Endocrine Reviews 20 (3): 418-434
Copyright © 1999 by The Endocrine Society
Selective Estrogen Receptor Modulators: Clinical Spectrum1
Felicia Cosman and
Robert Lindsay
Clinical Research and Regional Bone Centers, Helen Hayes Hospital,
New York State Department of Health, West Haverstraw, New York
10993
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Abstract
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- I. Introduction
- II. Breast Effects
- A. Women with primary breast cancer without metastases
- B. Women with metastatic disease
- C. Breast cancer prevention
- III. Reproductive System Effects
- A. Ovary
- B. Uterus
- C. Vagina
- D. Neuroendocrine
- IV. Skeletal Effects: Bone Mass, Bone Metabolism, and Fracture Occurrence
- A. Tamoxifen
- B. Raloxifene
- V. Vascular System Effects: Intermediate Markers and Disease Outcomes
- A. Intermediate markers
- B. Vascular disease outcomes
- VI. Central Nervous System Effects
- A. Cognitive function and mood
- B. Eye disease
- VII. Hepatic Effects
- VIII. Miscellaneous Effects
- IX. Conclusion
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I. Introduction
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ESTROGEN is the most frequently prescribed medication in
the United States and the most effective treatment for menopausal
symptoms such as hot flashes and urogenital atrophy (1, 2). Estrogen is
also a standard choice for the prevention and management of
osteoporosis and is approved by the Food and Drug Administration (FDA)
for these purposes (3, 4, 5). Estrogens exert multisystemic effects,
including a possible reduction in atherosclerotic disease through
beneficial effects on blood lipids, and direct effects on the
endothelial tissue of the arterial wall (6). Some evidence is beginning
to accumulate to suggest that estrogens exert positive effects on the
central nervous system, possibly reducing the incidence and severity of
Alzheimers type dementia and maintaining normal cognitive function in
healthy postmenopausal women (7, 8), although, in these areas, the
studies are not all consistently positive (9, 10).
The majority of data concerning long-term outcomes of exogenous
estrogen administration are based on epidemiological observations where
estrogen users are compared with nonusers either in prospective cohorts
or in retrospective case/control studies. Not all confounders can be
identified and controlled for in studies of this design. The recent
publication of results from the Heart and Estrogen/Progestin
Replacement Study [HERS (11)], a controlled clinical trial of
continuous combined hormone replacement therapy (HRT) in patients with
established heart disease, showing an increase in cardiovascular events
in the first year and only a modest effect on cardiovascular outcomes
thereafter, highlights the difficulty in drawing conclusions from
epidemiological data (12, 13). The results of this major clinical trial
also questioned whether symptomatic fracture occurrence is reduced with
estrogen use, but this study was designed and powered to examine
cardiac end points, not fracture end points. Furthermore, spinal
deformity was not assessed radiographically.
Even if the majority of the benefits documented by observational
data concerning estrogen replacement therapy or HRT are true, several
meta-analyses have also shown an increase in the risk of breast cancer,
particularly after long-term estrogen treatment (14, 15). Therefore,
the use of estrogens is often restricted to a small group of women and
is often used for insufficient time to provide significant positive
effects on chronic disease outcomes. Long-term compliance is often
estimated to be no more than 1540% (16). The fear of breast cancer
is so profound that many women mistakenly view it as the most common
cause of death among women (17). In addition, the stimulatory action of
estrogen on the uterine endometrium, although easily controlled with
progestins, also remains an issue, since for many regimens, regular
vaginal bleeding is necessary to protect the endometrium. Furthermore,
the risk of uterine cancer may be increased with some hormone
replacement regimens even when progestins are given (18, 19). The
increased risk of deep venous thrombosis (11, 20, 21, 22), breast
tenderness, and engorgement, increased risk of gallbladder disease, as
well as the perception that hormone replacement is associated with
weight gain, are other reasons that limit long-term use of this
therapy.
Agents that can maintain the benefits of estrogens but avoid the risks
are therefore needed to provide additional choices for women who are at
increased risk of diseases associated with chronic estrogen deficiency
or those who are interested in using medication for overall health
maintenance after menopause. Medications in the class now called
Selective Estrogen Receptor Modulators (SERMS) or estrogen analogs,
previously called antiestrogens (Fig. 1
), hold thispromise. A large body of
research in animal models beginning in the l960s suggested that these
compounds could have partial estrogenic activity in some tissues while
inhibiting mammary tumor growth. The historical perspective and the
interplay between animal experiments and clinical investigation are
reviewed by Jordan and Morrow in an accompanying article in this
journal. Some of these agents act as antagonists in human reproductive
tissues, but partial agonists on the skeletal system and on serum
lipoproteins. They might, therefore, be alternatives for prevention of
osteoporosis, particularly in women with an increased risk of breast or
uterine cancer, or in those women who are not willing to take estrogen
because of the fear of breast or uterine cancer. Each agent has its own
unique spectrum of activities, with qualitative and quantitative
variability in its agonist and antagonist properties at different
target tissues. A discussion of the mechanisms of variable actions of
these estrogen analogs is beyond the scope of this review but clearly,
mechanisms involve differential binding to different estrogen receptor
subtypes, different conformations produced with each agent when bound
to the estrogen receptor, availability of different coactivator and
corepressor proteins in different tissues, as well as differential
binding of these proteins to different estrogen analog-receptor
complexes.
This article will review studies involving the estrogen analogs in
clinical trials. The majority of discussion will concentrate on
tamoxifen (a triphenylethylene) and raloxifene (a benzothiophene), the
two agents that have broadest utility for health maintenance in women.
Toremifene (a chlorinated derivative of tamoxifen) has similar effects
on uterine tissue as tamoxifen, and similar effects on breast cancer.
It has recently been approved for treatment of breast cancer. Tamoxifen
was recently approved by the USFDA for prevention of breast cancer in
high-risk premenopausal and postmenopausal women, and raloxifene was
approved in December of 1997 for prevention of osteoporosis.
Clomiphene, a triphenylethylene derivative, is currently used for
fertility induction.
Other estrogen analogs are also in clinical development. One
triphenylethylene tamoxifen derivative, droloxifene, is in Phase III
trial for osteoporosis prevention and treatment. Both idoxifene and
levormeloxifene were in clinical development for osteoporosis, but
programs were aborted, apparently because of adverse uterine effects.
Two agents that were previously thought to be purely antiestrogenic,
ICI 164,384 and 182,780, are analogs of 17ß-estradiol with a long
alkylamine side chain, which are being tested for breast cancer
treatment potential. Recent studies indicate that both of these agents
have some tissue-selective estrogenic activity, on nonreproductive
estrogen target tissues.
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II. Breast Effects
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Effects of estrogen analogs on breast tissue, particularly breast
cancer, have largely driven the development of these compounds,
particularly that of tamoxifen. Clomiphene also has some activity
against advanced breast cancer (23, 24), but studies of its efficacy
were stopped due to the earlier emergence of tamoxifen for this
indication, the higher toxicity associated with chronic clomiphene use,
and the less robust effect seen with this compound vs.
tamoxifen (25).
Tamoxifen has been shown conclusively in an abundance of clinical
trials to decrease the risk of recurrent breast cancer, contralateral
breast cancer, and death, and increase disease-free survival in
patients with breast cancer at multiple stages of the disease (26, 27, 28, 29),
including small primary, node-negative disease as well as metastatic
disease.
A. Women with primary breast cancer without metastases
Overall, of more than 37,000 women with operable breast cancer in
55 randomized clinical trials of adjuvant tamoxifen therapy, after 10
yr of follow-up, annual breast cancer recurrence
was reduced by 26% and death by 14%
(27, 28). Recurrence and mortality data are shown separately for
node-negative and node-positive disease in Fig. 2
. The benefit of
tamoxifen is greatest when administered for 5 yr, rather than for a
shorter duration (27, 28, 29); however, treatment for longer than 5 yr does
not appear to be more effective than 5 (30, 31).

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Figure 2. No recurrence and survival rates for
tamoxifen-treated vs. control groups from the Early
Breast Cancer Trialist Collaborative Overview. [Adapted with
permission from Lancet 351:14511467, 1998 (27 ). © The
Lancet Ltd.]
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Tamoxifen has the greatest benefit in those patients with estrogen
receptor (ER)-positive breast tumors (28). Among women with ER-positive
breast tumors treated for 5 yr, tamoxifen reduced recurrence rate
annually by 50% and death rate annually by 28% (27). Whether
tamoxifen has any benefit on ER-negative tumors is controversial, with
an early meta-analysis suggesting it did (26), but a later
meta-analysis suggesting it did not (27). The fact that low
concentrations of ER on breast tumor specimens are sometimes
misclassified as ER-negative, in some laboratories, might account for
the finding that tamoxifen appears beneficial even in ER-negative cases
(28). The benefits are clearly greatest in those with a high
concentration of ER positivity (28).
The benefits of tamoxifen on breast cancer occur in both premenopausal
and postmenopausal women at all ages (27). Furthermore, when treating
women with ER-positive tumors, the combination of tamoxifen with
standard cytotoxic chemotherapy shows an advantage over cytotoxic
chemotherapy alone in all age groups (27). What is somewhat less clear
is whether combining standard chemotherapy with tamoxifen should be
routinely recommended (26, 32, 33, 34, 35, 36, 37, 38, 39, 40). In general, it seems that for
postmenopausal women with high-risk breast cancer, combination
chemotherapy plus tamoxifen is warranted.
B. Women with metastatic disease
Tamoxifen is also beneficial to women with metastatic disease.
Overall, 30% of women with metastatic breast cancer responded to
tamoxifen for an average of 1 yr and, in an additional 20%, the
disease did not progress for 6 months. ER status is an important
prognostic indicator, and menopausal status may vary responsivity as
well, with postmenopausal women showing greater response rates than
premenopausal women (28, 41, 42, 43, 44).
Toremifene has also been shown to be effective in the treatment of
advanced breast cancer, with overall treatment responses, including
complete or partial remissions of 4863% (45, 46, 47). Higher doses of
toremifene appear more effective than lower doses (48). In a relatively
large international trial of 648 women with metastatic breast cancer
(previously untreated) randomly assigned to one of two toremifene doses
vs. tamoxifen, there were no statistically significant
differences in response rates or response durations among any of the
treatment arms (49). Tamoxifen response rate was 19%, with median
survival 32 months. Toremifene, 60 mg, resulted in a response rate of
21% with median survival 38 months. Toremifene, 200 mg, resulted in a
23% response rate with median survival of 30 months. All end points
were superior in those patients with ER-positive tumors. These data
support the use of toremifene as an alternative to tamoxifen for
metastatic breast cancer.
Droloxifene has also been used in several small trials of women with
metastatic breast cancer with variable success (50, 51, 52, 53, 54). The largest is
a series of 369 women where three doses of droloxifene were compared
(53). Response rates varied from 3047%, without a clear
dose-response relationship. Raloxifene, originally called Keoxifene,
was also studied as an anti-breast cancer agent (54A ), but development
for this indication was dropped when no superior effect of keoxifene
over tamoxifen was found in tamoxifen-resistant breast cancer patients.
C. Breast cancer prevention
Because of the substantial effect of tamoxifen to reduce the
risk of contralateral breast cancer in women with primary breast cancer
(27, 28), investigations were initiated almost 10 yr ago to determine
whether tamoxifen could reduce the risk of breast cancer occurrence in
women at high risk. The largest of the three studies was the National
Cancer Institute (NCI) Breast Cancer Prevention Trial or National
Surgical Adjuvant Breast and Bowel (NSABP) P-1 Study (55). High risk
was considered age 60 or older (without additional risk factors),
between age 3559 with a 5-yr predicted risk for breast cancer of at
least 1.66% [based on the Gail model for breast cancer risk (56)] or
a history of lobular carcinoma in situ. Of the 13,388 women
entered into the trial, approximately 40% were premenopausal and 96%
were Caucasian. Because of a dramatic overall breast cancer incidence
reduction of approximately 50%, the NCI Breast Cancer Prevention Trial
was terminated early, at just under 4 yr instead of the planned 5 yr
(55). The breast cancer reduction was for both invasive and noninvasive
types (Table 1
) and occurred in both
premenopausal and postmenopausal women. For invasive breast cancer,
risk reduction was 44% in women under 49 yr of age and 55% for those
60 yr of age or older. For noninvasive breast cancer, reduction in
incidence was approximately 49% in the tamoxifen-treated group.
Reduction in breast cancer incidence was limited to those with
ER-positive tumors (see Section II). The annual rate
of ER-positive breast cancers was reduced by 69% in tamoxifen-treated
women, whereas there was no difference in the rate of appearance of
ER-negative tumors.
