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The new england journal of medicine

review article

drug therapy
Alastair J.J. Wood, M.D., Editor

Selective Estrogen-Receptor Modulators —


Mechanisms of Action and Application
to Clinical Practice
B. Lawrence Riggs, M.D., and Lynn C. Hartmann, M.D.

he selective estrogen-receptor modulators (serms) represent


From the Division of Endocrinology and
Metabolism, Department of Internal Medi-
cine (B.L.R.), and the Department of Oncol-
ogy (L.C.H.), Mayo Clinic and Mayo Foun-
dation, Rochester, Minn. Address reprint
requests to Dr. Riggs at the Mayo Clinic,
t a major therapeutic advance for clinical practice. Unlike estrogens, which are
uniformly agonists, and antiestrogens, which are uniformly antagonists, the
SERMs exert selective agonist or antagonist effects on various estrogen target tissues.
The SERMs are chemically diverse compounds that lack the steroid structure of estro-
200 First St. SW, N. 6 Plummer, Rochester,
MN 55905. gens (Fig. 1) but possess a tertiary structure that allows them to bind to the estrogen re-
ceptor. Although some members of this class of drugs have been available for decades,
N Engl J Med 2003;348:618-29. their tissue-specificity in humans has only recently been recognized. Certain phytoestro-
Copyright © 2003 Massachusetts Medical Society.
gens, such as genistein, also appear to have SERM-like properties.
In this article we review the emerging understanding of the molecular basis of action
of SERMs, summarize their tissue-selective agonist–antagonist effects, and place in per-
spective their therapeutic uses as compared with estrogen or nonestrogen alternatives.

mechanisms of action
In the classic model of estrogen action, the unoccupied nuclear estrogen receptor re-
sides in the nuclei of target cells in an inactive form. Binding to an agonist, such as
estradiol, alters the physicochemical properties of the estrogen receptor, allowing the
receptor dimer to interact with specific DNA sequences (estrogen response elements)
within the promoters of responsive genes.1 The DNA-bound estrogen receptor then reg-
ulates target-gene transcription, either positively or negatively (Fig. 2). However, the
recognition that tamoxifen and other SERMs have tissue-specific agonist–antagonist
activity led to the realization that the classic model was incomplete and that estrogen
action was more complex than had been thought.2,3 The mechanisms of the tissue-
selective, mixed agonist–antagonist action of SERMs, although still only partly under-
stood, are gradually becoming clearer.
Most of the unique pharmacology of SERMs can be explained by three interactive
mechanisms: differential estrogen-receptor expression in a given target tissue, differ-
ential estrogen-receptor conformation on ligand binding, and differential expression
and binding to the estrogen receptor of coregulator proteins (Fig. 2).
First, target cells for estrogen action contain varying concentrations of homodimers
of one or both of two species of estrogen receptors — estrogen receptor a and estrogen
receptor b — as well as estrogen receptor a–estrogen receptor b heterodimers. Mice
with genetic disruptions of estrogen receptor a and estrogen receptor b display differ-
ent phenotypes, demonstrating that each receptor has a distinct action.4,5 Estrogen
receptor a is almost always an activator, whereas estrogen receptor b can inhibit the
action of estrogen receptor a by forming a heterodimer with it. Moreover, microarray
analysis in mice with deletions of estrogen receptor a or estrogen receptor b showed

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drug therapy

N
O

OH
CH3

HO

17b-Estradiol Tamoxifen

N N

O O

OH
S
HO HO

Cl

Toremifene Raloxifene

Figure 1. Chemical Structure of 17b-Estradiol, the Main Physiologically Relevant Estrogen, and the Three SERMs Ap-
proved by the Food and Drug Administration.
17b-Estradiol has a cyclophenanthrene structure, whereas tamoxifen and toremifene have a triphenylethylene structure
and raloxifene has a benzothiophene structure. Although the primary structure of these SERMs differs strikingly from
that of estrogens, they have a conformation that allows them to bind to the ligand-binding domain of the estrogen receptor.

that estrogen receptor b inhibited the transcription Thus, the ligand binding results in various estrogen-
of 240 estrogen-responsive genes by 46 percent.6 receptor conformations that range from that as-
Thus, the relative levels of expression of these two sumed when the receptor is bound to estrogens at
receptor isoforms will affect the cellular respon- one extreme to that assumed when the receptor is
siveness to estrogens.7,8 Since two SERMs, ralox- bound to antiestrogens at the other extreme. SERM-
ifene and tamoxifen, also bind to both isoforms, bound estrogen receptors assume a continuum of
these drugs will affect the cellular responsiveness intermediate shapes.
as well. Indeed, these SERMs function as pure an- Third, more than 20 coregulator proteins have
tagonists when acting through estrogen receptor been discovered that bind to estrogen receptors and
b on genes containing estrogen response ele- modulate their function, each acting as either a pos-
ments but can function as partial agonists when itive or a negative transcriptional regulator (a coac-
acting on them through estrogen receptor a.8 tivator or a corepressor, respectively).13-16 Depend-
Second, protein crystallography and techniques ing on the unique receptor conformation induced
that evaluate surface changes have shown that bind- by ligand binding, varying combinations of coreg-
ing by estradiol, tamoxifen, raloxifene, or the pure ulator proteins interact with the estrogen receptor
estrogen antagonist ICI 164,384 results in a unique and modulate its function in a variety of ways. The
estrogen-receptor conformation for each ligand.9-12 relative and absolute levels of expression of coreg-

