 (95% CI 0.53 to 0.86)
(data not shown). The adjusted OR for >3 years of treatment duration
was 0.59 (95% CI 0.42 to 0.85) (Table 3). In addition, we subdivided the first
year into shorter periods of time. During the first 4 months, the OR
was 0.90 (95% CI 0.54 to 1.50) and thereafter was 0.72 (95% CI 0.46
to 1.15).
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The protective effect observed among long-term users of HRT was stronger for fatal events than for nonfatal events, with adjusted ORs of 0.38 (95% CI 0.21 to 0.68) and 0.77 (95% CI 0.59 to 0.98), respectively.
The ORs associated with long-term current-recent use of HRT by regimen,
route, and dose are displayed in Table 3
. The use of unopposed
therapy was associated with a greater reduction in the risk of
myocardial infarction than the use of opposed therapy, with adjusted
ORs of 0.52 (95% CI 0.35 to 0.78) and 0.79 (95% CI 0.59 to 1.08),
respectively. The majority of women used oral preparations (79%),
whereas 21% used transdermal therapy. The adjusted OR for long-term
use of oral estrogens was 0.66 (95% CI 0.50 to 0.88) and for
transdermal estradiol use was 0.75 (95% CI 0.47 to 1.21) (Table 3).
The effect of estrogens dose was examined among current-recent users of
long-term oral estrogens and transdermal estradiol, either unopposed or
opposed. Among them, 51% of cases and 61% of control subjects used
medium doses. The corresponding ORs for low, medium, and high doses
were 0.96 (95% CI 0.55 to 1.65), 0.59 (95% CI 0.42 to 0.82), and 0.75
(95% CI 0.48 to 1.19), respectively (Table 3). The ORs
associated with 0.625 mg of oral estrogens was 0.63 (95% CI 0.46 to
0.86) and with 50 µg of transdermal estradiol was 0.62 (95% CI
0.37 to 1.06).
The OR associated with past use of HRT was 0.73 (95% CI 0.51 to 1.03)
(Table 2). The benefit on the risk of myocardial infarction
provided by HRT was lost 
2 to 3 years after the cessation of use.
Among women who had stopped HRT >2 years before the index date, the OR
was 0.9 (95% CI 0.3 to 3.0).
A further stratified analysis was performed to determine whether the beneficial effect of the therapy on the risk of myocardial infarction varied in subgroups of women with different levels of coronary risk factors (data not shown). HRT was inversely related to the risk of myocardial infarction in all subgroups of women except in those who had history of hypercholesterolemia and/or used lipid-lowering drugs, as well in those with diabetes. However, numbers were limited in these 2 subgroups of women. Among diabetic women (11 exposed cases and 16 exposed control subjects), the OR was 1.4 (95% CI 0.6 to 3.3).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, current-recent use of HRT was associated with an overall 28% reduction in the risk of first myocardial infarction when compared with never-use of this therapy. Baseline differences in risk factors for myocardial infarction, such as age, history of smoking, hypertension, diabetes, and obesity, family history, type of menopause, comorbidity, use of aspirin, and calendar period, did not explain this beneficial effect.
The effect was stronger after the first year of continuous use of HRT, with a 32% reduction, and was present at medium-high doses (low dose was not associated with a reduced risk). The protective benefit appeared to diminish 2 to 3 years after cessation of the therapy. We did not observe any increase in the risk of first myocardial infarction associated with short-term HRT use.
The lack of information on some risk factors in a small proportion of women could have introduced some bias because of incomplete control of confounding. Information on smoking history was missing in 29% of women and was correlated to the use of HRT. Thus, recording of smoking was higher among women who ever-used hormones, suggesting that GPs were more likely to record smoking history among women who were willing to start HRT and were most likely at high risk of having a heart attack. Also, prevalence of recorded history of hypercholesterolemia, either treated or not with lipid-lowering drugs, was very low (4%). Although our cohort of postmenopausal women was free of cardiovascular disease history, this low percentage most likely reflects only the most severe cases of hypercholesterolemia.