Two other studies, one in England and one in Italy, investigating
tamoxifen for breast cancer prevention have shown very dissimilar
results from the Breast Cancer Prevention Trial (57, 58). The English
study (57), initiated in 1993, recruited 2,494 high-risk premenopausal
and postmenopausal women, with high risk defined as at least one
first-degree relative with breast cancer. Follow-up occurred for a
median of 70 months. Use of HRT was allowed and occurred in 650 women
over the course of the study (equally distributed across tamoxifen and
placebo arms of the study). In the Italian study (58), 5,408 women, who
were not at particularly high risk of breast cancer, but who had a
hysterectomy for nonmalignant disease, were recruited and followed for
a median of 46 months. This study had a larger drop-out rate than the
other two (
26%). In contrast to the NCI investigation, in neither
of these studies was an overall difference in breast cancer incidence
found between the tamoxifen and placebo groups (57, 58). Differences
between the NCI study and the other studies may be related to
differences in the populations, including age (more younger women in
the British study) and genetic factors (more with positive family
history in British study), compliance, length of follow-up period, and
study power (57, 58, 59). Another breast cancer prevention trial, the
International Breast Cancer Intervention Trial, might help resolve some
of these issues (59).
Raloxifene has been used in healthy women to test for efficacy in
osteoporosis prevention and in women with osteoporosis to test for
prevention of fracture. Although the main outcomes of these trials were
maintenance of bone mass and osteoporotic fracture occurrence, breast
cancer and uterine cancer were monitored for safety. The largest study
is the MORE trial (Multiple Outcomes of Raloxifene Evaluation),
involving 7,704 postmenopausal women up to age 80, mean age 66.5 yr,
with osteoporosis defined by prevalent vertebral deformity and/or bone
mass in the osteoporotic range at the spine or hip. Volunteers were
randomly assigned to placebo or one of two doses of raloxifene. After
28.9 months median follow-up, overall breast cancer risk was reduced by
74%, with no significant difference between results from the two doses
of raloxifene (60). If one looks at integrated risk of breast cancer
from all of the raloxifene osteoporosis studies (prevention and
treatment), which includes 14,800 patient-years cumulative exposure to
raloxifene and 6,750 patient-years exposure to placebo, relative risk
of breast cancer is reduced by 58% in raloxifene-treated volunteers
(61). These studies suggest a preliminary conclusion that raloxifene
produces a profound reduction in the risk of development of breast
cancer in postmenopausal women who were not selected for high risk of
this disease. Further confirmatory data are expected as safety
monitoring from these osteoporosis studies continues. Furthermore, a
large prevention study (STAR, Study of Tamoxifen and Raloxifene) in
22,000 postmenopausal women, comparing the effects of tamoxifen
vs. raloxifene on prevention of breast cancer, has now been
started. This study will confirm the efficacy of both drugs (using
expected frequency of breast cancer from the literature, but no actual
control group) and provide relative potency data in prevention of
breast cancer, while also providing information on relative toxicities.
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III. Reproductive System Effects
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A. Ovary
Several cohort investigations suggest that cyclical use of
clomiphene for infertility might increase the risk of ovarian cancer
(62, 63, 64, 65). Tamoxifen also increases the frequency of ovarian cysts
(66, 67), but there is no evidence that ovarian cancer incidence is
increased with tamoxifen use (55, 68, 69, 70, 71).
Rats treated with very high doses of raloxifene over 2 yr exhibited an
increased incidence of benign ovarian tumors of the granulosa/theca
cell type, but no increase in incidence of any ovarian cancer (72). In
mice also, increased frequency of benign ovarian tumors was seen after
21 months of exposure to raloxifene. At the highest doses, malignant
ovarian tumors were also seen in mice, but these were of the
granulosa/theca cell type, not of epithelial origin (73, 74). Similar
ovarian tumors in mice have been associated with the administration of
both tamoxifen and toremifene (75, 76). These mouse malignancies were
associated with substantial increments in LH, a hormonal change known
to produce these tumors in the mouse. This LH surge does not occur in
humans (see Section III.D below) and the mouse tumor cell
type is extremely rare in humans. Furthermore, in women, there has been
no increase in ovarian cancer frequency or in benign ovarian disease
associated with use of raloxifene (77).
B. Uterus
Tamoxifen increases the risk of benign uterine disease, including
fibroid tumors, adenomyosis, and endometrial hyperplasia, as well as
uterine cancer (55, 66, 67, 68, 69, 70, 71, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88). In the breast cancer treatment
trial NSABP B-14 (68), tamoxifen increased the relative risk of
endometrial cancer up to 7.5. Importantly, however, there were no data
in this study to indicate that uterine tumors in women receiving
tamoxifen were of a higher malignancy grade than those in women
receiving no medication or on estrogen replacement therapy. In the
British breast cancer prevention study, a subgroup of the original
cohort of women (n = 111) was investigated for effects on the
uterus (83). Women receiving tamoxifen had a larger uterus and greater
uterine blood flow than those on placebo. Thirty-nine percent of women
on tamoxifen had tissue evidence of abnormal endometrium compared with
10% in the placebo group. In the tamoxifen-treated group, 16% of
women had atypical hyperplasia and an additional 8% had an endometrial
polyp. In the NCI Breast Cancer Prevention Study (55),
tamoxifen-treated women had a 2.53 times greater risk of developing
invasive endometrial cancer than placebo-treated women. In women aged
50 or older, the relative risk was higher at 4.01 (95% CI,
1.710.90). All endometrial tumors that developed in this study were
Stage I, localized tumors. Thus, as also shown in the NSABP B-14
treatment trial, there was no evidence to suggest that uterine tumors
were of higher malignancy grade or aggressiveness than tumors
associated with estrogen or no hormonal therapy (55). Studies suggest
that toremifene has stimulatory effects on the uterus similar to those
of tamoxifen (89).
One of the major distinctions between tamoxifen and raloxifene is the
effect on the uterus. Unlike tamoxifen, raloxifene does not appear to
stimulate uterine tissue (77, 90). There have been no reports of any
increase in uterine or vaginal bleeding associated with raloxifene use
(90). In a short-term (8 week) study, no change in endometrial tissue
assessed by endometrial biopsies before and after treatment with
raloxifene was documented (91). Furthermore, approximately 400 women
had serial transvaginal ultrasonography over 2 yr in the multicenter
European osteoporosis prevention study (90). There was no significant
difference in endometrial thickness at any time during the study
between raloxifene and placebo-treated patients. More importantly,
preliminary analyses from the MORE study of raloxifene use in
postmenopausal women with osteoporosis suggest that raloxifene might be
associated with an actual reduction in the risk of uterine cancer (60).
Relative risk of endometrial cancer in a 2-yr analysis of 7,704 women
was 0.38 (P = 0.2). If two cases of endometrial cancer
that were diagnosed within 1 month of entry into the investigation were
excluded, relative risk was decreased to 0.13, P =
0.045.
Recently, clinical trials involving both levormeloxifene and idoxifene
were discontinued due to effects on the uterus, particularly uterine
prolapse.
C. Vagina
In the NCI Breast Cancer Prevention Trial (55), tamoxifen was
associated with an increase in the development of vaginal discharge
that was moderately bothersome (or worse) in 29% of the tamoxifen
group, in contrast to only 13% in the placebo group. In a small study
of postmenopausal women with breast cancer on tamoxifen compared with
healthy postmenopausal controls, vaginal pH was closer to premenopausal
levels in tamoxifen-treated women, and vaginal smears were well
estrogenized in most of the tamoxifen-treated women while all of the
controls showed atrophic changes (92).
Raloxifene was not associated with any vaginal complaints related to
atrophic vaginitis or dyspareunia in a study of 619 postmenopausal
women over a 3-yr period (93). In premenopausal women, however,
raloxifene produced a reduction in the vaginal maturation index,
suggesting a mild estrogen antagonist effect (94).
D. Neuroendocrine
Although clomiphene is effective at reducing fertility in rodents,
it actually increases fertility in humans and is currently used most
frequently as an ovulation inducer in women trying to conceive. This
fertility-enhancing effect appears to be mediated by
estrogen-antagonist effects on the neuroendocrine axis with a
subsequent stimulation of gonadotropin secretion (95). Tamoxifen was
first studied in rodent models as a possible postcoital contraceptive,
like clomiphene, but in women, was later found to induce ovulation.
Similarly to clomiphene, this agent exerts estrogen-antagonist effects
on the neuroendocrine axis in premenopausal women, and thereby boosts
gonadotropin production (96, 97, 98). In contrast, in postmenopausal women,
tamoxifen suppresses gonadotropin levels (96, 97, 99, 100, 101, 102, 103, 104, 105). Toremifene
also suppresses gonadotropin levels and increases sex hormone-binding
globulin levels slightly (106).
In both premenopausal and postmenopausal women, however, tamoxifen
increases hot flashes (30, 107, 108, 109, 110, 111, 112). In the Breast Cancer Prevention
Trial (55), hot flashes that were "quite a bit or extremely
bothersome" occurred in 46% of women in the tamoxifen group and 29%
of the placebo group. Similarly to tamoxifen, raloxifene increases the
incidence of hot flashes (77, 90, 91). Of 1,165 postmenopausal women
enrolled in osteoporosis prevention trials, 24.6% in the raloxifene
group complained of hot flashes compared with 18.3% in the placebo
group (77). In premenopausal women (94), similar to tamoxifen,
raloxifene increases serum FSH levels slightly (30% increase for the
100 mg raloxifene group), but no significant changes in serum levels of
LH were seen.
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IV. Skeletal Effects: Bone Mass, Bone Metabolism, and Fracture
Occurrence
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Although clomiphene has been shown to have some estrogen-agonist
skeletal activity in ovariectomized rats (113, 114), there have been no
human studies of skeletal effects in postmenopausal women. Droloxifene
(115) is currently being tested for effects on bone in Phase III trials
but no significant clinical data have yet been published. Idoxifene was
also in trial for prevention of osteoporosis (115A ) but investigations
have now been suspended.
A. Tamoxifen
1. Bone metabolism. Histomorphometric studies and bone
turnover assessments corroborate tamoxifens estrogen-like actions on
the skeleton in postmenopausal women (116, 117, 118, 119, 120, 121, 122). Bone biopsies were
obtained in 41 women with breast cancer, 22 of whom were treated with
tamoxifen for a mean of 33 months (minimum of 15 months) and 19
untreated controls (121). Tamoxifen reduced activation frequency of
remodeling by approximately 46% (but this difference was not
statistically significant). Tamoxifen reduced bone formation rate by
43% (P < 0.05)), and the remodeling period was
extended accordingly. Resorption cavity dimensions were also reduced in
tamoxifen-treated patients (all P < 0.03). In multiple
studies, tamoxifen has been shown to reduce biochemical indices of bone
turnover by 2040%, with variability dependent upon the specific
assay and the duration of treatment (116, 117, 118, 119, 121, 122). Tamoxifen has
also been associated with a reduction in serum calcium (116, 119, 122),
serum phosphorus (116, 119, 123), and urinary calcium (119), in
addition to an increase in serum PTH (119, 122), although this is not
consistent across all studies (118, 121, 124).
2. Bone mass. Tamoxifen was initially expected to show
negative effects on the skeleton because it was assumed that
antiestrogen action would dominate there, just as it did in the breast.
Early cross-sectional, retrospective, and finally prospective studies
in patients with breast cancer given tamoxifen, however, did not
demonstrate these negative effects, and in fact showed neutral or even
positive effects on the skeleton (116, 117, 123, 125, 126, 127, 128, 129, 130, 131). Love
et al. (118) subsequently studied 140 breast cancer patients
randomized to receive tamoxifen vs. placebo for 2 yr. Lumbar
spine mass in the tamoxifen-treated group increased significantly
(0.61%/yr) compared with placebo losses (1%/year), and radius losses
were steeper in placebo-treated vs. tamoxifen-treated
patients. Five year follow-up data of 62 of these original subjects who
were still on the no-tamoxifen or tamoxifen regimen to which they had
been originally assigned was published subsequently (132). At the 5-yr
point, bone mass of the lumbar spine was elevated by 0.8% above
baseline in the tamoxifen group and reduced by 0.7% in the placebo
group (group difference, P = 0.06).
