This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cosman, F. Articles by Lindsay, R. Search for Related Content PubMed PubMed Citation Articles by Cosman, F. Articles by Lindsay, R.

Selective Estrogen Receptor Modulators: Clinical Spectrum¹

Clinical Research and Regional Bone Centers, Helen Hayes Hospital, New York State Department of Health, West Haverstraw, New York 10993

	Abstract

Top Abstract I. Introduction II. Breast Effects III. Reproductive System Effects IV. Skeletal Effects: Bone... V. Vascular System Effects:... VI. Central Nervous System... VII. Hepatic Effects VIII. Miscellaneous Effects IX. Conclusion References

 

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

	I. Introduction

Top Abstract I. Introduction II. Breast Effects III. Reproductive System Effects IV. Skeletal Effects: Bone... V. Vascular System Effects:... VI. Central Nervous System... VII. Hepatic Effects VIII. Miscellaneous Effects IX. Conclusion References

 
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 Alzheimer’s 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 15–40% (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.

View larger version (20K): [in this window] [in a new window]   Figure 1. Structure of estrogen analogs in clinical use or clinical development.

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.

	II. Breast Effects

Top Abstract I. Introduction II. Breast Effects III. Reproductive System Effects IV. Skeletal Effects: Bone... V. Vascular System Effects:... VI. Central Nervous System... VII. Hepatic Effects VIII. Miscellaneous Effects IX. Conclusion References

 
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).

View larger version (27K): [in this window] [in a new window]   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 351:1451–1467, 1998 (27 ). © The Lancet Ltd.]

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 48–63% (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 30–47%, 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 35–59 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.

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.

	III. Reproductive System Effects

Top Abstract I. Introduction II. Breast Effects III. Reproductive System Effects IV. Skeletal Effects: Bone... V. Vascular System Effects:... VI. Central Nervous System... VII. Hepatic Effects VIII. Miscellaneous Effects IX. Conclusion References

 
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, 1.7–10.90). 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.

	IV. Skeletal Effects: Bone Mass, Bone Metabolism, and Fracture Occurrence

Top Abstract I. Introduction II. Breast Effects III. Reproductive System Effects IV. Skeletal Effects: Bone... V. Vascular System Effects:... VI. Central Nervous System... VII. Hepatic Effects VIII. Miscellaneous Effects IX. Conclusion References

 
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 tamoxifen’s 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 20–40%, 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.

View larger version (27K): [in this window] [in a new window]   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 14:78–84, 1996 (133 ).]

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, 0.63–1.05). 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, 0.46–1.68), 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, 0.60–1.05). 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 tamoxifen’s 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 2–8 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).

View larger version (25K): [in this window] [in a new window]   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 337:1641–1647, 1997 (90 ). © Massachusetts Medical Society. All rights reserved.]

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

Top Abstract I. Introduction II. Breast Effects III. Reproductive System Effects IV. Skeletal Effects: Bone... V. Vascular System Effects:... VI. Central Nervous System... VII. Hepatic Effects VIII. Miscellaneous Effects IX. Conclusion References

 
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 estrogen’s effect, high-density lipoprotein (HDL) cholesterol was not increased by tamoxifen, but actually decreased slightly in that study. Similarly to estrogen’s 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).

View larger version (14K): [in this window] [in a new window]   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 80:3191–3195, 1995 (144 ). © The Endocrine Society.]

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 15–18% 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 (12–14%), 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 58–59 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 = 0.27–1.61). If death from possible MI was added, relative risk became 0.85 (confidence interval = 0.46–1.58).

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 = 0.98–3.20).

