Vol. 91, Issue 6, 2776-2784, December 2001
HIGHLIGHTED TOPICS
Genome and Hormones: Gender Differences in Physiology
Invited Review: Pharmacogenetics of estrogen replacement
therapy
David M.
Herrington and
Karen Potvin
Klein
Department of Internal Medicine/Cardiology, Wake Forest
University School of Medicine, Winston-Salem, North Carolina 27157
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ABSTRACT |
There
are a number of genetic factors that likely modulate both the
beneficial and adverse effects of estrogen. An important domain
of consideration is the relationship of estrogen and thrombosis risk.
Gene polymorphisms among the key elements of the coagulation and
fibrinolytic cascade appear to influence the effects of estrogen on
risk for venous thromboembolic events and possibly arterial thrombosis as well. Emerging data also suggest that allelic variants in
the estrogen receptor-
may modulate estrogen's effects,
especially with respect to bone and lipid metabolism.
estrogen receptor-; polymorphisms; postmenopausal women; thrombosis; risk factors
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INTRODUCTION |
HORMONE REPLACEMENT THERAPY
(HRT) is one of the most frequently prescribed forms of drug therapy in
the United States. Approximately 15 million U.S. women take some
form of HRT daily. Although approved for treatment of perimenopausal
symptoms and osteoporosis, many women and their physicians feel
that HRT may also be useful for prevention of a variety of other
chronic illnesses, including heart disease. Recently, the results of
several randomized clinical trials of HRT for secondary prevention of
heart disease have shown that HRT does not appear to slow the clinical
or angiographic progression of coronary disease. Furthermore, there is
a growing body of evidence that HRT may also be associated with an
early increase in risk of arterial and venous thrombotic events (VTEs), perhaps in a subgroup of women who are uniquely at risk for an adverse
effect of HRT due to polymorphisms in genes that regulate coagulation
and fibrinolysis. These data indicate that the effects of HRT may be
far more complex than initially assumed and that a variety of genetic
factors may play an important role in modulating the risks and benefits
of HRT.
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OVERVIEW OF THE HERS TRIAL |
The Heart and Estrogen/progestin Replacement Study (HERS)
was a randomized, double-blind, placebo-controlled trial of HRT [given as conjugated estrogen (0.625 mg) and medroxyprogesterone acetate (2.5 mg) daily] for prevention of recurrent cardiovascular events in postmenopausal women with established coronary disease. After
an average of 4.1 yr of therapy, there was no difference in the rate of
primary coronary heart disease (CHD) events (myocardial infarction
or CHD death) between active therapy and placebo
(52). At baseline, extensive information about
cardiovascular disease risk factors, including smoking, diabetes, blood
pressure, exercise, and alcohol consumption, were documented with
standardized questionnaires. Plasma lipids were measured at baseline
and annually during follow-up. Reported clinical cardiovascular
events and fractures were confirmed on the basis of review of
hospital records and by an independent endpoint committee.
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EARLY RISK FOR CHD EVENTS WITH HRT IN HERS AND OTHER STUDIES |
In HERS, risk for a nonfatal myocardial infarction (MI) or CHD
death was increased by 50% during the first year of follow-up among
women on active therapy compared with placebo [relative hazard
(RH) = 1.52, 95% confidence intervals (CI) of 1.01-2.29] (52). The risk was greatest immediately after HRT was
initiated, with an RH of 2.30 for the first 4-mo period, 1.46 for the
second 4-mo period, and 1.16 for the third 4-mo period. The pattern of early increased risk for coronary thrombotic events mirrors the pattern
of excess risk for VTEs, which were also significantly increased during
the first year (RH = 3.29, 95% CI of 1.07-10.08).