Two prospective studies have also been performed in normal
postmenopausal women without history of breast cancer. In late
postmenopausal women (average time from menopause 11 yr, n
= 57), spine mass increased over 2 yr in tamoxifen-treated patients
(1.4% vs. loss of 0.7% in placebo group), but there was
only a minimal effect on total body bone mineral (group difference
0.5% at 2 yr) and no effect on hip bone mass (119). In the other
study, a subgroup of the British breast cancer prevention study (133),
bone loss occurred in premenopausal patients (n = 125) treated
with tamoxifen, but small bone gains occurred in the postmenopausal
group (n = 54) in both spine and hip (Fig. 3
). These investigations demonstrated
that tamoxifen could exert a net antiestrogenic effect in the presence
of normal premenopausal estrogen levels but a net estrogenic effect
when estrogen levels are low as seen in postmenopausal women.

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Figure 3. Changes in bone mass of the spine and hip in
normal postmenopausal and premenopausal women given tamoxifen over 3 yr
(133 ). [Reproduced with permission from T. J. Powles et
al.: J Clin Oncol 14:7884, 1996 (133 ).]
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3. Fracture occurrence. Fracture occurrence has been reported
in only two studies. The first is the Danish Breast Cancer Cooperative
Group (134). In this study of 1,716 women with high-risk breast cancer,
patients had radiotherapy and were assigned to receive tamoxifen, 30
mg/day, or no other therapy. Femoral fracture occurrence was recorded
over the course of one year. In the control group, a total of 51
patients had femoral fractures and in the tamoxifen group, 64 had
femoral fractures. The greatest apparent difference between control and
tamoxifen-treated women with regard to femoral fractures occurred in
the trochanteric region, where 11 women in the control group and 27
women in the tamoxifen-treated group had fractures [relative risk
2.12, 95% confidence interval (CI) = 1.124.01, P =
0.02]. Differences at other hip sites appeared insignificant. The
difference in trochanteric hip fracture incidence persisted when
increased survival was considered in the analysis. Of note, no other
fractures were counted in this study, and no assessment of vertebral
deformity from osteoporosis was made.
The occurrence of symptomatic fracture of the spine, hip, nonspecific
lower radius, and Colles fracture were recorded as primary end points
in the Breast Cancer Prevention Trial (55). A total of 955 women
experienced a fracture of any type, with 483 in the placebo group and
472 in the tamoxifen group, an inconsequential difference of 2.5%.
When evaluating occurrence of the classic osteoporotic fractures (hip,
wrist, and symptomatic spine only), 137 events occurred in the placebo
group, compared with 111 events in the tamoxifen group (relative risk
0.81; 95% CI, 0.631.05). These fracture data do not include
osteoporotic vertebral deformity incidence since routine spine
radiographs were not performed in this study. More importantly, the
data combine premenopausal and postmenopausal women. Since tamoxifen
might be deleterious to bone in premenopausal women (133), to include
the two groups together might underestimate any potential benefit to
the skeleton of postmenopausal women. Estimates of the incidence of
fracture relative to menopausal status can be gleaned from the
breakdown of fracture occurrence by age less than or greater than 50.
In those women less than 50 yr of age, 23 events occurred in the
placebo group and 20 in the tamoxifen group (relative risk 0.88; 95%
CI, 0.461.68), suggesting no beneficial or detrimental effect. In
those women 50 yr of age or greater, 114 events occurred in the placebo
group and 91 in the tamoxifen group (RR 0.79; 95% CI, 0.601.05).
From the available published data, one has to assume that
tamoxifen-treated patients had more fractures that were not labeled as
symptomatic spine, hip, or wrist fractures, since the overall number of
women having fractures was almost identical in the two groups (55).
Hopefully, more data to resolve these questions about tamoxifens
ability to reduce osteoporotic fracture will be available in the
future, from the NCI trial, as well as from the British, Italian, and
International Prevention trials still underway, and the recently
initiated STAR study.
B. Raloxifene
1. Bone metabolism. In a short-term, 8-week preliminary trial
of raloxifene in 251 healthy, postmenopausal women, two doses of
raloxifene (200 mg and 600 mg/day) were tested against conjugated
estrogen (0.625 mg/day) and placebo (91). These doses of raloxifene
were higher than the doses used in subsequent studies but active
bioavailable raloxifene is limited by the enterohepatic circulation and
probably does not substantially exceed that seen with the 60 mg
raloxifene dose. In this study, bone turnover variables, including
serum alkaline phosphatase, serum osteocalcin, urine pyridinoline, and
urine hydroxyproline, were measured and reductions occurred for all
markers except urinary hydroxyproline. Furthermore, reductions were
similar to those seen with estrogen for all markers except osteocalcin
in the lower dose raloxifene group. Likewise, urinary calcium was
reduced similarly to reductions seen with estrogen.
Bone turnover changes were also monitored in the European multicenter
osteoporosis prevention study of 601 normal postmenopausal women
randomly assigned to receive 30, 60, or 150 mg raloxifene/day or
placebo (90). After 24 months of treatment, median reductions of serum
bone-specific alkaline phosphatase and serum osteocalcin (markers of
bone formation), and urinary type I collagen C-telopeptide (a marker of
bone resorption) were 23.1%, 15%, and 34%, respectively, in the 60
mg raloxifene group. Reductions were significant for all three markers
at all raloxifene doses.
Raloxifene also decreased bone turnover in a small treatment study of
143 postmenopausal women with established osteoporosis. Subjects were
investigated after 1 yr of therapy with raloxifene, 60 or 120 mg/day,
compared with a calcium and vitamin D control group (135). Reductions
for the 60-mg dose were of similar magnitude to those above (15% for
serum bone alkaline phosphatase, 21% for serum osteocalcin, and 25%
for urinary C-telopeptide).
In an ongoing study of 65 postmenopausal women randomized to receive
raloxifene (60 or 120 mg/day) vs. placebo, bone biopsies
were obtained before and after 2 yr of drug therapy. Results showed
that bone quality was normal with both doses of raloxifene, with no
evidence of osteomalacia, osteocyte damage, woven bone, marrow
fibrosis, or other abnormality. Bone formation rate and activation
frequency were reduced in both raloxifene groups (76A ). Another small
histomorphometric study comparing the influence of 6 months of
treatment with raloxifene, 60 mg/day, vs. conjugated
estrogen, 0.625 mg/day, showed activation frequency and bone formation
to be reduced in both groups, although reductions were slightly greater
in the estrogen-treated patients (77).
Calcium metabolism studies have also compared raloxifene to estrogen in
33 early postmenopausal women (136). Both raloxifene and estrogen
induced positive calcium balance changes at both 1 month and 7 month
analyses. Urinary calcium declined in response to both medications, and
calcium absorption efficiency improved marginally. At the early time
point, remodeling change was the same for both agents, but at the
7-month point, remodeling suppression was greater for estrogen than for
raloxifene. Calcium balance, however, was similar for both agents at
both time points.
2. Bone mass. Raloxifene is being tested in both osteoporosis
prevention studies where bone mass is the major end point and in an
osteoporosis treatment study where fracture is the primary outcome.
There have been three large prevention studies, one in North America,
one in Europe, and one international study in women who had had a
hysterectomy, where raloxifene was compared with conjugated estrogen
(77). Data from a 2-yr interim analysis of the European study have now
been published (90). Healthy postmenopausal women (n = 601)
between the ages of 45 and 60, within 28 yr of menopause with lumbar
spine mass in the normal or low bone mass range, were recruited into
the trial. After baseline evaluation, patients were randomized to
receive one of three raloxifene doses (30, 60, or 150 mg/day) or
placebo. Bone density, bone turnover, and lipid biochemistry were
evaluated serially over 2 yr; 149 subjects (25%) dropped out of the
study, but there were no differences in discontinuation rates between
raloxifene and control groups. Bone mass increased at all measured
sites, including the lumbar spine, total hip, and total body, with all
raloxifene doses resulting in increments between 1 and 2%, compared
with losses in the placebo group of about 1% at each site (Fig. 4
and Ref. 90).

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Figure 4. Percent bone mass change over 2 yr in
postmenopausal women randomized to receive raloxifene (30, 60, or 150
mg) vs. placebo. [Reproduced with permission from
P. D. Delmas et al.: N Engl J
Med 337:16411647, 1997 (90 ). © Massachusetts Medical
Society. All rights reserved.]
|
|
Therefore, at 2 yr, differences between raloxifene- and placebo-treated
patients averaged 2.5% at all skeletal sites. Notably, bone mass
changes were almost identical at all skeletal sites, which is distinct
from what is usually seen with antiresorptive therapy such as estrogens
and alendronate (136A ), where a larger spine increment occurs in
contrast to the hip or total body increment (usually about 2:1 ratio of
increments, spine to other sites). Furthermore, the spinal bone mass
increment in the raloxifene group was lower than that of the conjugated
estrogen group in the estrogen comparator osteoporosis prevention study
(77). Finally, bone mass changes were very similar to those seen in a
similar group of normal postmenopausal women given tamoxifen in the
British breast cancer prevention study (133). Preliminary 2-yr data
from the osteoporosis treatment study (see below) also show a 23%
advantage to bone mass in both the spine and hip, when compared with
placebo losses (137).
3. Fracture occurrence. Raloxifene has been investigated as an
osteoporosis treatment agent in a large trial of 7,705 women with
osteoporosis defined by bone mass, with a subgroup of about 30% of the
women also having prevalent osteoporotic vertebral deformity at study
initiation. This study, entitled MORE (Multiple Outcomes of Raloxifene
Evaluation), is being conducted over 180 sites in 25 countries.
Subjects were randomized to receive either 60 or 120 mg raloxifene/day
or placebo, in addition to 500 mg calcium and 400 IU vitamin D/day.
Lateral spine radiographs were analyzed at 2 yr using a
semiquantitative grading technique followed by quantitative morphometry
to determine vertebral fracture incidence. Over the 2 yr, 5.5% of the
participants had one or more vertebral fractures. Raloxifene treatment
resulted in a reduction in relative risk for vertebral fracture of
44%, and an even larger reduction in risk (61%) was seen for the
occurrence of multiple vertebral fractures (137). In contrast, there
was no difference in the proportion of women reporting nonspine
fractures in this 2-yr interim analysis (raloxifene group, 6.3%,
vs. placebo, 6.8%).
 |
V. Vascular System Effects: Intermediate Markers and Disease
Outcomes
|
|---|
Intermediate markers
1. Serum lipoproteins. A cross-sectional study in 1988 in 55
breast cancer patients receiving tamoxifen therapy compared with 36
patients receiving no therapy, first showed that tamoxifen had some
estrogenic effect on circulating lipoproteins (138). Compared with
nontreated women, total and low-density lipoprotein (LDL) cholesterol
were lower in tamoxifen-treated patients, while triglycerides were
somewhat higher. Prospective data in breast cancer patients and
subsequently in normal women confirmed these original findings.
An extremely small (n = 8) prospective study in women with stable
breast cancer showed similar effects on serum lipoproteins after only 3
months of tamoxifen treatment (139). In 140 postmenopausal women with
breast cancer, Love et al. (140) showed mean reductions of
12% in total cholesterol and 20% in LDL cholesterol. In contrast to
estrogens effect, high-density lipoprotein (HDL) cholesterol was not
increased by tamoxifen, but actually decreased slightly in that study.
Similarly to estrogens effect, serum triglycerides increased. Serum
apolipoprotein A1 levels increased, while apolipoprotein B levels
decreased. In a 5-yr follow-up of the same study, the total cholesterol
and LDL cholesterol changes were still present, and in addition,
reduction in serum lipoprotein (a) was also documented (141). In 153
women with breast cancer evaluated for tamoxifen-induced changes in
serum lipoproteins from two separate adjuvant trials of tamoxifen,
current postmenopausal users of tamoxifen had lower serum levels of
total cholesterol, LDL cholesterol, and HDL cholesterol with higher
serum triglyceride levels (127).
A more recent investigation, also in women with a diagnosis of breast
cancer, that compared tamoxifen, 20 mg/day, with toremifene, 60 mg/day
(142), after 1 yr of therapy, documented that both estrogen analogs
reduced total and LDL cholesterol and apolipoprotein B levels.
Furthermore, both tamoxifen and toremifene decreased serum levels of
lipoprotein (a) (34% and 41%, respectively). Interestingly, in that
study, although tamoxifen did not increase serum HDL level as shown
previously, toremifene increased serum HDL levels by 14%.
In healthy postmenopausal women, tamoxifen reduced serum lipoprotein
(a) by 34% at 3 months (143). Furthermore, in 57 normal postmenopausal
women, tamoxifen reduced serum total cholesterol by 12% and LDL by
19% (144) during 2 yr of therapy. Serum HDL and HDL
subfractions and triglyceride and apolipoprotein A1 levels were not
significantly altered (Fig. 5
and Ref.