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= 1.15–9.27), and for deep vein thrombosis was 1.60 (CI = 0.91–2.86). 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

Top Abstract I. Introduction II. Breast Effects III. Reproductive System Effects IV. Skeletal Effects: Bone... V. Vascular System Effects:... VI. Central Nervous System... VII. Hepatic Effects VIII. Miscellaneous Effects IX. Conclusion References

 
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 raloxifene’s 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 = 1.01–1.29) and an increase in the relative risk of cataract surgery (RR 1.57; 95% CI, 1.16–2.14). 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

Top Abstract I. Introduction II. Breast Effects III. Reproductive System Effects IV. Skeletal Effects: Bone... V. Vascular System Effects:... VI. Central Nervous System... VII. Hepatic Effects VIII. Miscellaneous Effects IX. Conclusion References

 
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

Top Abstract I. Introduction II. Breast Effects III. Reproductive System Effects IV. Skeletal Effects: Bone... V. Vascular System Effects:... VI. Central Nervous System... VII. Hepatic Effects VIII. Miscellaneous Effects IX. Conclusion References

 
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

Top Abstract I. Introduction II. Breast Effects III. Reproductive System Effects IV. Skeletal Effects: Bone... V. Vascular System Effects:... VI. Central Nervous System... VII. Hepatic Effects VIII. Miscellaneous Effects IX. Conclusion References

 
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

Top Abstract I. Introduction II. Breast Effects III. Reproductive System Effects IV. Skeletal Effects: Bone... V. Vascular System Effects:... VI. Central Nervous System... VII. Hepatic Effects VIII. Miscellaneous Effects IX. Conclusion References

 