Subsequent to HERS, data have emerged from other epidemiological
studies that tend to corroborate this pattern of early risk. In the
Puget Sound Group Health Cooperative, healthy short-term HRT users had
double the risk for a MI vs. similar women who had used HRT for
1-2 yr (43). Among women with established heart disease in the Nurses' Health Study (n = 2,245), a
similar pattern was seen for risk of MI recurrence or CHD death
(39). In contrast, among healthy women in that cohort who
had used HRT for under 1 yr, the relative risk of cardiovascular events
was 0.40 (95% CI of 0.21-0.77). However, only nine cases were
identified (38). Interestingly, a retrospective analysis
of the Coronary Drug Project, which examined estrogen treatment in men
with CHD, showed evidence of early increased risk as well
(110). The Women's Health Initiative, a clinical trial of
HRT in mostly healthy postmenopausal women (n = 27,348), also announced a trend toward early increased cardiovascular risk that waned over time; however, because the trial is ongoing, details cannot be provided (see www.nhlbi.gov/whi/hrt-en.htm). Although the Nurses' Health Study and the Coronary Drug Project studied subjects with known heart disease, the Puget Sound Group Health
Cooperative and the Women's Health Initiative comprise primarily
healthy subjects free of clinically apparent coronary disease.
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THROMBOSIS GENE POLYMORPHISMS AND EARLY RISK WITH ESTROGEN |
There are several postulated mechanisms for the pattern of early
risk observed in HERS. One leading possibility is that the early
increase in coronary events was related to a prothrombotic effect of
estrogen. It is well established that both postmenopausal HRT and oral
contraceptives increase risk for venous thrombosis (14, 35,
56). The new data from women with established coronary disease
in HERS complement previous studies of oral contraceptive use in women
with coronary risk factors that have also observed an increased risk
for coronary thrombosis (74, 111).
Despite these clinical associations between estrogen use and risk for
venous or arterial thrombosis, the exact mechanism remains elusive.
Several studies have shown that estrogen promotes generation of both
thrombin and fibrin (as evidenced by increased levels of
F1.2, thrombin-antithrombin complexes, and fibrinopeptide
A) (62). This may be related to
estrogen-associated increases in factor VII and reductions in protein C
leading to higher levels of activated factor V (factor Va; Fig.
1). On the other hand, estrogen also
lowers antithrombin III and fibrinogen (the substrate for thrombin),
potentially blunting overall fibrin mass. In addition, estrogen appears
to augment the fibrinolytic cascade by lowering plasminogen activator
inhibitor-1 (PAI-1). The net effect may be that any incipient fibrin
that is generated is rapidly degraded, thereby preventing the formation
of clinically significant thrombosis.
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Fig. 1.
Effects of estrogen on the coagulation and fibrinolytic
cascades. Up or down arrows indicate effects of estrogen. Effects
thought to decrease risk for thrombosis are underlined; effects thought
to increase risk for thrombosis are italicized. ( ) indicates
inhibitory action. ATIII, antithrombin III; PAI-1, plasminogen
activator inhibitor-1; tPA, tissue plasminogen antigen.
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However, these compensatory effects could be overwhelmed by one or more
polymorphisms that alter gene expression of proteins that regulate
coagulation or fibrinolysis (Fig. 2).
Indeed, there are now preliminary data implicating several
thrombosis gene polymorphisms in the setting of estrogen therapy or
conditions commonly caused by estrogen. These polymorphisms may be
causes for an estrogen-associated increase in risk for thrombotic
events seen in the HERS trial.
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Fig. 2.
Postulated effects of polymorphisms that may alter the
coagulation or fibrinolytic cascades in the setting of estrogen
therapy. Up or down arrows indicate postulated effects of estrogen in
the presence of the polymorphism. Effects thought to decrease
risk for thrombosis are underlined; effects thought to increase risk
for thrombosis are italicized. Polymorphisms are indicated in
parentheses. () indicates inhibitory action. IL-6,
interleukin-6; TG, triglyceride.
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Selected thrombosis-related gene polymorphisms are discussed in more
detail below. Table 1 shows estimated
allele and genotype frequencies for these polymorphisms.
Factor V Leiden.