In our cohort of relatively healthy postmenopausal women, and
consistent with other results, the beneficial effect of HRT was
observed in women without coronary risk factors and in women
with 1 risk factor but no diabetes.16 17 Although this
finding is based on small numbers, it might suggest a potential effect
modification by diabetes. The existence of diabetes in premenopausal
women appears to abrogate the cardiovascular protective
effects of endogenous estrogens.18 Although
mechanisms by which diabetes obviates the
cardiovascular-protective effects of female sex
hormones are not well understood, enhanced platelet aggregation,
oxidative stress, coagulation, and fibrinolytic activity, as well as
lipoprotein abnormalities, endothelial dysfunction, and
a possible interaction between hyperglycemia and estradiol in
regulation of cardiovascular nitric oxide
production, have been invoked.19 To date, few
studies have specifically assessed the effects of HRT on the incidence
of CHD in diabetic women showing inconclusive
results.20 21 One of these studies observed a beneficial
effect with >6 years of estrogen therapy.20 A reduced
atherosclerosis measured by carotid wall thickness
associated with HRT use in women with and without diabetes has been
also reported.22 Further investigations are required to
evaluate if women with diabetes mellitus may receive the same benefit
from HRT as women without diabetes.
In our study, the beneficial effect on the risk of myocardial infarction was observed in users of either unopposed estrogens and estrogens opposed with progestogens, although unopposed therapy was associated with a greater risk reduction. To the best of our knowledge, this is the only study examining the association between the route of the HRT and the risk of CHD. Although the relative risk for oral therapy was somewhat lower than the one for transdermal therapy, this result is compatible with either no differences or differences in the protective effect by route. A similar cardioprotection conferred by oral and transdermal HRT was further supported by the results of the stratified dose-response analysis. However, relative risk estimators for transdermal preparations were based on small numbers, resulting in relatively wide confidence intervals.
Observational studies looking at the effect of HRT have the potential for selection bias. Several studies have shown that women who choose to use HRT are healthier than nonusers.23 24 It has been suggested that users of HRT had a better premenopausal cardiovascular risk factor profile than nonusers.25 26 This type of bias, if present in our study, would underestimate the risk of myocardial infarction among users of HRT, thus exaggerating its protective effect. However, the study was restricted to women without cardiovascular and other chronic diseases. Also, when we adjusted for recorded hypertension, hypercholesterolemia, diabetes, and other risk factors the effect remained practically unchanged. In addition, we estimated the number of visits of each woman to their GP within 1 year before the index date. If women who take hormones see a physician regularly, these visits may be associated with a decreased risk of CHD. Compared with nonusers, higher proportions of women taking HRT were seeing their GPs >10 times per year. However, when we adjusted the analysis by the number of visits, the estimate of risk associated with HRT was slightly decreased (OR 0.69; 95% CI 0.56 to 0.85), probably reflecting a high-risk profile of some of these women. In a prior study of the same population, no differences were observed in social class and self reported health indicators between HRT users and nonusers.27 Nonetheless, a potential healthy user effect cannot be completely discarded. Our results are consistent with those observed in the Nurses’ Health Study (NHS), a homogenous cohort of healthy postmenopausal women.17 After controlling for many risk factors, there was still a strong inverse association between current HRT and the risk of CHD. Compared with our cohort, the cohort of NHS was younger and correspondingly presented a lower age-adjusted incidence rate of CHD (1.3 per 1000 person-years in NHS versus 1.6 per 1000 person-years in our cohort).
In our study, women with a recorded history of cardiovascular disease, neoplasms, coagulopathies, vasculitis, and alcohol-related diseases were excluded. However, since many practices included in the General Practice Research Database only started entering data routinely at the beginning of the 1990s, historic medical information could be incompletely recorded for a number of patients. History of cardiovascular disease is an important risk factor for myocardial infarction, and it is possible that women with history were less or more likely to receive HRT. This might have influenced the results in a somewhat under or overestimated relative protective effect of HRT. However, only 7 (0.6%) potential cases were excluded as a result of a prior myocardial infarction after reviewing the medical records.
Women taking HRT might be subject to referral or diagnostic bias, which would overestimate the risk of myocardial infarction, but also among these women an early suspicion would likely result in an early diagnosis of an acute coronary event.23 Indeed, we observed a greater reduction on the risk of fatal cases than of nonfatal cases of myocardial infarction.
Nondifferential misclassification could be present if women not truly having myocardial infarction were included as cases, independent of their exposure status. However, in our study, a detailed validation process resulted in a high percentage of definite cases according to our diagnostic classification. When we used definite and possible events as separate end points, the estimates of the beneficial effect of HRT were similar (data not shown). Consequently, this level of misclassification is unlikely to have introduced bias.