144). Lipoprotein changes induced by tamoxifen are more prominent in
postmenopausal than in premenopausal women (145). There is also some
evidence that tamoxifen might reduce LDL oxidation (146, 147).

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Figure 5. Changes in serum lipoproteins after 2 yr therapy
with tamoxifen vs. placebo in normal postmenopausal
women. [Reproduced with permission from A. B. Grey et al.:
J Clin Endocrinol Metab 80:31913195, 1995 (144 ). © The
Endocrine Society.]
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Like tamoxifen, raloxifene has an estrogen agonist effect on several
serum lipoproteins, but there are some qualitative and quantitative
differences between the effects of estrogen and raloxifene on some
lipoproteins. Results of a fairly large study (n = 390 healthy
postmenopausal women) that compares raloxifene (60 mg and 120 mg) to
continuous combined HRT (conjugated equine estrogen, 0.625 mg, plus
medroxyprogesterone acetate, 2.5 mg) are shown in Table 2
for the 60-mg raloxifene dose
(148). Serum LDL was lowered to a similar extent by raloxifene and HRT
(1214%) but lipoprotein (a) was lowered only 78% by raloxifene in
contrast to 19% by HRT. Furthermore, HRT increased total serum HDL
cholesterol by 11%, whereas raloxifene produced no total HDL
increment. The HDL-2 subclass, however, was increased 33% by HRT
compared with 1517% increases with raloxifene.
These differences between effects of raloxifene and HRT might suggest
that HRT would be a better protector against atherogenesis than
raloxifene. However, there are two other independent variables where
raloxifene appears superior. Raloxifene did not increase triglyceride
levels significantly, whereas HRT resulted in a 20% increase.
Moreover, raloxifene lowered serum fibrinogen by 1214%, compared
with no effect for HRT (see below). Both of these effects might suggest
a possible advantage of raloxifene over HRT against atherogenesis.
Therefore, based on biochemical changes alone, it is difficult to
compare the theoretical potency of protective effect by raloxifene
vs. HRT against vascular disease.
In the multicenter European osteoporosis prevention study, within
3 months, total and LDL cholesterol were decreased with all raloxifene
doses, with no subsequent change thereafter. Consistent with the
investigation above, there was no change in serum HDL or triglycerides
(90). Similar results were obtained in the short-term investigation (8
weeks) of higher doses of raloxifene in normal postmenopausal women
(91).
2. Coagulation factors. A significant body of literature
suggests that tamoxifen lowers serum levels of antithrombin III, as
does estrogen (138, 149, 150, 151, 152, 153), although there is one small conflicting
cross-sectional study (154). In none of the investigations was serum
antithrombin III level reduced by more than 30%. Serum fibrinogen
levels were reduced 1518% by tamoxifen in at least three separate
investigations, one in healthy women (144) and two in women with breast
cancer (127, 151). A small decrease (9%) in platelet count (151),
reduced serum Protein C activity (153), and an increase in serum
plasminogen have also been reported with tamoxifen exposure (127).
In the Italian Breast Cancer Prevention trial, the first 77 healthy
postmenopausal women enrolled were evaluated for effects on coagulation
factors over the first 6 months (152). Platelet count and hemoglobin
decreased in tamoxifen-treated patients. Both placebo-treated and
tamoxifen-treated patients decreased serum fibrinogen levels, without a
clear treatment effect. No changes in Factor VII were documented, but
von Willebrand factor was increased in tamoxifen-treated patients
compared with those receiving placebo. As shown previously, serum
levels of antithrombin III decreased in tamoxifen-treated patients as
did Protein C.
In the study of healthy postmenopausal women, comparing continuous
combined HRT with raloxifene, 60 mg/day (148), raloxifene lowered
plasma fibrinogen level to a similar degree as seen with tamoxifen
(1214%), whereas estrogen had no effect in this study. Neither
raloxifene nor HRT changed determinations of fibrinopeptide A or
prothrombin fragments 1 and 2. While HRT decreased Plasminogen
Activator Inhibitor-1, raloxifene had no effect on this variable.
B. Vascular disease outcomes
1. Cardiovascular and cerebrovascular diseases.Two
separate European breast cancer studies using adjuvant tamoxifen
reported the occurrence of coronary heart disease. In the Scottish
breast cancer trial, McDonald originally reported that fatal myocardial
infarction (MI) was 63% less common in those patients who received
tamoxifen than in those who did not receive tamoxifen (155). In a
follow-up of this same study, vascular disease outcomes were tabulated
in 1,312 women after mastectomy who were randomly assigned to
receive adjuvant tamoxifen or no treatment unless a relapse occurred
(156). Women were followed on tamoxifen for a maximum of 14 yr.
Eighteen percent of these women were premenopausal at study entry and
mean age was 5859 yr. In the tamoxifen arm of the study, risk of MI
was reduced, and there was a trend toward reduction in other ischemic
heart disease events. When comparing women who had ever used tamoxifen
to women who had never used tamoxifen, relative risk for MI was
significantly higher for never used (2.03, P = 0.03),
and there was a trend toward increased development of ischemic heart
disease (RR 1.55, P = 0.16). There was no suggestion of
any change in risk of cerebrovascular disease. Results were similar
qualitatively but quantitatively even stronger if current tamoxifen
users were compared with never users.
In the Stockholm Breast Cancer Study, which investigated vascular
morbidity in 2,365 patients, a significant reduction in cardiac disease
was seen in tamoxifen-treated patients, and incidence of cardiac
disease requiring hospital admission was 32% less common in those
allocated to receive tamoxifen after breast cancer surgery (157).
Similar to the Scottish study (156), no difference in cerebrovascular
disease was noted.
Data from the NCI-sponsored breast cancer treatment study NSABP
B-14 trial (112) are consistent with the findings of the Scottish and
Swedish breast cancer studies, in terms of degree of effect against
fatal heart disease; however, findings were not statistically
significant. In this protocol, 2,885 women with breast cancer were
randomly assigned to tamoxifen or placebo and an additional 1,200 women
were later assigned to the tamoxifen arm of the protocol. Although the
cardiovascular mortality was lower in tamoxifen-treated patients, data
did not reach statistical significance. Relative risk for definite
fatal MI was 0.66 for tamoxifen users (confidence interval =
0.271.61). If death from possible MI was added, relative risk became
0.85 (confidence interval = 0.461.58).
The most distinct data on arteriovascular disease outcomes are from the
Breast Cancer Prevention Trial (55). This was the largest and cleanest
study and the only one performed in women who did not have a diagnosis
of breast cancer. Rates for ischemic heart and cerebrovascular disease
are shown in Table 1
. There was no significant difference in the number
of women in the tamoxifen group vs. placebo group who had a
MI, had angina requiring bypass graft or angioplasty, those diagnosed
with acute ischemic syndrome, or total events due to ischemic heart
disease (71 vs. 62). If events in women less than age 49 are
excluded, total ischemic episodes were 61 in the tamoxifen group and 57
in the placebo group. Furthermore, cerebrovascular disease was no less
common in women receiving tamoxifen vs. placebo, as was seen
in the breast cancer treatment studies. A total of 24 cerebrovascular
events occurred in the placebo group compared with 38 in the tamoxifen
group (difference not statistically significant). Excluding events in
younger women left 20 cerebrovascular events in placebo-treated and 35
in tamoxifen-treated women, a difference that nearly met statistical
significance (95% CI = 0.983.20).
To evaluate the vascular disease outcomes of raloxifene treatment,
Eli Lilly & Co. (Indianapolis, IN) has embarked on a large
prospective clinical trial entitled the RUTH (Raloxifene Use for the
Heart) study (158). The planned enrollment is approximately 10,000
postmenopausal women over the age of 55, with established heart disease
or at increased risk for heart disease. The primary outcomes will be
fatal and nonfatal MI, and secondary outcomes will be all-cause
mortality, all-cause hospitalization, revascularization incidence,
cerebrovascular events, and breast cancer. Results of this trial will
probably be available within about 7 yr. Frequency of cardiovascular
and cerebrovascular disease events from ongoing osteoporosis prevention
and treatment trials should be available sooner, but no data have yet
been published concerning these outcomes.
2. Venous thromboembolic disease. Although there was no
increase in venous thromboembolic disease documented in the Swedish
breast cancer study (157), in the Scottish Breast Cancer study (156),
risk was almost 2.5-fold in patients receiving tamoxifen compared with
the risk in untreated patients. Many other reports have confirmed the
increase in venous thromboembolic disease in women with breast cancer
treated with tamoxifen (68, 110, 159, 160, 161, 162). Furthermore, in healthy
women in the NCI-sponsored Breast Cancer Prevention Trial, relative
risk for pulmonary emboli in tamoxifen-treated to untreated was 3.01
(CI= 1.159.27), and for deep vein thrombosis was 1.60 (CI =
0.912.86). Similarly, raloxifene, like tamoxifen and estrogen (11, 20, 21, 22), has been associated with a 3-fold increase in risk of venous
thromboembolic disease, including deep venous thrombosis of the leg
veins, pulmonary embolism, and retinal vein thrombosis (77 162A ). The
absolute risk of venous thromboembolism is still quite small, however,
at approximately 2 or 3 cases for every 10,000 women each year.
 |
VI. Central Nervous System Effects
|
|---|
A. Cognitive function and mood
Recent studies have shown that estrogenic hormones modulate growth
of neural tissue and may affect cognitive function as well as
development and severity of dementia (9, 10). Confirmation of
particularly the latter effect is pending clinical trials currently
underway. Since both tamoxifen and raloxifene (91, 148) cross the
blood-brain barrier and produce an increase in symptomatic hot flashes
(see Section III.D above), it has been postulated
that these agents might also affect cognitive function, and that this
effect might be negative. No clinical trials have been performed to
assess this area specifically with tamoxifen. In the NCI Breast Cancer
Prevention Trial (55), an assessment of mood was performed using a
self-administered depression scale. Findings were identical in
tamoxifen-treated and placebo-treated women. Also, in a study of 140
women with node-negative breast cancer, tamoxifen was not associated
with depression, anxiety, or a reduction in overall quality of life
(163).
Effects of raloxifene on cognitive function have been studied in a
formal clinical trial of 143 postmenopausal women with osteoporosis
between the ages of 45 and 75 yr before and during assignment to
raloxifene, 60 mg/day, raloxifene, 120 mg/day, or placebo (164).
Cognitive tests included measures from the Memory Assessments Clinic
computerized psychometric battery and the Walter Reed Performance
Assessment Battery. An assessment of mood was also performed using the
Geriatric Depression Scale. Subjects underwent testing at baseline, 1,
6, and 12 months. At 6 and 12 months there were no significant
differences in performance on any of these tests among any of the
groups. These data suggest that raloxifene does not hinder or improve
performance on cognitive function testing or mood over a 1-yr period.
Ongoing studies of raloxifenes effect on the central nervous system
(from the MORE study) should provide further confirmatory data.
B. Eye disease
Tamoxifen use has been associated with ocular toxicity including
retinopathy in several small studies (165, 166, 167, 168, 169, 170, 171, 172, 173, 174). Many of these
findings, particularly the retinopathy, have not been substantiated,
however, in larger studies (55, 175). A subgroup of the NSABP B-14
breast cancer treatment study, with primary focus on ophthalmic
outcomes, indicated no vision-threatening ocular toxicity other than
posterior subcapsular opacities in tamoxifen-treated women (175).
Moreover, in the largest study involving tamoxifen use in healthy
women, the NCI Breast Cancer Prevention Trial (55), there was no
evidence of an increase in the risk of macular degeneration or any
other retinal toxicity. In contrast, there was an increase in the
relative risk of cataract development (RR 1.14; 95% CI =
1.011.29) and an increase in the relative risk of cataract surgery
(RR 1.57; 95% CI, 1.162.14). Raloxifene use has been associated with
increased risk of retinal vein thrombosis, but no other ocular toxicity
has been so far noted (77).
 |
VII. Hepatic Effects
|
|---|
Tamoxifen increases the risk of hepatic tumors and DNA
adducts in rodents given tamoxifen, suggesting a possible increase
among humans in the risk of hepatocellular carcinoma (176, 177). This
has never been demonstrated in the human, however, where only two cases
of hepatocellular carcinoma have been reported during adjuvant
chemotherapy with tamoxifen (178, 179). In the NSABP B-14 breast cancer
treatment trial (68), there was no increase in hepatic or
gastrointestinal cancer found in tamoxifen-treated patients.
