Selective estrogen receptor modulators. (Featured CME Topic).

Abstract: Because of recent concerns about the long-term risks of estrogen replacement therapy in postmenopausual women, there is growing interest in a group of compounds known as selective estrogen receptor modulators (SERMs). The SERMs bind to estrogen receptors and have tissue-specific effects that allow them to function as estrogen agonists in some tissues and estrogen antagonists in other tissues. There are four SERMs currently marketed in the United States. These include the triphenylethylenes--clomiphene citrate (Clomid), tamoxifen, and toremifene--and the benzothiophene, raloxifene. Clomid is used primarily in the treatment of infertility. Tamoxifen is indicated for the treatment and prevention of breast cancer. It has an estrogen antagonist effect on breast tissue, but an estrogen-like effect on lipids, bone, and the endometrium. Toremifene has an antagonist/agonist profile similar to that of tamoxifen. Raloxifene is approved for the prevention of osteoporosis in postmenopausal women. It is thought t o be an estrogen antagonist on the uterus and breast tissues and an estrogen agonist with respect to bone and serum lipids.

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Key Points

* The SERMs bind to estrogen receptors and have tissue specific actions such that they function as estrogen agonists in some tissues and estrogen antagonists in others.

* Tamoxifen is indicated for the treatment and prevention of breast cancer. It is thought to have an estrogen antagonist effect on breast tissue and an estrogen agonist effect on bone and endometrium.

* Raloxifene is indicated for the treatment and prevention of osteoporosis in postmenopausal women. It is thought to have an estrogen agonist effect on bone and an estrogen antagonist effect on breast tissue.

During the past decade, interest has been growing in estrogen replacement therapy (ERT) for the treatment of menopausal symptoms and for the prevention of the long-term effects of estrogen deficiency, such as osteoporosis and cardiovascular disease. Substantial evidence indicates that ERT not only controls hot flashes and vaginal dryness (1) but also helps prevent the development of osteoporosis and resultant fractures, (2) improves the lipoprotein profile in postmenopausal women, (3) and may result in overall decreased mortality in estrogen users compared with nonusers. (4) Despite the numerous benefits of ERT, enthusiasm for its use has been tempered by recent studies that have provided evidence of increased rates of breast cancer in women taking estrogen and progesterone (5) and a possible increased risk of cardiovascular death within the first year of use in women with known cardiovascular disease. (6) Because of these concerns, there has been increasing interest in the group of compounds known as selecti ve estrogen receptor modulators (SERMs). The SERMs are a heterogeneous group of compounds that can bind to the estrogen receptor and have "tissue-specific" effects such that they function as estrogen agonists in some tissues and as estrogen antagonists in other tissues. These compounds have been touted as "designer estrogens," (7) and there is hope that they will be able to provide the benefits of ERT without the increased risks. The four SERMs currently marketed in the United States are clomiphene citrate, tamoxifen citrate, toremifene citrate, and raloxifene hydrochloride. Clomiphene citrate, tamoxifen citrate, and toremifene citrate belong to the family of triphenylethylene compounds, and raloxifene is a benzothiophene. This review discusses the biology of the estrogen receptor, the mechanisms of action, and the risks, benefits, and recommended uses of currently available SERMs and SERMs in development (Table 1). For each SERM, the agonist/antagonist effects on breast tissue, the cardiovascular system, the skeletal system, the endometrium, and the central nervous system (ONS) are reviewed (Table 2).