One polymorphism of particular interest is the factor V Leiden
mutation. This point mutation (Arg 506
Glu) found in 5% of Caucasians in the United States (92) renders the factor V
molecule resistant to inactivation by activated protein C [activated
protein C (APC) resistance] (13). Case-control
and prospective cohort studies have documented a 2- to 7-fold increased
risk for venous thromboembolism among factor V Leiden heterozygotes and
a 40- to 80-fold increased risk among homozygotes (71).
Some (12, 23, 28, 75, 96, 106) but not all (7, 8,
11, 24, 27, 44, 63, 64, 70, 94) studies have suggested that individuals with factor V Leiden or activated protein C resistance are
also at increased risk for MI or stroke.
Importantly, risk for venous or arterial thrombosis appears to be
greatest among women with the factor V Leiden mutation who also have
increased exposure to endogenous or exogenous estrogen. In a study of
consecutive premenopausal women with idiopathic VTE, Vandenbroucke et
al. (107) found that women using oral contraceptives had a
3.8-fold increase in risk, whereas those with factor V Leiden had a
7.9-fold increase. In women using oral contraceptives who also had the
factor V Leiden mutation, the risk was roughly 35 times greater than
noncarriers who were not on oral contraceptives. Several other studies
have reported substantially greater APC resistance or prevalence of
factor V Leiden in women with VTEs that occurred during pregnancy or
while taking oral contraceptives (4, 40, 46, 50, 80). In
subjects with factor V Leiden, exogenous estrogen also appears to
augment risk for osteonecrosis, a thrombotic complication of bone
healing (31).
More recently, Glueck et al. (32) found the factor V
Leiden mutation in 12.5% of women who suffered an MI or stroke while on HRT, compared with only 4.3% among women on HRT who had not suffered a coronary or cerebrovascular event. In contrast, rates of
factor V Leiden in HRT-negative cases and controls were 5.5% and
7.6%, respectively (overall X2 P value = 0.005). These data suggest that women with the factor V Leiden mutation
may be at high risk for an estrogen-associated venous or arterial
thrombotic event.
Prothrombin (G20210A).
Prothrombin is the precursor to thrombin, a key enzyme in
thrombosis and hemostasis. In the 3' untranslated region of the prothrombin gene, there is a single nucleotide polymorphism GA at
position 20210 (18). This mutation, which occurs in
2-4% of the general population, is associated with 20% higher
levels of prothrombin (89) and a 2.7- to 4.8-fold
increased risk for venous thrombosis (21, 49, 69, 75, 89).
Several studies have also found an association between this
polymorphism and early MI (2, 23, 95, 108) or stroke
(21). Some evidence suggests this mutation may further
augment the risk for thrombotic events in subjects who also have the
factor V Leiden mutation or other inherited thrombophilic conditions
(22, 25, 115).
Like factor V Leiden, there are also preliminary data suggesting that
risk for venous or arterial thrombosis may be dramatically increased in
women with the prothrombin 20210A polymorphism who are taking exogenous
estrogen. This possibility was first alluded to in a case report of
celiac axis and splenic thrombosis in a woman with the prothrombin
20210A polymorphism who was taking oral contraceptives
(34). Subsequently, Martinelli et al. (76) reported an odds ratio of 150 for cerebral vein thrombosis in carriers
of the prothrombin mutation who were also on oral contraceptives. In a
study of 230 women with hyperlipidemia, Glueck et al. (33) found 86 (37%) had a diagnosis of MI or stroke and 8 (3.5%) were heterozygous for the prothrombin mutation. When analyzed with logistic
regression models, there was a significant interaction between use of
HRT and presence or absence of the prothrombin G20210A mutation with
respect to risk for MI or stroke (interaction odds ratio = 2.9, 95% CI of 1.4-6.2; P = 0.01).
In a large population-based case-control study conducted in a
Seattle-based health-maintenance organization, Psaty et al. (90) found that hypertensive carriers of the prothrombin
20210A variant who were taking HRT had a substantially higher risk of MI than those without the mutation. Compared with nonusers of HRT with
the wild-type genotype, women on HRT who were also carriers of the A
allele had an 111-fold increase in risk for MI (odds ratio of 10.9;
95% CI of 2.15-55.2).