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The new england journal of medicine

Corepressor
protein

X
Antagonist
ERE

Estrogen SERMs
receptor

ERE
Unidentified
Agonist coactivator

Coactivator
ERE

Figure 2. Estrogen-Receptor Action.


On binding an agonist or an antagonist, the estrogen receptor (the a or b isoform) undergoes a conformational change
that permits its spontaneous dimerization and facilitates the subsequent interaction of the dimer with estrogen re-
sponse elements (EREs) located within target genes. It has been determined that estrogen facilitates the interaction of
the estrogen receptor with coactivators. An antagonist-activated estrogen receptor, on the other hand, interacts prefer-
entially with a corepressor protein. The binding of different SERMs to the receptor permits it to adopt conformational
states distinct from that induced by classic agonists or antagonists. The weight of available evidence suggests that the
structure of some SERM–estrogen-receptor complexes favors corepressor recruitment and that of others favors some
affinity for known coactivators. Some SERMs may also facilitate the interaction of the estrogen receptor with yet-to-be-
identified coactivators with which it would not normally couple. The implication of this model is that SERM activity will
be influenced by the relative levels of expression of the cofactors (corepressors and coactivators) in target cells.

ulator proteins vary among estrogen target cells.13 Moreover, the agonist effect of tamoxifen was de-
In an important recent study, Shang and Brown17 pendent on a higher concentration of a key coacti-
found that tamoxifen and raloxifene, which are an- vator, steroid receptor coactivator-1 (SRC-1), in the
tiestrogens for the breast, act on mammary cells by endometrial cells. Thus, variable local concentra-
recruiting corepressors to estrogen-receptor tar- tions of different coregulator proteins may contrib-
get promoters. In contrast, tamoxifen, which is ute to the tissue-selective pharmacology of SERMs.
an estrogen agonist for the endometrium, acts in A model of the molecular action of estrogens and
endometrial cells by recruiting coactivators to the SERMs is shown in Figure 2.
estrogen-receptor target promoters, whereas this
recruitment does not occur with raloxifene, which
action on target tissues
has a neutral effect on the endometrium. The inves-
tigators also found that the tamoxifen–estrogen In recent years estrogen has been the most frequent-
receptor a complex activates transcription by teth- ly prescribed drug in the world. It was reported in
ering to promoters that do not contain estrogen 1999 to be used by 38 percent of postmenopausal
response elements through protein-to-protein con- American women.18 However, estrogen use has de-
tacts with other DNA-bound transcription factors. clined sharply in the wake of the early termination

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drug therapy

last summer of the Women’s Health Initiative after


the data and safety monitoring board decided that Table 1. Comparison of Selected Actions and Side Effects of Estrogen
and Clinically Available SERMs.*
risks exceeded benefits.19 The Women’s Health Ini-
tiative was a prospective trial, sponsored by the Side Effect Estrogen Tamoxifen Toremifene Raloxifene
National Institutes of Health, involving 16,608 post-
Hot flashes ↓↓↓ ↑† ↑† ↑†
menopausal women randomly assigned to treat-
ment daily with 0.625 mg of conjugated estrogen Uterine bleeding ↑↑↑ ↑ ↑ ←

and 2.5 mg of medroxyprogesterone acetate, a com- Risk of endometrial cancer ↑↑‡ ↑ ? ←