In summary, the results from this large population-based study are consistent with those of prior epidemiological studies, conducted in different populations with different methodologies, which show a 70% to 20% reduction in the risk of acute CHD events among current users of HRT in primary prevention.4 Our results also suggest that oral and transdermal therapy might have a similar cardioprotective effect at medium-high doses.
In our cohort of women, 50 to 74 years of age who did not use
replacement therapy, the age-adjusted risk of myocardial infarction was
1.8 per 1000 women per year. Among women who used HRT for >1 year,
this absolute risk was reduced by 32%. On average, this would result
in 7 prevented cases of myocardial infarction among 10 000 women
taking HRT. However, the magnitude of the protective effect would be
most pronounced in women with a higher baseline risk of disease, as
observed by others.28
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Acknowledgments |
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We thank the general practitioners for their collaboration and the Boston Collaborative Drug Surveillance Program for providing access to the General Practice Research Database. We also thank Marta Marcet for the data entry and the editing of this report.
Received August 3, 1999; revision received December 16, 1999; accepted December 22, 1999.
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 K. K. Koh, M.-S. Shin, I. Sakuma, J. Y. Ahn, D. K. Jin, H. S. Kim, D. S. Kim, S. H. Han, W.-J. Chung, and E. K. Shin Effects of Conventional or Lower Doses of Hormone Replacement Therapy in Postmenopausal Women Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1516 - 1521. [Abstract] [Full Text] [PDF]
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 M. Koga, K. Hirano, J. Nishimura, H. Nakano, and H. Kanaide Endothelium-Dependent and Independent Enhancement of Vascular Contractility in the Ovariectomized Rabbit Reproductive Sciences, July 1, 2004; 11(5): 272 - 279. [Abstract] [PDF]
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K. K. Koh and I. Sakuma Should Progestins Be Blamed for the Failure of Hormone Replacement Therapy to Reduce Cardiovascular Events in Randomized Controlled Trials? Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1171 - 1179. [Abstract] [Full Text] [PDF]
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 L. A. Garcia Rodriguez, C. Varas-Lorenzo, A. Maguire, and A. Gonzalez-Perez Nonsteroidal Antiinflammatory Drugs and the Risk of Myocardial Infarction in the General Population Circulation, June 22, 2004; 109(24): 3000 - 3006. [Abstract] [Full Text] [PDF]
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 E. Garbe and S. Suissa Issues to debate on the Women's Health Initiative (WHI) study: Hormone replacement therapy and acute coronary outcomes: methodological issues between randomized and observational studies Hum. Reprod., January 1, 2004; 19(1): 8 - 13. [Abstract] [Full Text] [PDF]
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C. E.D. Chilvers, R. C. Knibb, S. J. Armstrong, K. L. Woods, and R. F.A. Logan Post menopausal hormone replacement therapy and risk of acute myocardial infarction -- a case control study of women in the East Midlands, UK Eur. Heart J., December 2, 2003; 24(24): 2197 - 2205. [Abstract] [Full Text] [PDF]
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 J. Widder, T. Pelzer, C. von Poser-Klein, K. Hu, V. Jazbutyte, K.-H. Fritzemeier, C. Hegele-Hartung, L. Neyses, and J. Bauersachs Improvement of Endothelial Dysfunction by Selective Estrogen Receptor-{alpha} Stimulation in Ovariectomized SHR Hypertension, November 1, 2003; 42(5): 991 - 996. [Abstract] [Full Text] [PDF]
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 R. Chatrath, K. L. Ronningen, P. LaBreche, S. R. Severson, M. Jayachandran, M. P. Bracamonte, and V. M. Miller Effect of puberty on coronary arteries from female pigs J Appl Physiol, October 1, 2003; 95(4): 1672 - 1680. [Abstract] [Full Text] [PDF]
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K. K. Koh, J. Y. Ahn, D. K. Jin, B.-K. Yoon, H. S. Kim, D. S. Kim, W. C. Kang, S. H. Han, I. S. Choi, and E. K. Shin Significant Differential Effects of Hormone Therapy or Tibolone on Markers of Cardiovascular Disease in Postmenopausal Women: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study Arterioscler Thromb Vasc Biol, October 1, 2003; 23(10): 1889 - 1894. [Abstract] [Full Text] [PDF]