Biology of the Estrogen Receptor

Estrogen receptors are nuclear proteins belonging to the steroid/thyroid superfamily of "ligand-dependent" nuclear transcription factors. They can activate transcription of certain genes after binding with the appropriate ligand (estrogen or selective estrogen receptor modulator). The classic estrogen receptor (estrogen receptor [alpha]) was discovered in the 1960s and then later cloned from the rat uterus in 1986. (8) In 1996, a second estrogen receptor, estrogen receptor [beta], was identified. (9) The pattern of expression of estrogen receptors a and [beta] seems to differ, in that estrogen receptor [beta] is more prevalent in the CNS, cardiovascular and immune systems, urogenital tract, bone, kidney, and lung, whereas the estrogen receptor a predominates in the uterus and mammary gland. (10)

The structural organization of the nuclear receptor super-family of receptor proteins has been found to be similar regardless of ligand and includes several regions, including an amino terminal region, a DNA binding domain, a hinge region, and the ligand hormone binding domain." When estrogen encounters an estrogen receptor, a series of events occurs. The estrogen binds to the ligand-binding domain, the binding domain changes shape, and it attaches to a docking site called an estrogen response element on certain genes. Either the conformational change or the attachment then triggers the formation of a transcription complex, which is a cluster of cofactors and other proteins. The completed complex is subsequently able to interact with the gene and induce RNA polymerase to transcribe the gene. (12)

The SERM Concept

The extremely complex pharmacology of SERMs is not yet completely understood. It seems that there are at least two distinct mechanisms by which the SERMs may have differing actions within various cells.

First, various ligands induce various conformational changes. The binding of estrogen to an estrogen receptor induces a conformational change in the ligand-binding domain that promotes the binding of coactivator transcriptional mediators. Alternatively, the binding of a SERM to an estrogen receptor may result in a different conformational change, making the binding of the coactivators more difficult or even causing the binding of a corepressor. Certain cells may produce coactivators or corepressors that are able to bind to these abnormally shaped receptor complexes, and other cells may not. The myriad effects of SERMs in various cells may be the result of the ratios of different coactivators and corepressors and other cell-specific factors found in each individual cell. (11)

Second, since the discovery of two distinct estrogen receptors several years ago, it is now thought that the overall biologic activity of a compound reflects the product of its relative agonist/antagonist activity on the two receptors. It is known that estrogen receptors [alpha] and [beta] are expressed differently in some tissues. Estradiol 17-[beta] and tamoxifen appear to bind to the two receptors with equal affinity, but raloxifene has now been shown to have a higher affinity for estrogen receptor [alpha]. Despite these differences in tissues and in binding affinities, it is clear that the existence of a second receptor does not fully explain the complex pharmacology of the SERMs. (13)

Currently Available SERMs

The Triphenylethylenes

Clomiphene citrate. Clomiphene stimulates ovulation and is one of the most widely used drugs in the treatment of infertility. It functions primarily as an antiestrogen at the level of the pituitary where it enhances the release of folliclestimulating hormone. (14) Clomiphene may be an antiresorptive agent in bone. (15) There are few clinical data on the effect of clomiphene citrate on lipids, breast tissue, or the cardiovascular system. (16) As with other SERMs, hot flashes have been reported as a side effect of treatment with clomiphene. (17)

Tamoxifen. The U.S. Food and Drug Administration approved this drug in 1977. It is indicated for 1) the treatment of metastatic breast cancer in women and men; 2) the treatment of node-positive breast cancer in postmenopausal women after total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation; 3) the treatment of axillary node-negative breast cancer in women after total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation; and 4) risk reduction in women at high risk for developing breast cancer (Table 3). (18,19)

In breast cancer treatment, the anticancer effects of tamoxifen are thought to be due to antiestrogenic activity, mediated by competitive inhibition of the estrogen receptor. The expression of estrogen-regulated genes is subsequently inhibited, including growth factors and angiogenic factors secreted by tumor cells. (20-22)

As adjuvant therapy, postoperative treatment with tamoxifen has been shown to reduce the risk of recurrence and prolong survival in women with operable breast cancer in whom the tumors are confined to the breast and axillary nodes.