monly used regimen of hormone-replacement ther- Prevention of postmenopausal
apy, or with placebo. The trial was originally sched- bone loss ↑↑↑ ↑ ←
→ ↑↑
uled to last 8.5 years but was stopped after 5.2 years, Risk of breast cancer ↑↑ ↓↓ ↓↓§ ↓↓
although the subgroup of women who had under-
Favorable pattern of serum lipids ↑↑↑¶ ↑ ↑↑ ↑
gone hysterectomy and were taking estrogen with-
out medroxyprogesterone was allowed to contin- Venous thrombosis ↑↑ ↑↑ ? ↑↑
ue. Although other estrogen regimens or dosages
would not necessarily have provided similar re- * Ascending arrows indicate that the drug increases the effect, and descending ar-
rows that it decreases the effect. Horizontal arrows indicate no change. The num-
sults, the trial results bring into sharper focus the ber of arrows indicates the size of the change.
risks of hormone-replacement therapy in its asso- † In perimenopausal women the action would be ↑↑.
ciation with an increase in cardiovascular disease, ‡ This effect can be prevented by concurrent treatment with a progestin.
§ The only available data are for inhibition of breast-cancer growth.
stroke, pulmonary embolism, and breast cancer.19 ¶ This effect may be attenuated by concurrent treatment with androgen-derived
But the Women’s Health Initiative also provides the progestins.20
first controlled data demonstrating that hormone-
replacement therapy protects against osteoporotic
fractures and may decrease the occurrence of co- vertebral and hip fractures.19 This reduction oc-
lorectal cancer.19 curred even though the study subjects were at low
One consequence of the Women’s Health Initia- risk for fractures.
tive findings has been an increased interest in thera- Although early work established that tamoxi-
py with SERMs, because of their potential to retain fen was an estrogen antagonist for the breast, sub-
most of the beneficial effects of estrogen while sequent studies in animals24,25 and clinical stud-
avoiding most of its adverse effects. In the sections ies26,27 showed that it was a weak agonist for bone.
that follow, we review the corresponding and con- In postmenopausal women, however, the gain in
trasting actions of estrogen and SERMs on various bone density after two years of tamoxifen therapy
target tissues (Table 1). was small (Table 2), and half of this short-term in-
crease was lost after five years of continued treat-
bone ment.34 Tamoxifen has been reported both to
Estrogen acts on bone cells, which contain both increase35 and to decrease36 the risk of hip frac-
isoforms of estrogen receptors.21,22 However, con- ture. From the limited available data, toremifene ap-
centrations of estrogen receptor b are higher in de- pears to be a weaker bone agonist than tamoxifen.37
veloping cancellous bone, whereas concentrations The effects of raloxifene on bone are well estab-
of estrogen receptor a are higher in developing cor- lished. In postmenopausal women with osteoporo-
tical bone.23 Estrogen deficiency is the main cause sis, treatment with raloxifene decreased markers of
of postmenopausal osteoporosis.21 When estrogen bone turnover by 30 to 40 percent after one year and
is deficient, bone turnover increases, and bone re- increased bone density at several scanning sites by
sorption increases more than bone formation, lead- 2 to 3 percent after three years30-33 (Table 2). Ral-
ing to bone loss. Hormone-replacement therapy re- oxifene also decreased the incidence of vertebral
verses these changes in women in both the early and fractures by 30 to 50 percent, depending on dosage,
the late phases of the postmenopausal period.21 Al- but did not decrease the incidence of hip fracture or
though it had been demonstrated by many observa- other nonvertebral fractures.32 Although bispho-
tional studies, the Women’s Health Initiative was sphonate (alendronate or risedronate) therapy does
the first large, randomized clinical trial to show that decrease nonvertebral fractures, the decrease in ver-
hormone-replacement therapy reduces osteoporot- tebral fractures of approximately 50 percent is only
ic fractures, including a 34 percent reduction in both slightly greater than with raloxifene therapy,38,39

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The new england journal of medicine

Table 2. Results of Major Randomized Clinical Trials of SERMs with Regard to Bone Mineral Density.

Change in Bone Mineral Density


Trial Study Subjects Duration as Compared with Placebo Group

Total-Body Lumbar Proximal


Bone Mineral Spine Femur
months percent
Tamoxifen (20–30 mg/day)
Love et al.27 140 postmenopausal women with breast cancer 24 — 1.6* —
Grey et al.28 57 normal late-postmenopausal women 24 0.5† 2.1† 0.6
Powles et al.29 179 healthy women in chemoprevention trial for
breast cancer
54 postmenopausal women 36 — 4.7* 3.6†
125 premenopausal women 36 — ¡2.6* ¡4.3†
Raloxifene (60 mg/day)
Delmas et al.30 302 normal postmenopausal women 24 2.0* 2.4* 2.4*
Lufkin et al.31 143 postmenopausal women with osteoporosis 12 ¡0.1 1.8† 1.0†
and vertebral fractures
Ettinger et al.32 5140 postmenopausal women with osteoporosis 36 — 2.6* 2.1*
Johnston et al.33 576 healthy early-postmenopausal women 36 1.7* 2.6* 2.5*

* P<0.05 for the comparison with placebo.