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A. Ferrara, C. P. Quesenberry, A. J. Karter, C. W. Njoroge, A. S. Jacobson, and J. V. Selby Current Use of Unopposed Estrogen and Estrogen Plus Progestin and the Risk of Acute Myocardial Infarction Among Women With Diabetes: The Northern California Kaiser Permanente Diabetes Registry, 1995-1998 Circulation, January 7, 2003; 107(1): 43 - 48. [Abstract] [Full Text] [PDF]
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 M. P. Bracamonte, M. Jayachandran, K. S. Rud, and V. M. Miller Acute effects of 17beta -estradiol on femoral veins from adult gonadally intact and ovariectomized female pigs Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2389 - H2396. [Abstract] [Full Text] [PDF]
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 C. J. Crespo, E. Smit, A. Snelling, C. T. Sempos, and R. E. Andersen Hormone Replacement Therapy and Its Relationship to Lipid and Glucose Metabolism in Diabetic and Nondiabetic Postmenopausal Women: Results from the Third National Health and Nutrition Examination Survey (NHANES III) Diabetes Care, October 1, 2002; 25(10): 1675 - 1680. [Abstract] [Full Text] [PDF]
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T. Wallerath, G. Deckert, T. Ternes, H. Anderson, H. Li, K. Witte, and U. Forstermann Resveratrol, a Polyphenolic Phytoalexin Present in Red Wine, Enhances Expression and Activity of Endothelial Nitric Oxide Synthase Circulation, September 24, 2002; 106(13): 1652 - 1658. [Abstract] [Full Text] [PDF]
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K. K. Koh, J. Y. Ahn, D. K. Jin, B.-K. Yoon, H. S. Kim, D. S. Kim, M.-S. Shin, J. W. Son, I. S. Choi, and E. K. Shin Effects of Continuous Combined Hormone Replacement Therapy on Inflammation in Hypertensive and/or Overweight Postmenopausal Women Arterioscler Thromb Vasc Biol, September 1, 2002; 22(9): 1459 - 1464. [Abstract] [Full Text] [PDF]
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 K. K. Koh Effects of estrogen on the vascular wall: vasomotor function and inflammation Cardiovasc Res, September 1, 2002; 55(4): 714 - 726. [Full Text] [PDF]
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 H. D. Nelson, L. L. Humphrey, P. Nygren, S. M. Teutsch, and J. D. Allan Postmenopausal Hormone Replacement Therapy: Scientific Review JAMA, August 21, 2002; 288(7): 872 - 881. [Abstract] [Full Text] [PDF]
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 L. L. Humphrey, B. K.S. Chan, and H. C. Sox Postmenopausal Hormone Replacement Therapy and the Primary Prevention of Cardiovascular Disease Ann Intern Med, August 20, 2002; 137(4): 273 - 284. [Abstract] [Full Text] [PDF]
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M. Jayachandran and V. M. Miller Ovariectomy upregulates expression of estrogen receptors, NOS, and HSPs in porcine platelets Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H220 - H226. [Abstract] [Full Text] [PDF]
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F. A Babiker, L. J De Windt, M. van Eickels, C. Grohe, R. Meyer, and P. A Doevendans Estrogenic hormone action in the heart: regulatory network and function Cardiovasc Res, February 15, 2002; 53(3): 709 - 719. [Abstract] [Full Text] [PDF]
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D. A. Lewis, M. P. Bracamonte, K. S. Rud, and V. M. Miller Genome and Hormones: Gender Differences in Physiology: Selected Contribution: Effects of sex and ovariectomy on responses to platelets in porcine femoral veins J Appl Physiol, December 1, 2001; 91(6): 2823 - 2830. [Abstract] [Full Text] [PDF]
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M. E. Mendelsohn and R. H. Karas The Time Has Come to Stop Letting the HERS Tale Wag the Dogma Circulation, November 6, 2001; 104(19): 2256 - 2259. [Full Text] [PDF]
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K. K. Koh, D. K. Jin, S. H. Yang, S.-K. Lee, H. Y. Hwang, M. H. Kang, W. Kim, D. S. Kim, I. S. Choi, and E. K. Shin Vascular Effects of Synthetic or Natural Progestagen Combined With Conjugated Equine Estrogen in Healthy Postmenopausal Women Circulation, April 17, 2001; 103(15): 1961 - 1966. [Abstract] [Full Text] [PDF]
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