1. Ettinger B 1998 Overview of estrogen replacement therapy: a historical perspective. Proc Soc Exp Biol Med 217:2–5[CrossRef][Medline]
2. Ulmsten U 1997 Some reflections and hypotheses on the pathophysiology of female urinary incontinence. Acta Obstet Gynecol Scand 76:3–8
3. 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 122:9–16[Abstract/Free Full Text]
4. Lindsay R, Hart DM, Forrest C, Baird C 1980 Prevention of spinal osteoporosis in oophorectomised women. Lancet 2:1151–1154[Medline]
5. Lufkin EG, Wahner HW, O’Fallon WM, Hodgson SF, Kotowicz MA, Lane AW, Judd HL, Caplan RH, Riggs BL 1992 Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med 117:1–9
6. Nasr A, Breckwoldt M 1998 Estrogen replacement therapy and cardiovascular protection: lipid mechanisms are the tip of an iceberg. Gynecol Endocrinol 12:43–59[Medline]
7. Henderson VW 1997 The epidemiology of estrogen replacement therapy and Alzheimer’s disease. Neurology 48:S27–S35
8. Yaffe K, Sawaya G, Lieberburg I, Grady D 1998 Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA 9:688–695
9. Paganini-Hill A 1997 Does estrogen replacement therapy protect against Alzheimer’s disease? Osteopor Int 7[Suppl1]:S12–S17
10. 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 50:1249–1264[CrossRef][Medline]
11. 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 280:605–613[Abstract/Free Full Text]
12. Barrett-Connor E, Stuenkel CA 1998 Anticipating HERS: questions from the heart and estrogen/progestin replacement study. J Womens Health 7:395–397[Medline]
13. Barrett-Connor E 1991 Postmenopausal estrogen and prevention bias. Ann Intern Med 115:455–456
14. 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 217:30–37[CrossRef][Medline]
15. 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 350:1047–1059
16. Ravnikar VA 1992 Compliance with hormone replacement therapy: are women receiving the full impact of hormone replacement therapy preventive health benefits? Womens Health Issues 2:75–80[CrossRef][Medline]
17. 1995 Gallup Survey
18. 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 349:458–461[CrossRef][Medline]
19. Udoff L, Langenberg P, Adashi EY 1995 Combined continuous hormone replacement therapy: a critical review. Obstet Gynecol 86:306–316[CrossRef][Medline]
20. Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S 1996 Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 348:977–980[CrossRef][Medline]
21. 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 348:983–987[CrossRef][Medline]
22. 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 348:981–983[CrossRef][Medline]
23. Herbst AL, Griffiths CT, Kistner RW 1964 Clomiphene citrate in disseminated mammary carcinoma. Cancer Chemother Rep 43:39–41
24. 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 10:747–749
25. Clark JH, Markaverich BM 1982 The agonistic-antagonistic properties of clomiphene: a review. Pharm Ther 15:467–519
26. 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 339:1–15, 71–85[Medline]
27. Early Breast Cancer Trialists’ Collaborative Group 1998 Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 351:1451–1467[CrossRef][Medline]
28. Osborne CK 1998 Drug therapy. Tamoxifen in the treatment of breast cancer. N Engl J Med 339:1609–1618[Free Full Text]
29. Hortobagyi GN 1998 Treatment of breast cancer. N Engl J Med 339:974–984[Free Full Text]
30. 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 88:1529–1542[Abstract/Free Full Text]
31. 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 88:1828–1833[Abstract/Free Full Text]
32. 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 89:1673–1682[Abstract/Free Full Text]
33. 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 115:153–162
34. 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 27:699–705[Medline]
35. 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 12:2078–2085[Abstract/Free Full Text]
36. 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 15:2302–2311
37. 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 8:1005–1018[Abstract]
38. 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 15:1385–1394[Abstract]
39. Albain K, Green S, Osborne K, Cobau C, Levine E, Ingle J, Pritchard K, Schneider D, O’Sullivan 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)
40. 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 347:1066–1071[CrossRef][Medline]
41. 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 10:1284–1291[Abstract/Free Full Text]
42. 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 4:1326–1330[Abstract/Free Full Text]
43. 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 4:178–185[Abstract]
44. Muss HB, Smith LR, Cooper MR 1987 Tamoxifen rechallenge: response to tamoxifen following relapse after adjuvant chemohormonal therapy for breast cancer. J Clin Oncol 5:1556–1558[Abstract/Free Full Text]
45. 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 24:785–790[CrossRef][Medline]