† P<0.005 for the comparison with placebo.

despite the fact that bone density increases to a showed that hormone-replacement therapy was as-
much greater extent (4 to 9 percent more at the same sociated with a 27 percent relative increase in inva-
bone-density scanning sites).40,41 Although the ex- sive breast cancer (38 vs. 30 cases per 10,000 pa-
planation for this paradox is unclear, Riggs and Mel- tient years),19 a statistic similar to the 35 percent
ton42 have suggested that much of the antifracture increase found in a meta-analysis of 51 observa-
effect of antiresorptive drugs such as raloxifene at tional studies.44
cancellous bone sites results from normalization of Tamoxifen has demonstrated efficacy for the
the high level of bone turnover and thus the preven- treatment and prevention of estrogen-receptor–pos-
tion of further microarchitectural disruption. They itive breast cancer. Adjuvant tamoxifen therapy (ad-
have also suggested that it is necessary to reach only ministered after the initial surgery) significantly re-
a low therapeutic threshold to prevent osteoclasts duced the risk of recurrence and death from breast
from perforating the trabecular plates and thus to cancer in all age groups studied.45 In an overview of
reduce fractures at sites of cancellous bone, such as 37,000 women with breast cancer from 55 trials of
the vertebrae. This low threshold can be achieved adjuvant therapy,45 the proportional reduction in re-
with less potent antiresorptive drugs, such as ralox- currence was 47 percent after 5 years of treatment
ifene. However, to reduce fractures at sites of corti- with tamoxifen and the proportional reduction in
cal bone, such as the hip, it is necessary to increase mortality was 26 percent after 10 years. The absolute
bone density more substantially by using potent an- improvements in 10-year survival were 10.9 percent
tiresorptive or formation-stimulating agents. Ta- in node-positive and 5.6 percent in node-negative
ble 2 summarizes the effect of two SERMs on bone breast cancer. Women with estrogen-receptor–neg-
mineral density according to the results of major ative disease had little, if any, benefit.45,46
randomized, controlled trials. Best results appear to be achieved after five years
of treatment; thereafter, beneficial effects decrease
breast and toxicity increases,47-49 although the optimal du-
Estrogen stimulates the proliferation of breast epi- ration of administration is still under investigation.
thelial cells, and both endogenous and exogenous Tamoxifen is mainly cytostatic and slows the prolif-
estrogens have been implicated in the pathogenesis eration of breast-cancer cells by inhibiting their pro-
of breast cancer.43 The Women’s Health Initiative gression from the G1 phase of the cell cycle,48 but it

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drug therapy

also induces apoptosis in vitro and thus may pos- failed to demonstrate that tamoxifen reduced the
sess cytocidal properties in vivo.50 About half of risk of breast cancer (Table 3). The recently report-
women with advanced estrogen-receptor–positive ed International Breast Cancer Intervention Study I
breast cancer will have a response to tamoxifen (IBIS-I) trial showed a 25 percent reduction in inva-
therapy, whereas only 5 percent of those whose sive breast cancer with tamoxifen.54 However, no
cancer is estrogen-receptor–negative will have a trial has shown improvement in survival with ta-
response.48,51 moxifen; in fact, there were slightly more deaths in
The reduction in the risk of contralateral breast the tamoxifen group in the IBIS-I trial owing to an
cancer in adjuvant trials of tamoxifen led to its in- excess of thromboembolic events.54 The recent
clusion in randomized primary-prevention trials. technology assessment by the American Society of
Among the 13,388 participants in the Breast Can- Clinical Oncology concluded that tamoxifen’s fa-
cer Prevention Trial, there was a 49 percent reduc- vorable effect on the risk of breast cancer must be
tion in the risk of invasive breast cancer, but benefit weighed against its potential side effects in individ-
was limited to estrogen-receptor–positive tumors.36 ual women.55
Two smaller primary-prevention trials from the Roy- Toremifene is approved by the Food and Drug
al Marsden Hospital in London52 and from Italy53 Administration for the treatment of advanced breast

Table 3. Results of Major Trials of SERMs for the Primary Prevention of Breast Cancer.*

Royal Marsden
Variable NSABP P-1 Study36 Hospital Trial52 Italian Trial53 IBIS-I54

Primary outcome Breast cancer Breast cancer Breast cancer Breast cancer

Secondary outcome Bone, cardiovascular — Cardiovascular, Thromboembolic, car-


psychometrics diovascular, en-
dometrial cancer
Eligibility Age ≥60 yr, or 35–59 yr Age 30–70 yr with a Age 35–70 yr after Age 35–70 yr with a
with a 5-yr predicted family history hysterectomy family history, lob-
risk of ≥1.66%, ular carcinoma in
lobular carcinoma situ or atypia
in situ

No. of women 13,388 2471 5408 7152


Study drugs Tamoxifen vs. placebo Tamoxifen vs. placebo Tamoxifen vs. placebo Tamoxifen vs. placebo
Age distribution (%)
<50 yr 39 61 38 —†
50–60 yr 31 39 50
>60 yr 30 12
Family history of breast cancer 77 96 18 97
(%)
Mean follow-up (mo) 55 70 46 50

Effect on invasive breast cancer


No. taking placebo in 175 64 Not reported 85
whom breast cancer 89 54 — 64
developed ¡49‡ —§ —§ ¡25¶
No. taking tamoxifen in
whom breast cancer
developed
Relative difference (%)

* IBIS-I denotes International Breast Cancer Intervention Study I, and NSABP National Surgical Adjuvant Breast and Bowel Project.
† The median age in the trial was 51 years.
‡ P<0.001.
§ The difference was not significant.
¶ The confidence interval was 54 to 104.