In a meta-analysis including more than 37,000 women enrolled in 55 trials, tamoxifen was found to be associated with a significant reduction in recurrence and death after a median follow-up of 10 years. The annual reductions in recurrence and death with tamoxifen were 26 and 14% compared with placebo. (23) These benefits were greatest in women with trogen receptor-positive tumors. Whether tamoxifen improves outcome in women with few or no estrogen receptors has been controversial. (23)

Women with clinically evident metastatic disease may also benefit from tamoxifen. Overall, approximately 30% of women with metastatic breast cancer treated with tamoxifen have objective regression of the tumor for an average of 12 months, whereas in another 20%, the disease remains stable for at least 6 months. (24) A few women have remissions lasting years, but resistance to tamoxifen inevitably develops. (24) Postmenopausal women with strongly estrogen and progesterone receptor-positive tumors have the greatest response. (25)

The clinical data from the breast cancer treatment trials gave additional impetus for preventive trials with tamoxifen. In addition to the reductions in recurrence and mortality, it was noted that tamoxifen reduced the risk of contralateral breast cancers by 47% after 5 years of treatment. (23) The National Surgical Adjuvant Breast and Bowel Project (NSABP) began in 1992 and involved 13,388 women aged 35 years or older who were at high risk for breast cancer. The trial was terminated 14 months before completion because of compelling evidence of reductions in invasive and noninvasive breast cancer. Tamoxifen reduced the incidence of invasive breast cancer by 49% and noninvasive cancer by 50%. (26)

Two subsequent European trials did not confirm these results. The Royal Marsden Trial (27) studied 2,471 women between 30 and 70 years of age with a family history of breast cancer for 70 months and found no statistically significant decrease in breast cancer with tamoxifen use compared with placebo. The Italian Tamoxifen Prevention Study (28) recruited patients from the general population, with an overall lower risk of breast cancer, but this study also failed to confirm the NSABP findings. These discrepant results may be explained by differences in the study populations, increased use of estrogen replacement in the study populations of European trials, and limited statistical power of the Italian study to detect a benefit. (29)

Given these results, the U.S. Food and Drug Administration approved tamoxifen for the primary prevention of breast cancer in women at high risk in 1998, with the recommendation that the decision to use tamoxifen as prophylactic chemotherapy should be made only after a thorough evaluation of a woman's personal and family history and an assessment of the risks and benefits of treatment. (30)

A number of studies have reported that tamoxifen has a protective effect on bone mineral density in postmenopausal women, (31-33) although the beneficial effect on fracture reduction has not been as well established. In the NSABP, there was a nonsignificant decrease of hip, vertebral, and wrist fractures. (26) However, because the population was not selected for low bone density, the risk for fracture was low and the study was not powered to show a reduction in fractures. In another study of older nursing home residents receiving tamoxifen for more than 1.5 years, there was no significant decrease in hip fracture for those receiving 20 mg of tamoxifen compared with controls, though there was a small but significant risk reduction for those receiving a 10 mg/d dose of tamoxifen. (34) Although tamoxifen seems to have beneficial effects on bone mineral density and possibly fracture risk in postmenopausal women, Powles et a1 (35) reported that tamoxifen may cause bone loss in premenopausal women after at least 3 years of treatment.

Tamoxifen has been shown in a number of studies to have beneficial effects on cardiac risk factors and intermediate markers for cardiovascular disease. (36-39) In postmenopausal women, tamoxifen has been shown to reduce lowdensity lipoprotein (LDL) cholesterol by approximately 20% after 5 years or more of treatment but has not been shown to have a beneficial effect on high-density lipoprotein (HDL) cholesterol or triglycerides. (36) Tamoxifen has also been associated with a reduction in lipoprotein (a) (40) and homocysteine levels (41) in postmenopausal women.

Several studies have also suggested that tamoxifen may reduce the incidence of cardiovascular disease in women being treated for breast cancer. The Scottish Cancer Trials Breast Group studied 1,312 women who were randomized to receive tamoxifen or placebo for up to 14 years and found the hazard ratio for myocardial infarction in patients treated with tamoxifen was 0.29 in current users and 0.52 for all users. (42) In the Stockholm Randomized Trial of Adjuvant Tamoxifen, 2,365 postmenopausal women with established breast cancer were randomized to receive tamoxifen or placebo. Results showed a relative hazard of 0.68 for hospital admission due to cardiac disease. (43) In the NSABP, (26) however, there was no significant reduction in the incidence of myocardial infarction in the tamoxifen-treated versus the placebo-treated women, and the trend toward increased risk of stroke in the tamoxifen-treated women was nonsignificant.