46. Gunderson S 1990 Toremifene, a new antiestrogenic compound in the treatment of advanced breast cancer. Phase II study. Eur J Cancer
47. Modig H, Borgstrom M, Nilsson I, Westman G 1990 Phase II clinical study of toremifene in patients with metastatic breast cancer. J Steroid Biochem 36:235–236[CrossRef][Medline]
48. 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]:S37–S40
49. 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 13:2556–2566[Abstract]
50. 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:S40–S45
51. 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]:S36–S39
52. 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 31:425–428[Medline]
53. Rausching W, Pritchard KI 1994 Droloxifene, a new antiestrogen: its role in metastatic breast cancer. Breast Cancer Res Treat 31:93–94
54. 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 33:313–316[Medline]
54. Buzdar AU, Marcus C, Holmes F, Hug V, Hortobagyi G 1988 Phase II evaluation of Ly156758 in metastatic breast cancer. Oncology 45:344–345[Medline]
55. 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 90:1371–1388[Abstract/Free Full Text]
56. 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 81:1879–1886[Abstract/Free Full Text]
57. 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 352:98–101[Medline]
58. 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 352:93–97[Medline]
59. Pritchard KI 1998 Commentary — Is tamoxifen effective in prevention of breast cancer? Lancet 352:80–81[Medline]
60. 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 16–19, 1998, Los Angeles, CA
61. 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 16–19, 1998, 17 Los Angeles, CA
62. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG 1994 Ovarian tumors in a cohort of infertile women. N Engl J Med 331:771–776[Abstract/Free Full Text]
63. 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 136:1184–1203[Abstract/Free Full Text]
64. Spirtas R, Kaufman SC, Alexander NJ 1993 Fertility drugs and ovarian cancer: red alert or red herring? Fertil Steril 59:291–294[Medline]
65. 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 136:1204–1211[Abstract/Free Full Text]
66. 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 174:141–144[CrossRef][Medline]
67. 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 69:620–621
68. 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 86:527–537[Abstract/Free Full Text]
69. 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 87:1359–1364[Abstract/Free Full Text]
70. 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 87:645–651[Abstract/Free Full Text]
71. Neven P, De Muylder X, Van Belle Y, Vanderick G, De Muylder E 1979 Tamoxifen and the uterus and endometrium (letter). Lancet 1:385
71. Stewart HJ, Knight GM 1989 Tamoxifen and the uterus and endometrium (letter). Lancet 1:375–376[CrossRef][Medline]
72. 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,
73. 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
74. 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
75. 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 125–161
76. Prescribing information for Fareston® (toremifene), Schering
76. 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
77. Product circular 1997 Evista (raloxifene hydrocholoride). Eli Lilly and Company, Indianapolis, IN
78. Neven P, DeMulder X, van Belle Y, Campo R, Vanderick G 1994 Tamoxifen and the uterus. Br Med J 309:1313–1314[Free Full Text]
79. 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 81:660–664[Medline]
80. Thylan S 1995 Tamoxifen treatment and its consequences. Hum Reprod 10:2174–2178[Free Full Text]
81. 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 100:567–570[Medline]
82. Jaiyesimi IA, Buzdar AU, Decker DA, Hortobagyi GN 1995 Use of tamoxifen for breast cancer: twenty-eight years later. J Clin Oncol 113:513–529
83. 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 343:1318–1321[CrossRef][Medline]
84. Wolf DM, Jordan VC 1992 Gynecologic complications associated with long-term adjuvant tamoxifen therapy for breast cancer. Gynecol Oncol 45:118–128[CrossRef][Medline]
85. Morgan MA, Gincherman Y, Mikuta JJ 1994 Endometriosis and tamoxifen therapy. Int J Gynecol Obstet 45:55–57[CrossRef][Medline]
86. Uziely B, Lewin A, Brufman G, Dorembus D, Mor-Yosef S 1993 The effect of tamoxifen on the endometrium. Breast Cancer Res Treat 26:101–105[CrossRef][Medline]
87. Anderson M, Storm HH, Mouridsen HT 1992 Carcinogenic effects of adjuvant tamoxifen treatment and radiotherapy for early breast cancer. Acta Oncol 31:259–263[Medline]
88. 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 52:185–190[CrossRef][Medline]
89. 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 59:261–266[CrossRef][Medline]
90. 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 337:1641–1647[Abstract/Free Full Text]
91. 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 11:835–842[Medline]