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cancer. However, in head-to-head randomized tri- breast cancer,65 and phase 2 studies are under way.
als, tamoxifen and toremifene were found to have Several large trials addressing unresolved questions
very similar efficacy and side-effects profiles56,57 regarding the role of SERMs in the prevention and
and exhibited cross-resistance with each other.58 treatment of breast cancer are ongoing (Table 4).
In the Multiple Outcomes of Raloxifene Evalua-
tion (MORE) trial, which was designed to assess genitourinary tract
antifracture efficacy, raloxifene reduced the risk of Estrogen deficiency induces atrophic changes in the
breast cancer by 76 percent.59 Because the MORE genitourinary tract and symptoms of dyspareunia.
trial was conducted in older women with osteoporo- In postmenopausal women with an intact uterus,
sis who were not at increased risk for breast cancer, administration of unopposed estrogen increases
these favorable results cannot necessarily be extrap- the incidence of endometrial carcinoma.66 Com-
olated to younger women who are at high risk for bination treatment with progestin prevents this
breast cancer. This issue should be resolved by the increase,66 but the progestin component of hor-
ongoing Study of Tamoxifen and Raloxifene (STAR) mone-replacement therapy is the main cause of the
trial, which is a head-to-head comparison of the ef- common treatment-related problems of edema and
ficacy of raloxifene and tamoxifen in women at in- premenstrual syndrome–like symptoms. Yet anoth-
creased risk for breast cancer60 (Table 4). A phase 1 er major problem with hormone-replacement ther-
trial with arzoxifene (LY353381.HCl), a new third- apy is breakthrough and withdrawal vaginal bleed-
generation SERM, demonstrated stable disease in ing. The use of raloxifene obviates both problems,
6 of 32 tamoxifen-resistant patients with metastatic because it does not stimulate the endometrium and
does not require progestin treatment. Over a period
of three years, endometrial thickness as assessed by
ultrasonography and vaginal bleeding were similar
Table 4. Major Large-Scale Trials Involving SERMs.
in raloxifene-treated subjects and those given pla-
ATLAS (Adjuvant Tamoxifen Longer against Shorter) trial61* cebo.59 Moreover, hormone-replacement therapy,
Assessment of optimal duration of tamoxifen adjuvant therapy but not raloxifene or tamoxifen therapy, significant-
Accrual goal is 20,000 pre- and postmenopausal patients with breast cancer ly increases urinary incontinence.67 However, like
who are receiving adjuvant tamoxifen
Therapy: tamoxifen for 5 yr vs. 10 yr (or longer) estrogen, but unlike raloxifene, tamoxifen is asso-
ciated with a 2.5-fold increase in endometrial carci-
ATTOM (Adjuvant Tamoxifen Treatment Offers More) trial62*
Assessment of optimal duration of tamoxifen adjuvant therapy noma,36 so vaginal bleeding in women receiving ta-
Accrual goal is 8000–20,000 pre- and postmenopausal patients with breast moxifen should be promptly investigated.
cancer who are receiving adjuvant tamoxifen
Therapy: tamoxifen for 2 yr (group 1) vs. 7 yr (group 2)
cardiovascular system
IBIS2 (International Breast Cancer Intervention Study2)63* Coronary artery disease accounts for one third of all
Primary prevention of breast cancer
Accrual goal is 16,000 women at high risk for breast cancer (age, 35–70 yr) deaths in postmenopausal women.68 Both estrogen
Therapy: anastrozole vs. placebo and SERM therapy induce a beneficial serum lipid
STAR (Study of Tamoxifen and Raloxifene)60 profile, although the patterns of these changes dif-
Primary prevention of breast cancer fer (Table 5). The main serum lipid changes with
Accrual goal is 22,000 postmenopausal women at high risk for breast cancer oral estrogen are increases in high-density lipopro-
Therapy: 20 mg tamoxifen per day vs. 60 mg of raloxifene per day for 5 yr
tein (HDL) cholesterol and triglycerides and de-
CORE (Continuing Outcomes Relevant to Evista) creases in low-density lipoprotein (LDL) choles-
4000 postmenopausal women who were previous participants in the MORE
(Multiple Outcomes of Raloxifene Evaluation) trial terol. Tamoxifen, toremifene, and raloxifene also
Receiving raloxifene or placebo for an additional 4 yr, completion by 2003 decrease LDL cholesterol but, unlike estrogen, do
Primary end point is breast-cancer prevention; secondary end points are non- not increase triglycerides. Toremifene, unlike oth-
vertebral fractures and uterine safety
er SERMs, increases HDL cholesterol.71 Treatment
RUTH (Raloxifene Use in the Heart)64† with estrogen or SERMs changes the blood-coagu-
Effect of raloxifene vs. that of placebo in prevention of coronary events and
death from coronary causes lation indexes in the direction of enhanced clotting,
10,000 postmenopausal women at risk for coronary disease and estrogen, but not raloxifene, increases indexes
Duration of 7.5 yr, completion by 2005 of inflammation (Table 5). Also, estrogen, but not
raloxifene, retarded experimentally induced athero-
* The trial is not open in the United States.
† The trial has been completed, and the data are under analysis. sclerosis in a monkey model,74 whereas raloxifene
was 75 percent as effective as estrogen in a rabbit