Furthermore, there were no cases of hepatocellular carcinoma in the
Breast Cancer Prevention Trial (55), and all cancers other than those
of the breast and uterus were equally distributed in both the tamoxifen
and placebo groups (97 cases total in each). Unlike tamoxifen, neither
Toremifene (Schering Corp., Kenilworth, NJ) nor Droloxifene
(Pfizer, Inc., New York, NY) has been shown to induce hepatic tumors in
rodents. Furthermore, raloxifene is not associated with an increase in
hepatic tumors in rodents, nor is there any evidence, at this time, to
suggest that raloxifene is associated with an increase in hepatic or
any gastrointestinal disease in humans.
 |
VIII. Miscellaneous Effects
|
|---|
Thrombocytopenia (110) was described as a potential adverse effect
of tamoxifen. Leg cramps have been described with raloxifene (77).
Nonspecific headache seems reduced in incidence in women taking
raloxifene (77).
 |
IX. Conclusion
|
|---|
We are still in the early stages of investigation of the
estrogen analogs. Some of the benefits of medications such as tamoxifen
and raloxifene are known; however, ultimate target organ outcomes such
as incidence of heart attack and nonspine as well as spine fracture are
still to be determined. The demonstration that these estrogen analogs
can actually reduce the risk of breast cancer occurrence at least over
a 3- to 5-yr period is incredibly exciting, and it is virtually the
first time that a medication has been shown to substantially reduce
cancer risk. The optimal duration of therapy and the optimal timing of
therapy, however, remain unknown. Moreover, long-term effects on the
breast and on other systems, such as perineal tissues and the central
nervous system, also need to be ascertained. It is clear that these
drugs have tremendous potential for reducing the risk of a multitude of
chronic diseases in some groups of postmenopausal women. A more
complete understanding of the pharmacology and mechanisms of actions of
these agents will ultimately help us design the truly perfect estrogen
or estrogen/estrogen analog combination regimen to accomplish all of
the desired outcomes.
 |
Footnotes
|
|---|
Address reprint requests to: Felicia Cosman, M.D., Regional Bone Center, Helen Hayes Hospital, West Haverstraw, New York 10993 USA.
1 Supported in part by NIH Grants DK-46381 and AR-39191. 
 |
References
|
|---|
-
Ettinger B 1998 Overview of estrogen
replacement therapy: a historical perspective. Proc Soc Exp Biol Med 217:25[CrossRef][Medline]
-
Ulmsten U 1997 Some reflections and hypotheses
on the pathophysiology of female urinary incontinence. Acta Obstet
Gynecol Scand 76:38
-
Cauley JA, Seeley DG, Ensrud K, Ettinger B, Black D,
Cummings SR 1995 Estrogen replacement therapy and fractures in
older women. Study of Osteoporotic Fractures Research Group. Ann Intern
Med 122:916[Abstract/Free Full Text]
-
Lindsay R, Hart DM, Forrest C, Baird C 1980 Prevention of spinal osteoporosis in oophorectomised women. Lancet 2:11511154[Medline]
-
Lufkin EG, Wahner HW, OFallon WM, Hodgson SF,
Kotowicz MA, Lane AW, Judd HL, Caplan RH, Riggs BL 1992 Treatment
of postmenopausal osteoporosis with transdermal estrogen. Ann Intern
Med 117:19
-
Nasr A, Breckwoldt M 1998 Estrogen replacement
therapy and cardiovascular protection: lipid mechanisms are the tip of
an iceberg. Gynecol Endocrinol 12:4359[Medline]
-
Henderson VW 1997 The epidemiology of estrogen
replacement therapy and Alzheimers disease. Neurology 48:S27S35
-
Yaffe K, Sawaya G, Lieberburg I, Grady D 1998 Estrogen therapy in postmenopausal women: effects on cognitive function
and dementia. JAMA 9:688695
-
Paganini-Hill A 1997 Does estrogen replacement
therapy protect against Alzheimers disease? Osteopor Int
7[Suppl1]:S12S17
-
Haskell SG, Richardson ED, Horwitz RI 1997 The
effect of estrogen replacement therapy on cognitive function in women:
a critical review of the literature. J Clin Epidemiol 50:12491264[CrossRef][Medline]
-
Hulley S, Grady D, Bush T, Furberg C, Herrington D,
Riggs B, Vittinghoff E 1998 Randomized trial of estrogen plus
progestin for secondary prevention of coronary heart disease in
postmenopausal women. Heart and Estrogen/progestin Replacement Study
(HERS) Research Group. JAMA 280:605613[Abstract/Free Full Text]
-
Barrett-Connor E, Stuenkel CA 1998 Anticipating
HERS: questions from the heart and estrogen/progestin replacement
study. J Womens Health 7:395397[Medline]
-
Barrett-Connor E 1991 Postmenopausal estrogen and
prevention bias. Ann Intern Med 115:455456
-
Zumoff B 1998 Does postmenopausal estrogen
administration increase the risk of breast cancer? Contributions of
animal, biochemical, and clinical investigative studies to a resolution
of the controversy. Proc Soc Exp Biol Med 217:3037[CrossRef][Medline]
-
Collaborative Group on Hormonal Factors in Breast
Cancer 1997 Breast cancer and hormone replacement therapy:
collaborative reanalysis of data from 51 epidemiological studies of
52705 women with breast cancer and 108411 women without breast cancer.
Lancet 350:10471059
-
Ravnikar VA 1992 Compliance with hormone
replacement therapy: are women receiving the full impact of hormone
replacement therapy preventive health benefits? Womens Health Issues 2:7580[CrossRef][Medline]
-
1995 Gallup Survey
-
Beresford SA, Weiss NS, Voigt LF, McKnight B 1997 Risk of endometrial cancer in relation to use of oestrogen combined
with cyclic progestagen therapy in post menopausal women. Lancet 349:458461[CrossRef][Medline]
-
Udoff L, Langenberg P, Adashi EY 1995 Combined
continuous hormone replacement therapy: a critical review. Obstet
Gynecol 86:306316[CrossRef][Medline]
-
Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P,
Marsh S 1996 Risk of venous thromboembolism in users of hormone
replacement therapy. Lancet 348:977980[CrossRef][Medline]
-
Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE,
Colditz GA, Speizer FE, Willett WC, Hennekens CH 1996 Prospective
study of exogenous hormones and risk of pulmonary embolism in women.
Lancet 348:983987[CrossRef][Medline]
-
Jick H, Derby LE, Myers MW, Vasilakis C, Newton
KM 1996 Risk of hospital admission for idiopathic venous
thromboembolism among users of postmenopausal oestrogens. Lancet 348:981983[CrossRef][Medline]
-
Herbst AL, Griffiths CT, Kistner RW 1964 Clomiphene citrate in disseminated mammary carcinoma. Cancer Chemother
Rep 43:3941
-
Hecker E, Vegh I, Levy CM, Magin CA, Martinez JC,
Loureiro J, Garola RE 1974 Clinical trial of clomiphene in
advanced breast cancer. Eur J Cancer 10:747749
-
Clark JH, Markaverich BM 1982 The
agonistic-antagonistic properties of clomiphene: a review. Pharm Ther 15:467519
-
Early Breast Cancer Trialists Collaborative
Group 1992 Systemic treatment of early breast cancer by hormonal,
cytotoxic, or immune therapy. 133 Randomised trials involving 31000
recurrences and 24000 deaths among 75000 women. Lancet 339:115,
7185[Medline]
-
Early Breast Cancer Trialists Collaborative
Group 1998 Tamoxifen for early breast cancer: an overview of the
randomised trials. Lancet 351:14511467[CrossRef][Medline]
-
Osborne CK 1998 Drug therapy. Tamoxifen in the
treatment of breast cancer. N Engl J Med 339:16091618[Free Full Text]
-
Hortobagyi GN 1998 Treatment of breast cancer.
N Engl J Med 339:974984[Free Full Text]
-
Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham
DL, Wolmark N, Costantino J, Redmond C, Fisher ER, Bowman DM, Deschenes
L, Dimitrov NV, Margolese RG, Robidoux A, Shibata H, Terz J, Paterson
HG, Feldman MI, Farrar W, Evans J, Lickley HL 1996 Five
vs. more than five years of tamoxifen therapy for breast
cancer patients with negative lymph nodes and estrogen
receptor-positive tumors. J Natl Cancer Inst 88:15291542[Abstract/Free Full Text]
-
Tormey DC, Gray R, Falkson HC 1996 Postchemotherapy adjuvant tamoxifen therapy beyond five years in
patients with lymph node-positive breast cancer. J Natl Cancer
Inst 88:18281833[Abstract/Free Full Text]
-
Fisher B, Dignam J, Wolmark N, DeCillis A, Emir B,
Wickerham DL, Bryant J, Dimitrov NV, Abramson N, Atkins JN, Shibata H,
Deschenes L, Margolese RG 1997 Tamoxifen and chemotherapy for
lymph node-negative, estrogen receptor-positive breast cancer. J
Natl Cancer Inst 89:16731682[Abstract/Free Full Text]
-
Goldhirsch A, Gelber RD 1989 Adjuvant
chemo-endocrine therapy or endocrine therapy alone for postmenopausal
patients: Ludwig Studies III and IV. In: Senn HJ, Goldhirsch A, Gerber
RD, Osterwalder B (eds) Adjuvant Therapy of Primary Breast Cancer:
Recent Results in Cancer Research. Springer-Verlag, Berlin, Germany,
vol 115:153162
-
Mouridsen HT, Rose C, Overgaard M, Dombernowsky P,
Panduro J, Thorpe S, Rasmussen BB, Blichert-Toft M, Andersen
KW 1988 Adjuvant treatment of postmenopausal patients with high
risk primary breast cancer. Results from the Danish adjuvant trials
DBCG 77 C and DBCG 82 C. Acta Oncol 27:699705[Medline]
-
Rivkin SE, Green S, Metch B, Cruz AB, Abeloff MD,
Jewell WR, Costanzi JJ, Farrar WB, Minton JP, Osborne CK 1994 Adjuvant CMFVP vs. tamoxifen vs. concurrent CMFVP
and tamoxifen for postmenopausal, node-positive, and estrogen
receptor-positive breast cancer patients: a Southwest Oncology Group
study. J Clin Oncol 12:20782085[Abstract/Free Full Text]
-
Pritchard KI, Paterson AHG, Fine S, Paul NA, Zee B,
Shepherd LE, Abu-Zahra H, Ragaz J, Knowling M, Levine MN, Verma S,
Perrault D, Walde PLD, Bramwell VHC, Poljicak M, Boyd N, Warr D, Norris
BD, Bowman D, Armitage GR, Weizel H, Buckman RA and The National Cancer
Institute of Canada Clinical Trials Group Breast Cancer Site Group1997 Randomized trial of cyclophosphamide, methotrexate, and
fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in
postmenopausal women with node-positive estrogen and/or progesterone
receptor-positive breast cancer: a report of the National Cancer
Institue of Canada Institute of Canada Clinical Trials Group. J
Clin Oncol 15:23022311
-
Fisher B, Redmond C, Legault-Poisson S, Dimitrov NV,
Brown AM, Wickerham DL, Wolmark N, Margolese RG, Bowman D, Glass AG,
Kardinal CG, Robidoux A, Jochimsen P, Cronin W, Deutsch M, Fisher ER,
Myers DB, Hoehn JL 1990 Postoperative chemotherapy and
tamoxifen compared with tamoxifen alone in the treatment of
positive-node breast cancer patients aged 50 years and older with
tumors responsive to tamoxifen: results from the National Surgical
Adjuvant Breast and Bowel Project B-16. J Clin Oncol 8:10051018[Abstract]
-
The International Breast Cancer Study Group 1997 Effectiveness of adjuvant chemotherapy in combination with tamoxifen
for node-positive postmenopausal breast cancer patients. J Clin
Oncol 15:13851394[Abstract]
-
Albain K, Green S, Osborne K, Cobau C, Levine E, Ingle
J, Pritchard K, Schneider D, OSullivan J, Hess E, Martino S for SWOG,
ECOG, CALGB, NCCTG and NCI-Canada 1997 Tamoxifen (T)
vs. cyclophosphamide, Adriamycin® and 5-FU plus either
concurrent or sequential tamoxifen in postmenopausal receptor (+) note
(+) breast cancer: a Southwest Oncology Group phase III intergroup
trial (SWOG-8814, INT-0100). Proc Am Soc Clin Oncol 16:128a (Abstract)
-
Gelber RD, Cole BF, Goldhirsch A, Rose C, Fisher B,
Osborne CK, Boccardo F, Gray R, Gordon NH, Bengtsson NO, Sevelda P 1996 Adjuvant chemotherapy plus tamoxifen compared with tamoxifen alone
for postmenopausal breast cancer: meta-analysis of quality-adjusted
survival. Lancet 347:10661071[CrossRef][Medline]
-
Ravdin PM, Green S, Dorr TM, McGuire WL, Fabian C,
Pugh RP, Carter RD, Rivkin SE, Borst JR, Belt RJ, Metch B, Osborne
CK 1992 Prognostic significance of progesterone receptor
levels in estrogen receptor-positive patients with metastatic breast
cancer treated with tamoxifen: results of a prospective Southwest
Oncology Group study. J Clin Oncol 10:12841291[Abstract/Free Full Text]
-
Buchanan RB, Blamey RW, Durrant KR, Howell A,
Paterson AG, Preece PE, Smith DC, Williams CJ, Wilson RG 1986 A
randomized comparison of tamoxifen with surgical oophorectomy in
premenopausal patients with advanced breast cancer. J Clin Oncol 4:13261330[Abstract/Free Full Text]
-
Ingle JN, Krook JE, Green SJ, Kubista TP, Everson LK,
Ahmann DL, Chang MN, Bisel HF, Windschitl HE, Twito DI, Pfeifle
DM 1986 Randomized trial of bilateral oophorectomy
vs. tamoxifen in premenopausal women with metastic breast
cancer. J Clin Oncol 4:178185[Abstract]
-
Muss HB, Smith LR, Cooper MR 1987 Tamoxifen
rechallenge: response to tamoxifen following relapse after adjuvant
chemohormonal therapy for breast cancer. J Clin Oncol 5:15561558[Abstract/Free Full Text]
-
Valavaara R, Pyrhonen S, Heikkinen M, Rissanen P,
Blanco G, Tholix E, Nordman E, Taskinen P, Holsti L, Hajba A 1988 Toremifene, a new antiestrogenic compound, for treatment of advanced
breast cancer. Phase II study. Eur J Cancer Clin Oncol 24:785790[CrossRef][Medline]
-
Gunderson S 1990 Toremifene, a new antiestrogenic
compound in the treatment of advanced breast cancer. Phase II study.