92. Miodrag A, Ekelund P, Burton R, Castleden CM 1991 Tamoxifen and partial oestrogen agonism in postmenopausal women. Age Aging 20:52–54[Abstract/Free Full Text]
93. 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
94. 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 83:6–13[Abstract/Free Full Text]
95. Baker VL, Jaffe RB 1995 Clinical uses of antiestrogens. Obstet Gynecol Survey 51:45–59
96. 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 47:624–630[Abstract/Free Full Text]
97. 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 83:1488–1491[Abstract/Free Full Text]
98. 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 48:1026–1029[Abstract/Free Full Text]
99. Jordan VC, Fritz NF, Tormey DC 1987 Long-term adjuvant therapy with tamoxifen: effects on sex hormone binding globulin antithrombin III. Cancer Res 47:4517–4519[Abstract/Free Full Text]
100. Patterson JS 1981 Clinical aspects and development of antioestrogen therapy: a review of the endocrine effects of tamoxifen in animals and man. J Endocrinol 89:67–75
101. 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 52:491–496[CrossRef][Medline]
102. 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 23:1451–1459[CrossRef][Medline]
103. 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 20:135–140[Medline]
104. 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 70:189–192[Medline]
105. 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 70:61–68
106. 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:154–158 (Abstract)
107. Heel RC, Brogden RN, Speight TM 1978 Tamoxifen: a review of its pharmacological properties and therapeutic use in the treatment of breast cancer. Drugs 16:1–24[Medline]
108. Mouridsen HT, Palshof T, Patterson J, Battersby L 1978 Tamoxifen in advanced breast cancer. Cancer Treat Rev 5:131–141[CrossRef][Medline]
109. 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 46:3152–3156[Abstract/Free Full Text]
110. 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 320:479–484
111. Love RR, Cameron L, Connell BL, Leventhal H 1991 Symptoms associated with tamoxifen treatment in postmenopausal women. Arch Intern Med 151:1842–1947[Abstract/Free Full Text]
112. Costantino JP, Kuller LH, Ives DG, Fisher B, Dignam J 1997 Coronary heart disease mortality and adjuvant tamoxifen therapy. J Natl Cancer Inst 89:776–782[Abstract/Free Full Text]
113. 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 37:1550–1552[CrossRef][Medline]
114. 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 36:123–125[CrossRef][Medline]
115. Ke HZ, Simmons HA, Pirie CM, Crawford DT, Thompson DD 1995 Droloxifene, a new estrogen antagonist/agonist, prevents bone loss in ovariectomized rats. Endocrinology 136:2435–2441[Abstract]
115. 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)
116. 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 12:992–997[Abstract/Free Full Text]
117. 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 22:87–94[Medline]
118. 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 326:852–856[Abstract]
119. 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 99:636–641[CrossRef][Medline]
120. 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 306:429–430
121. 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 9:153–159[Medline]
122. 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 80:3287–3291[Abstract]
123. Gotfredsen A, Christiansen C, Palshof T 1984 The effect of tamoxifen on bone mineral content in premenopausal women with breast cancer. Cancer 53:853–857[CrossRef][Medline]
124. Deleted in proof
125. 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 12:297–302[CrossRef][Medline]
126. 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 8:1019–1024[Abstract]
127. 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:15–21
128. Fentiman IS, Caleffi M, Rodin A, Murby B, Fogelman I 1989 Bone mineral content of women receiving tamoxifen for mastalgia. Br J Cancer 60:262–264[Medline]
129. 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 71:1086–1088
130. 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 2:39–41[CrossRef][Medline]
131. Fentiman IS, Saad Z, Caleffi M, Chaudary MA, Fogelman I 1992 Tamoxifen protects against steroid-induced bone loss. Eur J Cancer 28:684–685
132. 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 154:2585–2588[Abstract/Free Full Text]
133. 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 14:78–84[Abstract]
134. 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 39:321–326[CrossRef][Medline]
135. 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 13:1747–1754[CrossRef][Medline]
136. Heaney RP, Draper MW 1997 Raloxifene and estrogen: comparative bone remodeling kinetics. J Clin Endocrinol Metab 82:3425–3429[Abstract/Free Full Text]
136. 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 338:485–492[Abstract/Free Full Text]
137. 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
138. 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 12:307–310[CrossRef][Medline]