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model.75 Moreover, in ovariectomized rats, ralox-


ifene was as effective as estrogen in enhancing nitric Table 5. Comparative Effects of Oral Hormone-Replacement Therapy and
SERMs on Serum Lipids, Indexes of Inflammation, and Blood Coagulation.*
oxide–induced coronary-artery dilatation76 and in
retarding injury-induced intimal thickening of the Hormone-
carotid artery.77 Replacement
Variable Therapy Tamoxifene Toremifene Raloxifene
Observational studies have found that women
receiving hormone-replacement therapy have a 30 percent difference from change with placebo
to 35 percent lower risk of coronary disease.78 Thus, Low-density lipoprotein ¡12† ¡19† ¡21† ¡12†
the reports of two randomized clinical trials of hor- cholesterol
mone-replacement therapy that failed to show ben- High-density lipoprotein 7† ¡2 14† 0
efit in postmenopausal women with established cholesterol
coronary artery disease79,80 were unexpected, al- Triglycerides 18† 31† ¡4 ¡4
though another trial demonstrated that estrogen
Apolipoprotein A-I 13† 5 13† 3
therapy retarded the development of subclinical
atherosclerosis.81 However, the results of the Wom- Apolipoprotein B ¡4 ¡9† ¡10† ¡9†
en’s Health Initiative in postmenopausal women, Lp(a) lipoprotein ¡19† ¡14† ¡53† ¡7†
the large majority of whom were not at high risk for Fibrinogen ¡1 — — ¡10†
coronary heart disease, are of particular concern:
Plasminogen activator ¡19† — — 8
participants had a 23 percent increase in cardiovas- inhibitor type 1
cular disease (37 vs. 30 cases per 10,000 person-
Homocysteine ¡7† — — ¡8†
years) and a 38 percent increase in strokes (29 vs.
21 cases per 10,000 person-years).19 Thus, there is C-reactive protein 84† — — ¡7
no current justification for the use of hormone- Tumor necrosis factor a ¡11† — — ¡5†
replacement therapy to prevent or treat cardiovas- Interleukin-6 11 — — 1
cular disease.
How to reconcile these findings with previous * Data are from the Postmenopausal Estrogen/Progestin Interventions Trial Writing
data showing benefit is unclear. One possible in- Group,20 Love et al.,69 Walsh et al.,70 Saarto et al.,71 Walsh et al.,72 and Cox et al.73
terpretation is that cardiovascular outcomes asso- † P<0.05 for the comparison with placebo.

ciated with hormone-replacement therapy represent


the algebraic summation of its prothrombotic or
proinflammatory effects and its antiatherosclerotic of 1.5 to 3 in venous thromboembolic disease, al-
effects and that the balance between them will be though the absolute risk is small.84
determined by such variables as oral as compared
with transdermal administration, the types and dos- central nervous system
ages of estrogens and progestins, the age at onset of Estrogen has diverse effects on brain function.85 Es-
therapy, and other factors. Consistent with this trogen receptor a is found mainly in the hypothala-
speculation is the recent report that raloxifene de- mus. Estrogen receptor b is more widely distributed
creased cardiovascular events by 40 percent in the throughout the brain4,22 and is concentrated at loci
1035 women in the MORE trial who had cardiovas- involved in cognition and memory. Many studies
cular risk factors at base line.82 A prospective study have shown that estrogen treatment enhances both
of 27,939 healthy U.S. women found that the serum of these functions.85 However, data from objective
level of C-reactive protein was a stronger predictor testing carried out during the Heart and Estrogen/
of cardiovascular events than the LDL cholesterol Progestin Replacement Study (HERS)86 failed to
level.83 Hormone-replacement therapy increases show that hormone-replacement therapy increased
C-reactive protein levels, whereas raloxifene does energy levels or improved mental health and depres-
not (Table 5). The large, yet to be reported, random- sive symptoms any more than placebo. A recent
ized trial of Raloxifene Use in the Heart (RUTH)64 is 3-year prospective observational study in elderly
specifically powered to determine whether ralox- women in Cache County, Utah, found that estrogen
ifene is cardioprotective for postmenopausal wom- use for 10 or more years reduced the risk of Alzhei-
en at risk for coronary artery disease (Table 4). mer’s disease by 67 percent.87 However, this protec-
Estrogen,19,78,84 tamoxifen,36 and raloxifene32 tion has not as yet been demonstrated in random-
therapy are associated with increases by a factor ized clinical trials.88 No studies of the effect of