Factor VII (R353Q).
Factor VII plays a central role in tissue factor-mediated thrombin
generation. Several studies have found factor VII levels to be
independently associated with risk for MI (45, 78, 79). Several polymorphisms have been identified in the 12.8-kb factor VII
gene, which resides on the long arm of chromosome 13 (83). The R353Q polymorphism refers to a coding change resulting in ArgGlu
at position 353. Individuals who have one or two copies of the Q allele
(~20% of the population) have 20-25% lower levels of FVIIc and
FVIIag (37). Iacoviello et al. (55) found
that individuals who were homozygous for the wild-type allele (R/R) had
a 20-25% higher risk of MI than subjects with one or two copies of the mutant allele. However, others have failed to confirm this association (9, 66). Interestingly, among wild-type
homozygotes, FVIIc levels correlate with triglyceride levels, whereas
in individuals with one or two copies of the mutant allele no such
correlation exists (53, 65). This raises the possibility
that R/R individuals with estrogen-induced hypertriglyceridemia may
also have elevated factor VII levels and increased risk for a
thrombotic event.
PAI-1 (4G/5G).
PAI-1 inhibits the activity of tissue plasminogen antigen and
urokinase, thereby inhibiting fibrinolysis. The PAI-1 gene is a 12.3-kb
gene with nine exonic regions located in the long arm of chromosome 7 (103). This gene is known to have a promoter region
(675) polymorphism characterized by an additional G residue in a run
of four consecutive G. This polymorphism has an allele frequency of
50%. The 4G allele is associated with dramatic increases in PAI-1
secretion in human hepatoma cell lines in response to interleukin-1
(16, 26) and higher circulating levels in vivo, especially
in diabetic subjects (73, 85) and subjects with coronary
disease (16, 113). This is clinically important, as elevated PAI-1 levels are associated with increased risk for VTE (15) and MI (41, 57), presumably by
inhibiting the fibrinolytic cascade.
Of particular relevance for HRT users is the relationship between
triglycerides and PAI-1 levels. PAI-1 release is stimulated by very
low-density lipoprotein cholesterol in vitro (102). In humans, PAI-1 and triglyceride levels are correlated in normal subjects
(59) and even more so in subjects with vascular disease (41, 58). However, this correlation is most apparent
in individuals who are homozygous for the 4G allele. Panahloo et al.
(85) reported a correlation of 0.65 between PAI-1 and
triglycerides among 4G/4G diabetic individuals, with much weaker
correlations being evident in 4G/5G and 5G/5G individuals. Whether
4G/4G women (~25% of the population) are at higher risk for venous
or arterial thrombotic events in the setting of estrogen-induced
hypertriglyceridemia remains unknown.
Fibrinogen (455G/A).
Fibrinogen is the precursor of fibrin, a major constituent of thrombus.
It also binds to platelet glycoprotein IIb/IIIa on platelets, providing
a molecular link that leads to platelet aggregates. Numerous studies
have found a significant association between fibrinogen levels and risk
for MI (37, 78). Synthesis of the B
-chain is the
rate-limiting step in determining circulating levels of the mature
fibrinogen molecule, which is composed of A-, B-, and
-components (97). There are two promoter region polymorphisms (455 G/A and 148C/T) in high degree of linkage disequilibrium (105). The mutant allele A (allele
frequency of ~19%) is associated with higher levels of fibrinogen
(54), progression of coronary (17) and
peripheral arterial disease (100), and increased risk of
stroke (82). The 148C/T polymorphism is in the
interleukin-6 promoter element for the B-molecule, which may explain
the higher levels of fibrinogen in 148T smokers (36), since smoking leads to increases in interleukin-6. Recently, it has
become clear that estrogen replacement leads to increases in C-reactive
protein (10, 93), an acute-phase reactant whose synthesis
is regulated by the proinflammatory cytokine interleukin-6. It is
possible that estrogen-associated changes in interleukin-6 and
C-reactive protein might prove uniquely detrimental in 455A(148T) women.