139. Bagdade JD, Wolter J, Subbaiah PV, Ryan W 1990 Effects of tamoxifen treatment on plasma lipids and lipoprotein lipid composition. J Clin Endocrinol Metab 70:1132–1135[Abstract/Free Full Text]
140. 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 115:860–864
141. 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 86:1534–1539[Abstract/Free Full Text]
142. 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 14:429–433[Abstract/Free Full Text]
143. 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 14:1586–1593[Abstract/Free Full Text]
144. 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 80:3191–3195[Abstract]
145. 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 15:83–90[Medline]
146. 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 292:635–638
147. 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 76:1072–1073[CrossRef][Medline]
148. 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 279:1445–1455[Abstract/Free Full Text]
149. Enck RE, Rios CN 1984 Tamoxifen treatment of metastatic breast cancer and antithrombin III levels. Cancer 53:2607–2609[CrossRef][Medline]
150. Jordan VC, Fritz NF, Tormey DC 1987 Long-term adjuvant therapy with tamoxifen: effects on sex hormone binding globulin and antithrombin III. Cancer Res 47:4517–4519
151. Love RR, Surawicz TS, Williams EC 1992 Antithrombin III level, fibrinogen level, and platelet count changes with adjuvant tamoxifen therapy. Arch Intern Med 152:317–320[Abstract/Free Full Text]
152. 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 156:1806–1810[Abstract/Free Full Text]
153. Pemberton KD, Melissari E, Kakkar VV 1993 The influence of tamoxifen in vivo on the main natural anticoagulants and fibrinolysis. Blood Coagul Fibrinolysis 4:935–942[Medline]
154. Auger MJ, Mackie MJ 1988 Effects of tamoxifen on blood coagulation. Cancer 61:1316–1319[CrossRef][Medline]
155. McDonald CC, Stewart HJ 1991 Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. The Scottish Breast Cancer Committee. Br Med J 303:435–437
156. 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 311:977–980[Abstract/Free Full Text]
157. 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 85:1398–1406[Abstract/Free Full Text]
158. Eli Lilly and Company 1998 Worldwide Trial To Assess the Efficacy of Evista in Preventing Heart Attacks, Press Release March 24,
159. Enck RE, Rios CN 1984 Tamoxifen treatment of metastatic breast cancer and antithrombin III levels. Cancer 53:2607–2609
160. 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 11:105–116
161. Saphner T, Tormey DC, Gray R 1991 Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol 9:286–294[Abstract]
162. "Nolvadex" Adjuvant Trial Organisation 1988 Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer. Br J Cancer 57:608–611[Medline]
162. Delmas PD, Mitlak BH, Christiansen C 1998 Effects of raloxifene in postmenopausal women (letter). N Engl J Med 338:1313–1314[Free Full Text]
163. Love RR, Cameron L, Connell BL, Leventhal H 1991 Symptoms associated with tamoxifen treatment in postmenopausal women. Arch Intern Med 151:1842–1847
164. 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 24:115–128[CrossRef][Medline]
165. Ashford AR, Donev I, Tiwari RP, Garrett TJ 1988 Reversible ocular toxicity related to tamoxifen therapy. Cancer 61:33–35[CrossRef][Medline]
166. Kaiser-Kupfer MI, Lippman ME 1978 Tamoxifen retinopathy. Cancer Treat Rep 62:315–320[Medline]
167. Heier JS, Dragoo RA, Enzenauer RW, Waterhouse WJ 1994 Screening for ocular toxicity in asymptomatic patients treated with tamoxifen. Am J Ophthalmol 117:772–775[Medline]
168. Costa RH, Dhooge MR, Van Wing F, De Rouck AF 1990 Tamoxifen retinopathy: a case report. Bull Soc Belge Ophtalmol 238:161–168[Medline]
169. Gerner EW 1989 Ocular toxicity of tamoxifen. Ann Ophthalmol 21:420–423[Medline]
170. Mihm LM, Barton TL 1994 Tamoxifen-induced ocular toxicity. Ann Pharmacol 28:740–741[Medline]
171. Bently CR, Davies G, Aclimandos WA 1992 Tamoxifen retinopathy: a rare but serious complication. Br Med J 304:495–496
172. Longstaff S, Sigurdsson H, O’Keeffe 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 25:1805–1808[CrossRef][Medline]
173. 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 69:2961–2964[CrossRef][Medline]
174. Chang T, Gonder JR, Ventresca MR 1992 A case report. Low dose tamoxifen retinopathy. Can J Ophthalmol 27:148–149[Medline]
175. 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 125:493–501[CrossRef][Medline]
176. Williams GM, Iatropoulos MJ, Djordjevic MV, Kaltenberg OP 1993 The triphenylethylene drug tamoxifen is a strong liver carcinogen in the rat. Carcinogenesis 14:315–317[Abstract/Free Full Text]
177. 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 53:4534–4541[Abstract/Free Full Text]
178. 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 1:117–120[Medline]
179. 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 16:1651–1654[Abstract/Free Full Text]