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SERMs in reducing the risk of Alzheimer’s disease units of vitamin D daily is advisable. Tamoxifen and
have been undertaken. toremifene are not indicated for the treatment of
Although estrogen is highly effective in reducing osteoporosis.
hot flashes, all SERMs studied thus far act as anti- There are now several effective treatment options
estrogens for the hypothalamic centers regulating for osteoporosis, including the bisphosphonates,
gonadotrophin secretion. During the early post- nasal-spray calcitonin, and raloxifene.91 Estrogen is
menopausal period, tamoxifen increased the inci- also effective, although its risk–benefit ratio must
dence of hot flashes by 17 percent as compared with now be reevaluated.19 Treatment should be tailored
placebo,37 and raloxifene increased them by 7 per- to the individual patient. Because raloxifene, like
cent.33 This is less of a problem in women who nasal-spray calcitonin, is a less potent antiresorp-
are in the late postmenopausal period; hot flashes tive drug than alendronate, risedronate, or estro-
caused only 0.7 percent of the patients to discon- gen,19,37,38,41,91 it is best suited for the prevention
tinue therapy.32 In studies in ovariectomized rats, of bone loss or the treatment of mild osteoporosis.
raloxifene was able to reproduce the ability of es- Because clinical trials have demonstrated that ral-
trogen to restore the reduction in choline acetyl- oxifene decreases the risk of vertebral fracture but
transferase activity in the hippocampus but not in have failed to demonstrate that it decreases the risk
the hypothalamus.89 It is important to note, howev- of extravertebral fracture, it should be used mainly in
er, that raloxifene treatment does not impair cogni- postmenopausal women with predominantly spinal
tion in postmenopausal women.90 osteoporosis.

treatment and prevention of breast cancer


therapeutic uses
The treatment of breast cancer is complex and in-
general volves surgery, radiation, chemotherapy, and hor-
Because of their selective estrogen-agonist proper- monal therapy, used singly or in combination, de-
ties, SERMs can be used to prevent or treat diseases pending on the stage and estrogen-receptor status
caused by estrogen deficiency, such as osteoporosis, of the disease in the individual patient.53 Tamoxi-
without most of the undesirable actions of estro- fen remains a mainstay of the hormonal treatment
gen. Conversely, because of their selective estrogen- of all phases of estrogen-receptor–positive breast
antagonist properties, they can be used to prevent or cancer. The aromatase inhibitors, which block es-
treat diseases, such as breast cancer, in which estro- trogen synthesis, are an alternative to tamoxifen for
gen-agonist activity is undesirable for a given tissue. hormonal therapy and, unlike tamoxifen, are not as-
Currently available SERMs have two major limita- sociated with an increased risk of thromboembolic
tions: they are only weak estrogen agonists and they complications or endometrial cancer.92-95 Howev-
aggravate hot flashes, the most common indication er, in postmenopausal women, aromatase inhibi-
for estrogen therapy. Because tamoxifen stimulates tors elevate the rate of bone turnover96 and increase
the endometrium, raloxifene is the preferred SERM the risk of fracture.95 In postmenopausal women
for uses other than the prevention or treatment of with advanced estrogen-responsive breast cancer,
breast cancer. The Food and Drug Administration tamoxifen and aromatase inhibitors have similar
has approved three SERMs for clinical use: tamoxi- antitumor efficacy.92-94
fen for the prevention and treatment of breast can- For adjuvant therapy in postmenopausal women,
cer, toremifene for the treatment of advanced breast however, the recently published results of the Arim-
cancer, and raloxifene for the prevention and treat- idex, Tamoxifen Alone or in Combination (ATAC)
ment of postmenopausal osteoporosis. trial found that the aromatase inhibitor anastrozole
alone was equivalent or superior to both tamoxifen
prevention and treatment of osteoporosis and a combination of anastrozole and tamoxifen
Raloxifene at a dose of 60 mg per day is effective in with regard to various response indexes when stud-
preventing and treating postmenopausal osteoporo- ied over a period of 33 months.95 Nonetheless,
sis. It has a very low incidence of side effects, may pending further studies, the American Society of
protect against the development of breast cancer, Clinical Oncology Technology Assessment state-
and retains at least some of the putative extraskele- ment continues to recommend tamoxifen as the
tal benefits of estrogen. As with other medications preferred hormonal adjuvant therapy for estrogen-
used as antiresorptive therapy, combined treatment receptor–positive breast cancer.97 Also, because
with 1000 mg or more of elemental calcium and 400 there is insufficient information on safety and effi-