PlA1/A2.
Platelet glycoprotein IIb/IIIa is the fibrinogen receptor that mediates
cross-linking of platelets and subsequent thrombus formation. The
PlA2 polymorphism is a base-pair change resulting in a
leucineproline substitution at residue 33 of the
3-subunit of glycoprotein IIb/IIIa receptor protein
(81). The PlA2 allele, which has an allele
frequency of 15% (114), is associated with increased
platelet aggregability (29) and has also been associated
with risk for premature MI in some (79a, 87, 109) but not
other (30, 47, 72, 91) studies. In a recent meta-analysis of PlA1/A2 and risk of MI, the risk of the A2 allele was
greatest among women (odds ratio = 1.4); however, the CIs were
wide and included unity because of the relatively few data currently
available in women (114). Conversely, in platelets from
men with the A2 allele, incubation with estrogen produces significant
inhibition. A1/A1 subjects require 1,000-fold higher concentrations of
estrogen to achieve the same degree of platelet inhibition
(5). These data suggest that gender and estrogen status
may have a significant impact on the relationship between
PlA1/A2 genotypes and risk for thrombosis.
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OTHER PROMISING AREAS FOR PHARMACOGENETIC RESEARCH WITH HRT |
The estrogen receptors ER- and ER-, ligand-activated
transcription factors, modulate expression of many proteins responsible for cell function. Several lines of evidence suggest that polymorphisms in ER- may influence estrogen action. The human ER- gene, located at 6q24.1, has been cloned, sequenced, and expressed in various cell
lines, and site-directed mutagenesis has identified domains that are
highly conserved across species and responsible for hormone or DNA
binding or transcriptional activation (88). Associations between several naturally occurring ER- sequence variants and a
variety of clinical phenotypes have been examined. The phenotypes include risk (1, 99), age of onset (86), and
estrogen receptor status (48, 112) in breast cancer; risk
for spontaneous abortion (3, 67); bone mineral density
(BMD) (19, 42, 61, 98); body mass index (19);
hypertension (68); lipids (60, 77); and
coronary atherosclerosis (77). Most of these studies have focused on the IVS1-401 and IVS1-354 polymorphisms. In two
clinical studies examining HRT and BMD, HRT had a greater effect
on vertebral BMD in women with the IVS1-401 C allele (20,
84).
In human vascular smooth muscle cells, significant heterogeneity in
ER- mRNA transcripts has been reported, including variants with
missing exons encoding hormone-binding domain regions
(51). The clinical literature includes a case of a man
with a premature stop codon in exon 2 and no functional ER-
receptors (101) who also had low high-density-lipoprotein
cholesterol and premature atherosclerosis (104). Work is
underway in several laboratories to determine whether there are other
ER- or ER- polymorphisms that may have important impact on the
clinical effects of HRT.
Another more classical area of pharmacogenetic research that remains
selectively unexplored involves the genetic regulation of estrogen
synthesis and catabolism (Fig. 3).
Several of the cytochrome P-450 enzymes are responsible for
critical steps in the conversion of estrone to estradiol and its
subsequent catabolism. Polymorphisms in several of these genes are
known to influence the metabolism of other steroid hormones. However,
relatively few data are available concerning the effects of these
cytochrome P-450 enzymes on clinical responses to HRT. This
is another promising area of our research.
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Fig. 3.