Eur J Cancer
-
Modig H, Borgstrom M, Nilsson I, Westman G 1990 Phase II clinical study of toremifene in patients with metastatic
breast cancer. J Steroid Biochem 36:235236[CrossRef][Medline]
-
Hietanen T, Baltina D, Johansson R, Numminen S, Hakala
T, Helle L, Valavaara R 1990 High dose toremifene (240 mg daily)
is effective as first line hormonal treatment in advanced breast
cancer. An ongoing phase-II multicenter Finnish-Latvian cooperative
study. Breast Cancer Res Treat 16[Suppl]:S37S40
-
Hayes DF, Van Zyl JA, Hacking A, Goedhals L, Bezwoda
WR, Mailliard JA, Jones SE, Vogel CL, Berris RF, Shemano I,
Schoenfelder J 1995 Randomized comparison of tamoxifen and
two separate doses of toremifene in postmenopausal patients with
metastic breast cancer. J Clin Oncol 13:25562566[Abstract]
-
Abe O 1991 Japanese early phase II study of
droloxifene in the treatment of advanced breast cancer. Preliminary
dose-finding study. Am J Clin Oncol 14 [Suppl]2:S40S45
-
Bellmunt J, Sole L 1991 European early phase II
dose finding study of droloxifene in advanced breast cancer. Am J
Clin Oncol 14[Suppl 2]:S36S39
-
Haarstad H, Gundersen S, Wist E, Raabe N, Mella O,
Kvinnsland S 1992 Droloxifene a new anti-estrogen. A phase II
study in advanced breast cancer. Acta Oncol 31:425428[Medline]
-
Rausching W, Pritchard KI 1994 Droloxifene, a new
antiestrogen: its role in metastatic breast cancer. Breast Cancer Res
Treat 31:9394
-
Buzdar AU, Kau S, Hortobagyi GN, Theriault RL, Booser
D, Holmes FA, Walters R, Krakoff IH 1994 Phase I trial of
droloxifene in patients with metastatic breast cancer. Cancer Chemother
Pharmacol 33:313316[Medline]
-
Buzdar AU, Marcus C, Holmes F, Hug V, Hortobagyi G 1988 Phase II evaluation of Ly156758 in metastatic breast cancer.
Oncology 45:344345[Medline]
-
Fisher B, Costantino JP, Wickerham DL, Redmond
CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J,
Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N 1998 Tamoxifen for
prevention of breast cancer: report of the National Surgical Adjuvant
Breast and Bowel Project P-1 Study. J Natl Can Inst 90:13711388[Abstract/Free Full Text]
-
Gail MH, Brinton LA, Byar DP, Corle DK, Green SB,
Schairer C, Mulvihill JJ 1989 Projecting individualized
probabilities of developing breast cancer for white females who are
being examined annually. J Natl Cancer Inst 81:18791886[Abstract/Free Full Text]
-
Powles T, Eeles R, Ashley S, Easton D, Chang J,
Dowsett M, Tidy A, Viggers J, Davey J 1998 Interim analysis of the
incidence of breast cancer in the Royal Marsden Hospital tamoxifen
randomised chemoprevention trial. Lancet 352:98101[Medline]
-
Veronesi U, Maisonneuve P, Costa A, Sacchini V,
Maltoni C, Robertson C, Rotmensz N, Boyle P 1998 Prevention of
breast cancer with tamoxifen: preliminary findings from the Italian
randomised trial among hysterectomised women. Lancet 352:9397[Medline]
-
Pritchard KI 1998 Commentary Is tamoxifen
effective in prevention of breast cancer? Lancet 352:8081[Medline]
-
Cummings SR, Norton L, Eckert S, Grady D, Cauley J,
Knickerbocker R, Black DM, Nickelsen T, Glusman J, Krueger K, et
al 1998 Raloxifene reduces the risk of breast cancer and
may decrease the risk of endometrial cancer in post-menopausal women.
Two-year findings from the multiple outcomes of raloxifene evaluation
(more) trial. Program/Proceedings of the 34th Annual Meeting of the
American Society of Clinical Oncology, May 1619, 1998, Los
Angeles, CA
-
Jordan VC, Glusman JE, Eckert S, Lippman M, et
al, Incident primary breast cancers are reduced by
raloxifene: integrated data from multicenter, double-blind, randomized
trials in
12,000 postmenopausal women. Program/Proceedings of the
34th Annual Meeting of the American Society of Clinical Oncology, May
1619, 1998, 17 Los Angeles, CA
-
Rossing MA, Daling JR, Weiss NS, Moore DE, Self
SG 1994 Ovarian tumors in a cohort of infertile women. N Engl
J Med 331:771776[Abstract/Free Full Text]
-
Whittemore AS, Harris R, Itnyre J 1992 Characteristics relating to ovarian cancer risk: collaborative analysis
of 12 US case control studies. II. Invasive epithelial ovarian cancers
in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol 136:11841203[Abstract/Free Full Text]
-
Spirtas R, Kaufman SC, Alexander NJ 1993 Fertility drugs and ovarian cancer: red alert or red herring? Fertil
Steril 59:291294[Medline]
-
Harris R, Whittemore AS, Itnyre J 1992 Characteristics relating to ovarian cancer risk: collaborative analysis
of 12 US case-control studies. III. Epithelial tumors of low malignant
potential in white women. Collaborative Ovarian Cancer Group. Am J
Epidemiol 136:12041211[Abstract/Free Full Text]
-
Shushan A, Peretz T, Uziely B, Lewin A, Mor-Yosef
S 1996 Ovarian cysts in premenopausal tamoxifen-treated women with
breast cancer. Am J Obstet Gynecol 174:141144[CrossRef][Medline]
-
Cohen I, Rosen DJ, Altaras M, Beyth Y, Shapira J,
Yigael D 1993 Tamoxifen treatment in premenopausal breast cancer
patients may be associated with ovarian overstimulation, cystic
formations and fibroid overgrowth. Br J Obstet Gynecol 69:620621
-
Fisher B, Costantino JP, Redmond CK, Fisher ER,
Wickerham DL, Cronin WM 1994 Endometrial cancer in
tamoxifen-treated breast cancer patients: findings from the National
Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl
Cancer Inst 86:527537[Abstract/Free Full Text]
-
Cook LS, Weiss NS, Schwartz SM, White E, McKnight B,
Moore DE, Daling JR 1995 Population-based study of tamoxifen
therapy and subsequent ovarian, endometrial, and breast cancers. J
Natl Cancer Inst 87:13591364[Abstract/Free Full Text]
-
Rutqvist LE, Johansson H, Signomklao T, Johansson U,
Fornander T, Wilking N 1995 Adjuvant tamoxifen therapy for early
stage breast cancer and second primary malignancies. Stockholm Breast
Cancer Study Group. J Natl Cancer Inst 87:645651[Abstract/Free Full Text]
-
Neven P, De Muylder X, Van Belle Y, Vanderick G,
De Muylder E 1979 Tamoxifen and the uterus and endometrium
(letter). Lancet 1:385
-
Stewart HJ, Knight GM 1989 Tamoxifen and the
uterus and endometrium (letter). Lancet 1:375376[CrossRef][Medline]
-
Francis PC 1997 An oncogenic study and companion
blood level study in Fischer 344 rats administered raloxifene
(LY139481) hydrochloride in the diet for 2 years. Toxicology Report No.
60. Lilly Research Laboratories,
-
Francis PC 1997 An oncogenic study and companion
blood level study in CD-1 mice administered raloxifene (LY139481)
hydrochloride in the diet for 21 months. Toxicology Report No. 59.
Lilly Research Laboratories, Indianapolis, IN
-
Francis PC 1995 A subchronic toxicity study and
companion blood level study in CD-1 mice given raloxifene (LY139481)
hydrochloride in the diet for 3 months. Toxicology Report No. 32. Lilly
Research Laboratories, Indianapolis, IN
-
Tucker MJ, Adam HK, Patterson JS 1984 Tamoxifen.
In Laurence DR, McLean AEM, Weatherall M (eds) Safety Testing of New
Drugs, Academic Press, London, pp 125161
-
Prescribing information for Fareston® (toremifene),
Schering
-
Ott SM, Oleksik A, Lu Y, Harper K, Lips P 1998
Bone histomorphometric results of a 2 year randomized, placebo
controlled trial of raloxifene in postmenopausal women. Bone 23 [Suppl
1]: TS295
-
Product circular 1997 Evista (raloxifene
hydrocholoride). Eli Lilly and Company, Indianapolis, IN
-
Neven P, DeMulder X, van Belle Y, Campo R, Vanderick
G 1994 Tamoxifen and the uterus. Br Med J 309:13131314[Free Full Text]
-
Lahti E, Blanco G, Kauppila A, Apaja-Sarkkinen M,
Taskinen PJ, Laatikainen T 1993 Endometrial changes in
postmenopausal breast cancer patients receiving tamoxifen. Obstet
Gynecol 81:660664[Medline]
-
Thylan S 1995 Tamoxifen treatment and its
consequences. Hum Reprod 10:21742178[Free Full Text]
-
Cohen I, Rosen DJ, Shapira J, Cordoba M, Gilboa S,
Altaras MM, Yigael D, Beyth Y 1993 Endometrial changes in
postmenopausal women treated with tamoxifen for breast cancer. Br
J Obstet Gynaecol 100:567570[Medline]
-
Jaiyesimi IA, Buzdar AU, Decker DA, Hortobagyi GN 1995 Use of tamoxifen for breast cancer: twenty-eight years later.
J Clin Oncol 113:513529
-
Kedar RP, Bourne TH, Powles TJ, Collins WP, Ashley SE,
Cosgrove DO, Campbell S 1994 Effects of tamoxifen on uterus and
ovaries of postmenopausal women in a randomized breast cancer
prevention trial. Lancet 343:13181321[CrossRef][Medline]
-
Wolf DM, Jordan VC 1992 Gynecologic complications
associated with long-term adjuvant tamoxifen therapy for breast cancer.