Data regarding tamoxifen's effect on the human CNS are extremely limited. One study evaluated cognitive function in breast cancer patients who received adjuvant chemotherapy compared with those who received no adjuvant therapy and found significantly more cognitive impairment in the chemotherapy group than in the control group. (44) Cognitive impairment was noticed in several domains of cognitive function, including attention, speed of processing, visual memory, and motor processing. No difference was noted between the 20 of 39 patients who had received tamoxifen along with standard chemotherapy in terms of self-reports of symptoms or measured cognitive function.

In the rat brain, tamoxifen has been shown to restore 5-hydroxytryptamine (5-FIT) receptor levels (which are decreased after ovariectomy) in the striatum only, whereas treatment with estradiol or raloxifene restores 5-HT receptor density in cingulate and frontal cortices, stratum, and nucleus accumbens. (45)

Tamoxifen has been shown to have several effects on the uterus, including proliferation of the endometrium with increased thickness as assessed by performing ultrasonography (46,47) and an increased risk of endometrial polyps, leiomyomas, and postmenopausal bleeding. (48) Several large studies have also shown an increased risk of endometrial carcinoma associated with tamoxifen treatment. (49,50) Some oft his apparent increase in risk may be due to increased identification of endometrial cancers in women taking tamoxifen because of heightened surveillance or increased postmenopausal bleeding leading to further evaluation.

Other adverse effects associated with tamoxifen include hot flashes, vaginal dryness or discharge, nausea, ocular toxicity, and venous thromboembolic events. (51) The risk of venous thromboembolism appears to be similar to that of estrogen replacement therapy and is approximately two to three times that of placebo-treated groups in clinical trials. (51)

Toremifene citrate. Toremifene is a triphenylethylene derivative of tamoxifen and is indicated for the treatment of breast cancer in postmenopausal women with tumors that are estrogen receptor positive or of unknown receptor status. Toremifene has been directly compared with tamoxifen in prospective, randomized clinical trials of postmenopausal breast cancer patients with estrogen receptor positive or estrogen receptor unknown status and found to have similar efficacy and similar adverse effects. (52,53)

A recent small study compared the effects of tamoxifen and toremifene on markers of bone turnover and bone mineral density. Toremifene was found to have a weaker effect on biochemical markers of bone metabolism than tamoxifen. (54)

With regard to the cardiovascular system, toremifene appears to reduce total cholesterol, LDL cholesterol, and apolipoprotein B to an extent comparable with tamoxifen. In one study, toremifene was also shown to increase HDL by 14%. (55) No data are available yet on the effect of toremifene on the CNS.

Limited clinical evidence now suggests that toremifene and tamoxifen have comparable stimulatory effects on the uterus (as documented by ultrasonography), although the percentage of patients with marked changes to the endometrium, including hyperplasia and polyps, appears to be higher with tamoxifen. (56)

The Beuzothiophenes

Raloxifene. This drug is approved for the prevention of osteoporosis in postmenopausal women. It is thought to be an estrogen antagonist on the uterus and mammary tissues and an estrogen agonist with respect to bone and serum lipids and breast tissue. Unlike women treated with estrogen, women treated with raloxifene report no increased incidence of breast discomfort. (57) In addition, pooled data from raloxifene trials involving more than 10,000 women showed that raloxifene significantly reduced the incidence of primary breast cancers. (58) The incidence of newly diagnosed breast cancer in the raloxifene-treated groups was 1.7 per 1,000 compared with 3.7 per 1,000 in the placebo groups (relative risk [RR], 0.46). In the MORE trial (Multiple Outcomes of Raloxifene Evaluation) involving 7,705 postmenopausal women with osteoporosis, raloxifene-treated women showed a 75% lower incidence of newly diagnosed breast cancer than the placebo-treated group after 3 years of treatment. (59) However, these trials were all designed to study women with osteoporosis and did not specifically target women at risk for breast cancer. The STAR trial (Study of Tamoxifen and Raloxifene) is currently ongoing and hopes to enroll 22,000 women aged 35 to 59 at risk for breast cancer and women aged 60 and older with no additional risk factors. The women will be assigned to tamoxifen or raloxifene for 5 years.