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Copyright © 2003 Massachusetts Medical Society. All rights reserved.
drug therapy

cacy, aromatase inhibitors are not recommended tional drug design will replace the current empiri-
for premenopausal women with breast cancer. cal method for the discovery of new SERMs. It is
Tamoxifen is the only approved hormonal agent probable that the ultimate goal of SERM research
for primary prevention of breast cancer. Debate con- will be achieved — the discovery of a tissue-selective
tinues about who should receive it for this indica- drug that has all the beneficial effects of estrogen,
tion, although reasonable candidates include wom- has none of its adverse effects, and offers protection
en with a strong family history of breast cancer and against breast cancer. Development of a SERM with
those with atypical hyperplasia or lobular carcinoma superagonist protective actions on the cardiovascu-
in situ. Women with mutant BRCA1 or BRCA2 genes lar and skeletal systems may also become feasible.
are also potential candidates, especially since pro- Finally, recent studies suggest the even more excit-
phylactic ovariectomy has recently been shown to ing possibility that the plasticity of estrogen action
reduce their risk of breast cancer by about 50 per- exhibited by SERMs will be found to be a general
cent.98,99 However, because 80 percent of the breast feature of the steroid nuclear-receptor family of
cancers that develop in carriers of BRCA1 mutations molecules. If so, corticosteroids may soon become
are estrogen-receptor–negative, the efficacy of ta- available that suppress immune function without
moxifen in this group has been questioned.100 causing bone loss, as may androgens that are ana-
Although the substantial reduction in the risk of bolic without producing masculinizing effects or
breast cancer in postmenopausal women reported adverse lipid patterns, progestins that can induce
from the MORE trial was encouraging, the use of endometrial atrophy without producing fluid reten-
raloxifene in primary prevention should await the tion, and vitamin D analogues that increase bone
results of the STAR trial.60 A cautionary note on the density without inducing hypercalcemia or hyper-
use of tamoxifen for prevention in premenopausal calciuria. Should these events come to pass, the ini-
women is that it acts as a bone antagonist that re- tial observation that tamoxifen has tissue-specific
sults in bone loss in this age group29 (Table 2). The effects will have proved to be the golden thread of
presumed mechanism is competition with the more Ariadne. It will have led to the development of re-
potent bone agonist 17b-estradiol for the estrogen markable new drugs that will selectively express the
receptor. desirable actions and selectively suppress the un-
desirable actions of the various steroid hormones.
Supported by grants (AR27065, AG04775, CA80181, and
future directions CA15083) from the National Institutes of Health and by the Komen
Foundation.
As the molecular mechanisms of the action of We are indebted to Dr. Donald P. McDonnell for his assistance
SERMs become more completely understood, ra- with the section on the molecular actions of SERMs and Figure 2.

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New England Journal of Medicine

CORRECTION

Selective Estrogen-Receptor Modulators —


Mechanisms of Action and Application to Clinical
Practice

Selective Estrogen-Receptor Modulators — Mechanisms of Action


and Application to Clinical Practice . There was an error in Figure
2; a corrected figure is shown here.

Figure 2. Estrogen-Receptor Action.

Each class of SERMs (orange symbols) has a slightly different shape,


although all will bind to the estrogen receptor. When it binds to an
estrogen, antiestrogen, or SERM, the estrogen receptor undergoes a
conformational change that permits its spontaneous dimerization and
facilitates the subsequent interaction of the dimer with estrogen re-
sponse elements (EREs) located within target genes. The estrogen-
receptor–ligand complex also leads to binding of various coregulator
proteins that vary with its conformational structure. Some estrogen-
receptor–SERM complexes favor corepressor recruitment (red) that,
in a given target cell, increases its antagonist activity, and others fa-
vor coactivator recruitment (blue) that increases its agonist activity.
Some SERMs may also facilitate the interaction of the estrogen recep-
tor with yet-to-be-identified coactivators (green) with which estrogens
or antiestrogens would not normally couple. It has now been deter-
mined that estrogen facilitates the interaction of the estrogen receptor
with coactivators. The antagonist-activated estrogen receptor, on the
other hand, interacts preferentially with corepressors. The binding of
different SERMs to the receptor permits the receptor to adopt con-
formational states that are different from each other and also distinct
from that induced by classic estrogen agonists or antagonists.The im-
plication of this model is that SERM activity will be influenced by the
relative levels of expression of the coregulator proteins (corepressors
and coactivators) that are expressed in different target cells.

N Engl J Med 2003;348:1192-a

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