Pathways of estrogen synthesis and catabolism and the
sensitivity of tissue to estrogens. 3-HSD, 3-hydroxysteroid
dehydrogenase; 17-HSD, 17-hydroxysteroid dehydrogenase; DHEA,
dehydroepiandrosterone; P-450, cytochrome P-450; SCC, side
chain-cleavage enzyme; CYP17, 17-hydroxylase; CYP21, 21-hydroxylase;
CYP11, 11-hydroxylase; E1, estrone; E2,
estradiol; 2-OH-E1, 2-hydroxyestrone; 2-OH-E2,
2-hydroxyestradiol; 2-MeO-E1, 2-methoxyestrone;
2-MeO-E2, 2-methoxyestradiol; 2-OH-3-MeO-E1,
2-hydroxyestrone 3-methyl ether; 2-OH-3-MeO-E2,
2-hydroxyestradiol 3-methyl ether; 4-OH-E1,
4-hydroxyestrone; 4-OH-E2, 4-hydroxyestradiol;
4-OH-3-MeO-E1, 4-hydroxyestrone 3-methyl ether;
4-OH-3-MeO-E2, 4-hydroxyestradiol 3-methyl ether;
16-OH-E1, 16-hydroxyestrone; 16-OH-E2,
16-hydroxyestradiol; CYP1A1, cytochrome P-450 1A1;
CYP1B1, cytochrome P-450 1B1; COMT, catechol
O-methyltransferase. [Reprinted with permission from
Clemons M and Goss P. Estrogen and the risk of breast cancer.
N Engl J Med 344: 276-285, 2001. Copyright
2001 Massachusetts Medical Society.]
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POTENTIAL IMPORTANCE OF PHARMACOGENETICS OF ESTROGEN |
The significance of these data revolves around three
interrelated issues of tremendous public-health importance: prevention of cardiovascular disease in postmenopausal women, safety of HRT, and
drug-gene interactions. Cardiovascular disease remains the top killer
of postmenopausal women in the United States. Initial enthusiasm for
estrogen for primary and secondary prevention of cardiovascular disease
has been questioned because of the null results in HERS. However, a
real benefit of HRT could have been obscured by an increased risk of
cardiovascular disease in a subset of women prone to a thrombotic
complication. If verified, this theory suggests that HRT may still be
useful to prevent cardiovascular disease in a large number of
postmenopausal women still in need of effective preventive strategies,
a hypothesis that nevertheless will need to be tested in future
clinical studies. Even without unequivocal proof of a cardiovascular
benefit, HRT remains one of the most frequently prescribed drugs in the
United States, largely for the approved indications to treat
perimenopausal symptoms and osteoporosis. However, there may be a
subgroup among the 11-15 million U.S. women currently using HRT
who are at high risk for a thrombotic complication. Excluding these
women could significantly improve the safety of HRT for others hoping
to treat or prevent these common conditions. Drug safety is especially
important when used in otherwise healthy individuals to prevent future
disease. One emerging avenue to improve drug safety and efficacy is
through an understanding of drug-gene interactions. This area could
become one of the most productive means to improve public health in the next decade. More research is needed to elicit fundamentally important new information about the impact of genomic variation on other effects
of estrogen and estrogen agonists and provide another example of the
clinical utility of this broad class of investigational agents.
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SUMMARY |
Clinical trials of estrogen for secondary prevention of CHD in
postmenopausal women have not found the beneficial effects predicted in
observational studies and in animal models of atherosclerosis. The
reasons for this lack of benefit are not yet clear; however, preliminary evidence implicates several thrombosis gene polymorphisms in the setting of estrogen therapy as one possible reason for the
disappointing results. Several candidate polymorphisms, among them
factor V Leiden, prothrombin G20210A, factor VII (R353Q), PAI-1
(4G/5G), fibrinogen (455G/A), and PlA1/A2, may have been
involved in the estrogen-associated increased risk for thrombotic
events observed in the HERS trial. Investigations into polymorphisms of
ER- and ER- are needed to elucidate how they affect response to
estrogen therapy. A better understanding of the complex role of
these and other genetic modifiers of estrogen action may help maximize
the safety and efficacy of HRT.
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ACKNOWLEDGEMENTS |
This work was supported in part by National Heart, Lung, and Blood
Institute Grant U01 HL-45488 and by a grant from Wyeth-Ayerst Research.
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FOOTNOTES |
Address for reprint requests and other correspondence: D. M. Herrington, Dept. of Internal Medicine/Cardiology, Wake Forest Univ.
School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 (E-mail: kklein{at}wfubmc.edu).
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