This article has been cited by other articles:

				F. Saad, J. D. Adachi, J. P. Brown, L. A. Canning, K. A. Gelmon, R. G. Josse, and K. I. Pritchard Cancer Treatment-Induced Bone Loss in Breast and Prostate Cancer J. Clin. Oncol., November 20, 2008; 26(33): 5465 - 5476. [Abstract] [Full Text] [PDF]

				C. Prakash, K. A. Johnson, C. M. Schroeder, and M. J. Potchoiba Metabolism, Distribution, and Excretion of a Next Generation Selective Estrogen Receptor Modulator, Lasofoxifene, in Rats and Monkeys Drug Metab. Dispos., September 1, 2008; 36(9): 1753 - 1769. [Abstract] [Full Text] [PDF]

				G. Coiret, A.-S. Borowiec, P. Mariot, H. Ouadid-Ahidouch, and F. Matifat The Antiestrogen Tamoxifen Activates BK Channels and Stimulates Proliferation of MCF-7 Breast Cancer Cells Mol. Pharmacol., March 1, 2007; 71(3): 843 - 851. [Abstract] [Full Text] [PDF]

				M Maggiolini, A G Recchia, D Bonofiglio, S Catalano, A Vivacqua, A Carpino, V Rago, R Rossi, and S Ando The red wine phenolics piceatannol and myricetin act as agonists for estrogen receptor {alpha} in human breast cancer cells J. Mol. Endocrinol., October 1, 2005; 35(2): 269 - 281. [Abstract] [Full Text] [PDF]

				C. J. Larson, D. L. Osburn, K. Schmitz, L. Giampa, S.-M. Mong, K. Marschke, H. M. Seidel, J. Rosen, and A. Negro-Vilar Peptide Binding Identifies an ER{alpha} Conformation That Generates Selective Activity in Multiple In Vitro Assays J Biomol Screen, September 1, 2005; 10(6): 590 - 598. [Abstract] [PDF]

				T. Takahashi, M. Ohmichi, J. Kawagoe, C. Ohshima, M. Doshida, T. Ohta, M. Saitoh, A. Mori-Abe, B. Du, H. Igarashi, et al. Growth Factors Change Nuclear Distribution of Estrogen Receptor-{alpha} via Mitogen-Activated Protein Kinase or Phosphatidylinositol 3-Kinase Cascade in a Human Breast Cancer Cell Line Endocrinology, September 1, 2005; 146(9): 4082 - 4089. [Abstract] [Full Text] [PDF]

				J. E Sanchez-Criado, C. Bellido, R. Aguilar, and J. C Garrido-Gracia A paradoxical inhibitory effect of oestradiol-17{beta} on GnRH self-priming in pituitaries from tamoxifen-treated rats J. Endocrinol., July 1, 2005; 186(1): 43 - 49. [Abstract] [Full Text] [PDF]

				A. Tamrazi, K. E. Carlson, A. L. Rodriguez, and J. A. Katzenellenbogen Coactivator Proteins as Determinants of Estrogen Receptor Structure and Function: Spectroscopic Evidence for a Novel Coactivator-Stabilized Receptor Conformation Mol. Endocrinol., June 1, 2005; 19(6): 1516 - 1528. [Abstract] [Full Text] [PDF]

				J. Gauduchon, F. Gouilleux, S. Maillard, V. Marsaud, J.-M. Renoir, and B. Sola 4-Hydroxytamoxifen Inhibits Proliferation of Multiple Myeloma Cells In vitro through Down-Regulation of c-Myc, Up-Regulation of p27Kip1, and Modulation of Bcl-2 Family Members Clin. Cancer Res., March 15, 2005; 11(6): 2345 - 2354. [Abstract] [Full Text] [PDF]

				J E Sanchez-Criado, J M. de las Mulas, C Bellido, R Aguilar, and J C Garrido-Gracia Gonadotrope oestrogen receptor-{alpha} and -{beta} and progesterone receptor immunoreactivity after ovariectomy and exposure to oestradiol benzoate, tamoxifen or raloxifene in the rat: correlation with LH secretion J. Endocrinol., January 1, 2005; 184(1): 59 - 68. [Abstract] [Full Text] [PDF]

				R. F. Casper Phytoestrogens, Clomiphene, and the Uterus Reproductive Sciences, July 1, 2004; 11(5): 261 - 262. [PDF]

				M. Tena-Sempere, V.M. Navarro, A. Mayen, C. Bellido, and J.E. Sanchez-Criado Regulation of Estrogen Receptor (ER) Isoform Messenger RNA Expression by Different ER Ligands in Female Rat Pituitary Biol Reprod, March 1, 2004; 70(3): 671 - 678. [Abstract] [Full Text] [PDF]

				A. Tamrazi, K. E. Carlson, and J. A. Katzenellenbogen Molecular Sensors of Estrogen Receptor Conformations and Dynamics Mol. Endocrinol., December 1, 2003; 17(12): 2593 - 2602. [Abstract] [Full Text] [PDF]

				M. Dutertre and C. L. Smith Ligand-Independent Interactions of p160/Steroid Receptor Coactivators and CREB-Binding Protein (CBP) with Estrogen Receptor-{alpha}: Regulation by Phosphorylation Sites in the A/B Region Depends on Other Receptor Domains Mol. Endocrinol., July 1, 2003; 17(7): 1296 - 1314. [Abstract] [Full Text] [PDF]