Gynecol Oncol 45:118128[CrossRef][Medline]
-
Morgan MA, Gincherman Y, Mikuta JJ 1994 Endometriosis and tamoxifen therapy. Int J Gynecol Obstet 45:5557[CrossRef][Medline]
-
Uziely B, Lewin A, Brufman G, Dorembus D, Mor-Yosef
S 1993 The effect of tamoxifen on the endometrium. Breast Cancer
Res Treat 26:101105[CrossRef][Medline]
-
Anderson M, Storm HH, Mouridsen HT 1992 Carcinogenic effects of adjuvant tamoxifen treatment and radiotherapy
for early breast cancer. Acta Oncol 31:259263[Medline]
-
Cohen I, Rosen DJ, Shapira J, Cordoba M, Gilboa S,
Altaras MM, Yigael D, Beyth Y 1994 Endometrial changes with
tamoxifen: comparison between tamoxifen-treated and nontreated
asymptomatic, postmenopausal breast cancer patients. Gynecol Oncol 52:185190[CrossRef][Medline]
-
Tomas E, Kauppila A, Blaco G, Apaja-Sarkkinen M,
Laatikainen T 1995 Comparison between the effects of tamoxifen and
toremifene on the uterus in postmenopausal breast cancer patients.
Gynecol Oncol 59:261266[CrossRef][Medline]
-
Delmas PD, Bjarnason NH, Mitlak BH, Ravoux A-C, Shah
AS, Huster WJ, Draper M, Christiansen C 1997 Effects of raloxifene
on bone mineral density, serum cholesterol concentrations, and uterine
endometrium in postmenopausal women. N Engl J Med 337:16411647[Abstract/Free Full Text]
-
Draper MW, Flowers DE, Huster WJ, Neild JA, Harper KD,
Arnaud C 1996 A controlled trial of raloxifene (LY139481) HC1:
impact on bone turnover and serum lipid profile in healthy
postmenopausal women. J Bone Miner Res 11:835842[Medline]
-
Miodrag A, Ekelund P, Burton R, Castleden CM 1991 Tamoxifen and partial oestrogen agonism in postmenopausal women. Age
Aging 20:5254[Abstract/Free Full Text]
-
Cohen F, Watts S, Beymer K, et al, Vaginal
complaints in healthy postmenopausal women: data from a 3-year trial
comparing raloxifene with conjugated estrogens or placebo. Program of
the North American Menopause Society, Toronto, CA, September
1998
-
Baker VL, Draper M, Paul S, Allerheiligen S, Glant M,
Shifren J, Jaffe RB 1998 Reproductive endocrine and endometrial
effects of raloxifene hydrochloride, a selective estrogen receptor
modulator, in women with regular menstrual cycles. J Clin
Endocrinol Metab 83:613[Abstract/Free Full Text]
-
Baker VL, Jaffe RB 1995 Clinical uses of
antiestrogens. Obstet Gynecol Survey 51:4559
-
Jordan VC, Fritz NF, Tormey DC 1987 Endocrine
effects of adjuvant chemotherapy and long-term tamoxifen administration
on node-positive patients with breast cancer. Cancer Res 47:624630[Abstract/Free Full Text]
-
Jordan VC, Fritz NF, Langan-Fahey SM, Thompson M,
Tormey DC 1991 Alteration of endocrine parameters in premenopausal
women with breast cancer during long-term adjuvant therapy with
tamoxifen as the single agent. J Natl Cancer Inst 83:14881491[Abstract/Free Full Text]
-
Ravdin PM, Fritz NF, Tormey DC, Jordan VC 1988 Endocrine status of premenopausal node-positive breast cancer patients
following adjuvant chemotherapy and long-term tamoxifen. Cancer Res 48:10261029[Abstract/Free Full Text]
-
Jordan VC, Fritz NF, Tormey DC 1987 Long-term
adjuvant therapy with tamoxifen: effects on sex hormone binding
globulin antithrombin III. Cancer Res 47:45174519[Abstract/Free Full Text]
-
Patterson JS 1981 Clinical aspects and development
of antioestrogen therapy: a review of the endocrine effects of
tamoxifen in animals and man. J Endocrinol 89:6775
-
Lonning PE, Johannessen DC, Lien EA, Ekse D, Fotsis T,
Adlercreutz H 1995 Influence of tamoxifen on sex hormones,
gonadotrophins and sex hormone binding globulin in postmenopausal
breast cancer patients. J Steroid Biochem Mol Biol 52:491496[CrossRef][Medline]
-
Gasparini G, Canobbio L, Galligioni E, Fassio T, Brema
F, Crivellari D, Villalta D, Di Fronzo G, Talamini R, Monfardini S 1987 Sequential combination of tamoxifen and high dose
medroxyprogesterone acetate: therapeutic and endocrine effects in
postmenopausal advanced breast cancer patients. Eur J Cancer Clin Oncol 23:14511459[CrossRef][Medline]
-
Alexieva-Figusch J, Blankenstein MA, de Jong FH,
Lamberts SW 1984 Endocrine effects of the combination of megestrol
acetate and tamoxifen in the treatment of metastatic breast cancer. Eur
J Cancer Clin Oncol 20:135140[Medline]
-
Luciani L, Oriana S, Spatti G, Secreto G, Recchione C,
Grignoglio E, Andreola S, Coradini D, Ronchi E, Di Fronzo G 1984 Hormonal and receptor status in postmenopausal women with endometrial
carcinoma before and after treatment with tamoxifen. Tumori 70:189192[Medline]
-
Boccardo F, Guarneri D, Rubagotti A, Casertelli GL,
Bentivoglio G, Conte N Campanella G, Gaggero G, Comelli G, Zanardi S,
Nicolo G 1984 Endocrine effects of tamoxifen in
postmenopausal breast cancer patients. Tumori 70:6168
-
Szamel I, Hindy I, Vincze B, Eckhardt S, Kangas L,
Hajba A 1994 Influence of toremifene on the endocrine regulation
in breast cancer patients. Eur J Cancer 30A:154158 (Abstract)
-
Heel RC, Brogden RN, Speight TM 1978 Tamoxifen: a
review of its pharmacological properties and therapeutic use in the
treatment of breast cancer. Drugs 16:124[Medline]
-
Mouridsen HT, Palshof T, Patterson J, Battersby
L 1978 Tamoxifen in advanced breast cancer. Cancer Treat
Rev 5:131141[CrossRef][Medline]
-
Sawka CA, Pritchard KI, Paterson AH, Sutherland DJ,
Thomson DB, Shelley WE, Myers RE, Mobbs BG, Malkin A, Meakin JW 1986 Role and mechanism of action of tamoxifen in premenopausal women
with metastatic breast carcinoma. Cancer Res 46:31523156[Abstract/Free Full Text]
-
Fisher B, Costantino J, Redmond C, Poisson R, Bowman D,
Couture J, Dimitrov NV, Wolmark N, Wickerman DL, Fisher ER, Margolese
R, Robidoux A, Shibata H, Terz J, Paterson AHG, Feldman MI, Farrar W,
Evans J, Lickley HL, Ketner RN 1989 A randomized clinical
trial evaluating tamoxifen in the treatment of patients with
node-negative breast cancer who have estrogen-receptor-positive tumors.
N Engl J Med 320:479484
-
Love RR, Cameron L, Connell BL, Leventhal H 1991 Symptoms associated with tamoxifen treatment in postmenopausal women.
Arch Intern Med 151:18421947[Abstract/Free Full Text]
-
Costantino JP, Kuller LH, Ives DG, Fisher B, Dignam
J 1997 Coronary heart disease mortality and adjuvant tamoxifen
therapy. J Natl Cancer Inst 89:776782[Abstract/Free Full Text]
-
Willson TM, Henke BR, Momtahen TM, Charifson PS,
Batchelor KW, Lubahn DB, Moore LB, Oliver BB, Sauls HR, Triantafillou
JA, Wolfe SG, Baer PG 1994 3-[4-(1,2-Diphenylbut-1-enyl)phenylacrylic acid: a non-steroidal
estrogen with functional selectivity for bone over uterus in rats.
J Med Chem 37:15501552[CrossRef][Medline]
-
Beall PT, Misra LK, Young RL, Spjut HJ, Evans HJ,
LeBlanc A 1984 Clomiphene protects against osteoporosis in the
mature ovariectomized rat. Calcif Tissue Int 36:123125[CrossRef][Medline]
-
Ke HZ, Simmons HA, Pirie CM, Crawford DT, Thompson
DD 1995 Droloxifene, a new estrogen antagonist/agonist, prevents
bone loss in ovariectomized rats. Endocrinology 136:24352441[Abstract]
-
Chesnut C, Weiss S, Mulder H, Wasnich R, Greenwald M,
Eastell R, Fitts D, Jensen C, Haines A, MacDonald B 1998 Idoxifene
increases bone mineral density on osteopenic postmenopausal women. Bone
23:S389 (Abstract)
-
Kristensen B, Ejlertsen B, Dalgaard P, Larsen L,
Holmegaard SN, Transbol I, Mouridsen HT 1994 Tamoxifen and bone
metabolism in postmenopausal low-risk breast cancer patients: a
randomized study. J Clin Oncol 12:992997[Abstract/Free Full Text]
-
Ward RL, Morgan G, Dalley D, Kelly PJ 1993 Tamoxifen reduces bone turnover and prevents lumbar spine and proximal
femoral bone loss in early postmenopausal women. Bone Miner 22:8794[Medline]
-
Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA,
Jordan VC, Carbone PP, DeMets DL 1992 Effects of tamoxifen on bone
mineral density in postmenopausal women with breast cancer. N Engl
J Med 326:852856[Abstract]
-
Grey AB, Stapleton JP, Evans MC, Tatnell MA, Ames
RW, Reid IR 1995 The effect of the antiestrogen tamoxifen on bone
mineral density in normal late postmenopausal women. Am J Med 99:636641[CrossRef][Medline]
-
Wright CDP, Mansell RE, Gazet JC, Compston JE 1993 Effect of long term tamoxifen treatment on bone turnover in women with
breast cancer. Br Med J 306:429430
-
Wright CDP, Garrahan NJ, Stanton M, Gazet JC, Mansell
RE, Compston JE 1994 Effect of long term tamoxifen therapy on
cancellous bone remodeling and structure in women with breast cancer.
J Bone Miner Res 9:153159[Medline]
-
Kenny AM, Prestwood KM, Pilbeam CC, Raisz LG 1995 The short term effects of tamoxifen on bone turnover in older women.
J Clin Endocrinol Metab 80:32873291[Abstract]
-
Gotfredsen A, Christiansen C, Palshof T 1984 The
effect of tamoxifen on bone mineral content in premenopausal women with
breast cancer. Cancer 53:853857[CrossRef][Medline]
-
Deleted in proof
-
Love RR, Mazess RB, Tormey DC, Barden HS, Newcomb PA,
Jordan VC 1988 Bone mineral density in women with breast cancer
treated with adjuvant tamoxifen for at least two years. Breast Cancer
Res Treat 12:297302[CrossRef][Medline]
-
Fornander T, Rutqvist LE, Sjoberg HE, Blomqvist L,
Mattsson A, Glas U 1990 Long-term adjuvant tamoxifen in early
breast cancer: effect on bone mineral density in postmenopausal women.
J Clin Oncol 8:10191024[Abstract]
-
Cuzick J, Allen D, Baum M, Barrett J, Clark G, Kakkar
V, Melissari E, Moniz C, Moore J, Parsons V, Pemberton K, Pitt R,
Richmond W, Houghton J, Riley D 1993 Long term effects of
tamoxifen. Biological effects of Tamoxifen Working Party. Eur J Cancer
29A:1521
-
Fentiman IS, Caleffi M, Rodin A, Murby B, Fogelman
I 1989 Bone mineral content of women receiving tamoxifen for
mastalgia. Br J Cancer 60:262264[Medline]
-
Turken S, Siris E, Seldin D, Flaster E, Hyman G,
Lindsay R 1989 Effects of tamoxifen on spinal bone density in
women with breast cancer. J Natl Cancer Inst 71:10861088
-
Ryan WG, Wolter J, Bagdade JD 1991 Apparent
beneficial effects of tamoxifen on bone mineral content in patients
with breast cancer: preliminary study. Osteoporos Int 2:3941[CrossRef][Medline]
-
Fentiman IS, Saad Z, Caleffi M, Chaudary MA, Fogelman
I 1992 Tamoxifen protects against steroid-induced bone loss. Eur J
Cancer 28:684685
-
Love RR, Barden HS, Mazess RB, Epstein S, Chappell
RJ 1994 Effect of tamoxifen on lumbar spine bone mineral density
in postmenopausal women after 5 years. Arch Intern Med 154:25852588[Abstract/Free Full Text]
-
Powles TJ, Hickish T, Kanis JA, Tidy A, Ashley S 1996 Effect of tamoxifen on bone mineral density measured by dual
energy x-ray absorptiometry in healthy premenopausal and postmenopausal
women. J Clin Oncol 14:7884[Abstract]
-
Kristensen B, Ejlertsen B, Mouridsen HT, Andersen KW,
Lauritzen JB 1996 Femoral fractures in postmenopausal breast
cancer patients treated with adjuvant tamoxifen. Breast Cancer Res
Treat 39:321326[CrossRef][Medline]
-
Lufkin EG, Whitaker MD, Nickelsen T, Argueta R, Caplan
RH, Knickerbocker RK, Riggs BL 1998 Treatment of established
postmenopausal osteoporosis with raloxifene: a randomized trial. J
Bone Miner Res 13:17471754[CrossRef][Medline]
-
Heaney RP, Draper MW 1997 Raloxifene and estrogen:
comparative bone remodeling kinetics. J Clin Endocrinol Metab 82:34253429[Abstract/Free Full Text]
-
Hosking D, Chilvers CED, Christiansen C, Pernille R,
Wasnich R, Ross P, McClung M, Balske A, Thompson D, Daley M, Yates
J 1998 Prevention of bone loss with alendronate in postmenopausal
women under 60 years of age. N Engl J Med 338:485492[Abstract/Free Full Text]
-
Ettinger B, Black D, Cummings S, Genant H, Gluer C,
Lips P, Knickerbocker R, Eckert S, Nickelsen T, Mitlak B 1998 Raloxifene reduces the risk of incident vertebral fractures:
24-month interim analyses. Proceedings of the European Congress on
Osteoporosis. Osteoporos Int 8(S3):11
-
Bertelli G, Pronzato P, Amoroso D, Cusimano MP, Conte
PF, Montagna G, Bertolini S, Rosso R 1988 Adjuvant tamoxifen in
primary breast cancer: influence on plasma lipids and antithrombin III
levels. Breast Cancer Res Treat 12:307310[CrossRef][Medline]
-
Bagdade JD, Wolter J, Subbaiah PV, Ryan W 1990 Effects of tamoxifen treatment on plasma lipids and lipoprotein lipid
composition. J Clin Endocrinol Metab 70:11321135[Abstract/Free Full Text]
-
Love RR, Wiebe DA, Newcomb PA, Cameron L, Leventhal H,
Jordan VC, Feyzi J, DeMets DL 1991 Effects of tamoxifen on
cardiovascular risk factors in postmenopausal women. Ann Intern Med 115:860864
-
Love RR, Wiebe DA, Feyzi JM, Newcomb PA, Chappell
RJ 1994 Effects of tamoxifen on cardiovascular risk factors in
postmenopausal women after 5 years of treatment. J Natl Cancer
Inst 86:15341539[Abstract/Free Full Text]
-
Saarto T, Blomqvist C, Ehnholm C, Taskinen MR, Elomaa
I 1996 Antiatherogenic effects of adjuvant antiestrogens: a
randomized trial comparing the effects of tamoxifen and toremifene on
plasma lipid levels in postmenopausal women with node-positive breast
cancer. J Clin Oncol 14:429433[Abstract/Free Full Text]
-
Shewmon DA, Stock JL, Rosen CJ, Heiniluoma KM,
Hogue MM, Morrison A, Doyle EM, Ukena T, Weale V, Baker S 1994 Tamoxifen and estrogen lower circulating lipoprotein(a) concentrations
in healthy postmenopausal women. Arterioscler Thromb 14:15861593[Abstract/Free Full Text]
-
Grey AB, Stapleton JP, Evans MC, Reid IR 1995 The
effect of the anti-estrogen tamoxifen on cardiovascular risk factors in
normal postmenopausal women. J Clin Endocrinol Metab 80:31913195[Abstract]
-
Ilanchezhian S, Thangaraju M, Sachdanadam P 1995 Plasma lipids and lipoprotein alterations in tamoxifen-treated breast
cancer women in relation to menopausal status. Cancer Biochem Biophys 15:8390[Medline]
-
Wiseman H, Paganga G, Rice-Evans C, Halliwell
B 1993 Protective actions of tamoxifen and 4-hydroxytamoxifen
against oxidative damage to human low-density lipoproteins: a mechanism
accounting for the cardioprotective action of tamoxifen? Biochem J 292:635638
-
Guetta V, Lush RM, Figg WD, Waclawiw MA, Cannon III
RO 1995 Effects of the antiestrogen tamoxifen on low-density
lipoprotein concentrations and oxidation in postmenopausal women.
Am J Cardiol 76:10721073[CrossRef][Medline]
-
Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M,
Lawrence JB, Shah AS, Anderson PW 1998 Effects of raloxifene on
serum lipids and coagulation factors in healthy postmenopausal women.
JAMA 279:14451455[Abstract/Free Full Text]
-
Enck RE, Rios CN 1984 Tamoxifen treatment of
metastatic breast cancer and antithrombin III levels. Cancer 53:26072609[CrossRef][Medline]
-
Jordan VC, Fritz NF, Tormey DC 1987 Long-term
adjuvant therapy with tamoxifen: effects on sex hormone binding
globulin and antithrombin III. Cancer Res 47:45174519
-
Love RR, Surawicz TS, Williams EC 1992 Antithrombin III level, fibrinogen level, and platelet count changes
with adjuvant tamoxifen therapy. Arch Intern Med 152:317320[Abstract/Free Full Text]
-
Mannucci PM, Bettega D, Chantarangkul V, Tripodi A,
Sacchini V, Veronesi U 1996 Effect of tamoxifen on measurements of
hemostasis in healthy women. Arch Intern Med 156:18061810[Abstract/Free Full Text]
-
Pemberton KD, Melissari E, Kakkar VV 1993 The
influence of tamoxifen in vivo on the main natural
anticoagulants and fibrinolysis. Blood Coagul Fibrinolysis 4:935942[Medline]
-
Auger MJ, Mackie MJ 1988 Effects of tamoxifen on
blood coagulation. Cancer 61:13161319[CrossRef][Medline]
-
McDonald CC, Stewart HJ 1991 Fatal myocardial
infarction in the Scottish adjuvant tamoxifen trial. The Scottish
Breast Cancer Committee. Br Med J 303:435437
-
McDonald CC, Alexander FE, Whyte BW, Forrest AP,
Stewart HJ 1995 Cardiac and vascular morbidity in women receiving
adjuvant tamoxifen for breast cancer in a randomised trial. The
Scottish Cancer Trials Breast Group. Br Med J 311:977980[Abstract/Free Full Text]
-
Rutqvist LE, Mattsson A 1993 Cardiac and
thromboembolic morbidity among postmenopausal women with early stage
breast cancer in a randomized trial of adjuvant tamoxifen. The
Stockholm Breast Cancer Study Group. J Natl Cancer Inst 85:13981406[Abstract/Free Full Text]
-
Eli Lilly and Company 1998 Worldwide Trial To
Assess the Efficacy of Evista in Preventing Heart Attacks, Press
Release March 24,
-
Enck RE, Rios CN 1984 Tamoxifen treatment of
metastatic breast cancer and antithrombin III levels. Cancer 53:26072609
-
Fisher B, Redmond C 1992 Systemic therapty in
node-negative patients: updated findings from NSABP clinical trials.
National Surgical Adjuvant Breast and Bowel Project. J Natl Cancer
Inst Monogr 11:105116
-
Saphner T, Tormey DC, Gray R 1991 Venous and
arterial thrombosis in patients who received adjuvant therapy for
breast cancer. J Clin Oncol 9:286294[Abstract]
-
"Nolvadex" Adjuvant Trial Organisation 1988 Controlled trial of tamoxifen as a single adjuvant agent in the
management of early breast cancer. Br J Cancer 57:608611[Medline]
-
Delmas PD, Mitlak BH, Christiansen C 1998 Effects
of raloxifene in postmenopausal women (letter). N Engl J Med 338:13131314[Free Full Text]
-
Love RR, Cameron L, Connell BL, Leventhal H 1991 Symptoms associated with tamoxifen treatment in postmenopausal women.
Arch Intern Med 151:18421847
-
Nickelsen T, Lufkin EG, Riggs BL, Cox DA, Crook TH 1999 Raloxifene hydrochloride, a selective estrogen receptor modulator:
safety assessment of effects on cognitive function and mood in
postmenopausal women. Psychoneuroendocrinology 24:115128[CrossRef][Medline]
-
Ashford AR, Donev I, Tiwari RP, Garrett TJ 1988 Reversible ocular toxicity related to tamoxifen therapy. Cancer 61:3335[CrossRef][Medline]
-
Kaiser-Kupfer MI, Lippman ME 1978 Tamoxifen
retinopathy. Cancer Treat Rep 62:315320[Medline]
-
Heier JS, Dragoo RA, Enzenauer RW, Waterhouse WJ 1994 Screening for ocular toxicity in asymptomatic patients treated
with tamoxifen. Am J Ophthalmol 117:772775[Medline]
-
Costa RH, Dhooge MR, Van Wing F, De Rouck AF 1990 Tamoxifen retinopathy: a case report. Bull Soc Belge Ophtalmol 238:161168[Medline]
-
Gerner EW 1989 Ocular toxicity of tamoxifen. Ann
Ophthalmol 21:420423[Medline]
-
Mihm LM, Barton TL 1994 Tamoxifen-induced ocular
toxicity. Ann Pharmacol 28:740741[Medline]
-
Bently CR, Davies G, Aclimandos WA 1992 Tamoxifen
retinopathy: a rare but serious complication. Br Med J 304:495496
-
Longstaff S, Sigurdsson H, OKeeffe M, Osgton S,
Preece P 1989 A controlled study of the ocular effects of
tamoxifen in conventional dosate in the treatment of breast carcinoma.
Eur J Cancer Clin Oncol 25:18051808[CrossRef][Medline]
-
Pavlidis N, Petris C, Briassoulis E, Klouvas G, Psilas
C, Rempapis J, Retroutsos G 1992 Clear evidence that long-term,
low dose tamoxifen treatment can induce ocular toxicity. A prospective
study of 63 patients. Cancer 69:29612964[CrossRef][Medline]
-
Chang T, Gonder JR, Ventresca MR 1992 A case
report. Low dose tamoxifen retinopathy. Can J Ophthalmol 27:148149[Medline]
-
Gorin MB, Day R, Costantino JP, Fisher B, Redmond CK,
Wickerham L, Gomolin JE, Margolese RG, Mathen MK, Bowman DM, Kaufman
DI, Dimitrov NV, Singerman LJ, Bornstein R, Wolmark N, Kaufman DI 1998 Long-term tamoxifen citrate use and potential ocular toxicity.
Am J Ophthalmol 125:493501[CrossRef][Medline]
-
Williams GM, Iatropoulos MJ, Djordjevic MV, Kaltenberg
OP 1993 The triphenylethylene drug tamoxifen is a strong liver
carcinogen in the rat. Carcinogenesis 14:315317[Abstract/Free Full Text]
-
Hard GC, Iatropoulos MJ, Jordan K, Radi L, Kaltenberg
OP, Imondi AR, Williams GM 1993 Major differences in the
hepatocarcinogenicity and DNA adduct forming ability between toremifene
and tamoxifen in female Crl:CD(BR) rats. Cancer Res 53:45344541[Abstract/Free Full Text]
-
Fornander T, Rutqvist LE, Cedermark BV, Glas U,
Mattsson A, Silfversward C, Skoog L, Somell A, Theve T, Wilking N,
Askergren J, Hjalmar ML 1989 Adjuvant tamoxifen in early
breast cancer: occurrence of new primary cancers. Lancet 1:117120[Medline]
-
Martin EA, Rich KJ, White IN, Woods KL, Powles TJ,
Smith LL 1995 32P-Postlabelled DNA adducts in liver obtained from
women treated with tamoxifen. Carcinogenesis 16:16511654[Abstract/Free Full Text]
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[Full Text]
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|
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[Full Text]
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|

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[Full Text]
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[Full Text]
[PDF]
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|

|
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[Abstract]
[Full Text]
|
 |
|

|
 |

|
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J Natl Cancer Inst Monographs,
July 1, 2000;
2000(27):
135 - 145.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
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Lasofoxifene (CP-336,156), a Selective Estrogen Receptor Modulator, Prevents Bone Loss Induced by Aging and Orchidectomy in the Adult Rat
Endocrinology,
April 1, 2000;
141(4):
1338 - 1344.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
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Selective Androgen Receptor Modulators (SARMs): A Novel Approach to Androgen Therapy for the New Millennium
J. Clin. Endocrinol. Metab.,
October 1, 1999;
84(10):
3459 - 3462.
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
N. K. Shevde, A. C. Bendixen, K. M. Dienger, and J. W. Pike
Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression
PNAS,
July 5, 2000;
97(14):
7829 - 7834.
[Abstract]
[Full Text]
[PDF]
|
 |
|