				A. Cagnacci, A. M. Paoletti, A. Zanni, S. Arangino, G. Ibba, M. Orru, G. B. Melis, and A. Volpe Raloxifene Does Not Modify Insulin Sensitivity and Glucose Metabolism in Postmenopausal Women J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4117 - 4121. [Abstract] [Full Text] [PDF]

				T. Simoncini, G. Varone, L. Fornari, P. Mannella, M. Luisi, F. Labrie, and A. R. Genazzani Genomic and Nongenomic Mechanisms of Nitric Oxide Synthesis Induction in Human Endothelial Cells by a Fourth-Generation Selective Estrogen Receptor Modulator Endocrinology, June 1, 2002; 143(6): 2052 - 2061. [Abstract] [Full Text] [PDF]

				H. Brady, S. Desai, L. M. Gayo-Fung, S. Khammungkhune, J. A. McKie, E. O'Leary, L. Pascasio, M. K. Sutherland, D. W. Anderson, S. S. Bhagwat, et al. Effects of SP500263, a Novel, Potent Antiestrogen, on Breast Cancer Cells and in Xenograft Models Cancer Res., March 1, 2002; 62(5): 1439 - 1442. [Abstract] [Full Text] [PDF]

				T. S Mikkola and T. B Clarkson Estrogen replacement therapy, atherosclerosis, and vascular function Cardiovasc Res, February 15, 2002; 53(3): 605 - 619. [Abstract] [Full Text] [PDF]

				J. M. Fitts, R. M. Klein, and C. A. Powers Estrogen and Tamoxifen Interplay with T3 in Male Rats: Pharmacologically Distinct Classes of Estrogen Responses Affecting Growth, Bone, and Lipid Metabolism, and Their Relation to Serum GH and IGF-I Endocrinology, October 1, 2001; 142(10): 4223 - 4235. [Abstract] [Full Text] [PDF]

				S. Nilsson, S. Makela, E. Treuter, M. Tujague, J. Thomsen, G. Andersson, E. Enmark, K. Pettersson, M. Warner, and J.-A. Gustafsson Mechanisms of Estrogen Action Physiol Rev, October 1, 2001; 81(4): 1535 - 1565. [Abstract] [Full Text] [PDF]

				B. H. Arjmandi The Role of Phytoestrogens in the Prevention and Treatment of Osteoporosis in Ovarian Hormone Deficiency J. Am. Coll. Nutr., October 1, 2001; 20(90005): 398S - 402. [Abstract] [Full Text]

				M. Dutertre and C. L. Smith Molecular Mechanisms of Selective Estrogen Receptor Modulator (SERM) Action J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 431 - 437. [Abstract] [Full Text]

				D. M. Kraichely, J. Sun, J. A. Katzenellenbogen, and B. S. Katzenellenbogen Conformational Changes and Coactivator Recruitment by Novel Ligands for Estrogen Receptor-{alpha} and Estrogen Receptor-{beta}: Correlations with Biological Character and Distinct Differences among SRC Coactivator Family Members Endocrinology, October 1, 2000; 141(10): 3534 - 3545. [Abstract] [Full Text] [PDF]

				S. Tamir, M. Eizenberg, D. Somjen, N. Stern, R. Shelach, A. Kaye, and J. Vaya Estrogenic and Antiproliferative Properties of Glabridin from Licorice in Human Breast Cancer Cells Cancer Res., October 1, 2000; 60(20): 5704 - 5709. [Abstract] [Full Text]

				R. B. Dickson and G. M. Stancel Chapter 8: Estrogen Receptor-Mediated Processes in Normal and Cancer Cells J Natl Cancer Inst Monographs, July 1, 2000; 2000(27): 135 - 145. [Abstract] [Full Text] [PDF]

				H. Z. Ke, H. Qi, D. T. Crawford, K. L. Chidsey-Frink, H. A. Simmons, and D. D. Thompson 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]

				A. Negro-Vilar 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]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cosman, F. Articles by Lindsay, R. Search for Related Content PubMed PubMed Citation Articles by Cosman, F. Articles by Lindsay, R.