Several studies have evaluated the effects of raloxifene on biochemical markers of bone turnover, bone mineral density, and fracture risk. In a multicenter European study, (60) 600 early postmenopausal women were randomized to receive raloxifene or placebo. Raloxifene prevented bone loss at multiple skeletal sites, with a 2.4% increase in bone mineral density over placebo at the lumbar spine and total hip after 2 years of treatment. Bone turnover also decreased, as shown by markers of bone formation-that is, a 23% reduction in serum osteocalcin, a 15% reduction in bone-specific alkaline phosphatase, and a 34% reduction in urinary excretion of type I collagen c-telopeptide. (60) The effect of raloxifene on fracture risk has also been evaluated. The MORE trial (61) showed a 30 to 50% reduction in vertebral fractures in osteoporotic women treated with raloxifene for 3 years compared with those given placebo.

The effects of raloxifene on markers of cardiovascular disease have been evaluated in several studies. (60,62) In one study, 390 healthy postmenopausal women were randomized to receive either raloxifene at a dosage of 60 mg daily, raloxifene at 120 mg daily, conjugated equine estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg daily, or placebo. Lipid levels and coagulation parameters were measured at 3 and 6 months. Compared with placebo, raloxifene lowered LDL cholesterol by 12% at both dosages, whereas estrogen lowered LDL by 14%. Raloxifene had no effect on HDL cholesterol or triglycerides. (63) A large-scale, prospective, randomized trial, the RUTH (Raloxifene Use for the Heart) trial, is currently enrolling patients for a 5- to 7 112-year trial and plans to enroll 10,000 patients and evaluate the combined endpoints of coronary death and nonfatal myocardial infarction.

The estrogen agonist-antagonist effects of raloxifene on the CNS are still under investigation. Raloxifene had initially been thought to be a possible estrogen antagonist in the CNS because of its propensity to induce hot flashes. (63) However, animal studies have shown conflicting results and some evidence that raloxifene may be at least a partial estrogen agonist in the CNS. (64-67) In humans, two randomized trials have now evaluated the effect on raloxifene versus placebo on cognitive function in postmenopausal women. The first trial was designed as a safety assessment of the effect of raloxifene on cognition and mood in women participating in a randomized, double-blind, osteoporosis treatment trial. One hundred forty-two women were assigned to 60 mg of raloxifene, 120 mg of raloxifene, or placebo, and psychometric tests were administered at 1, 6, and 12 months. After 12 months, there was no significant difference in the raloxifene or placebo groups, but there was a slight increase in performance favoring 120-mg dosage of raloxifene in an assessment of verbal memory after 1 month of treatment. (68) Recently released data from cognitive testing in the MORE trial included 7,500 women with osteoporosis. They were randomized to receive 60 or 120 mg of raloxifene or placebo for 3 years, and cognitive testing was done at baseline, at 6 months, and at 1, 2, and 3 years. Although there was no significant difference among the groups, there was a trend toward less decline in the combined raloxifene groups on two tests of verbal memory and attention. (69)

Unlike tamoxifen, raloxifene does not appear to stimulate the endometrium. Several studies have found no difference in the incidence of vaginal bleeding or spotting in women given raloxifene versus placebo. (70,71) In a 12-month comparative study of the effects of raloxifene, estrogen, and placebo on the postmenopausal endometrium, raloxifene has not been shown to increase endometrial thickness. (72) In the MORE trial, there was no increase in the incidence of endometrial carcinoma after 36 months of treatment. (71) In animals, there may be a uterotropic response in immature rats treated with raloxifene after ovariectomy, (73) and long-term studies are needed in humans to fully evaluate the effect of raloxifene on the endometrium.

Compounds in Development

A number of new compounds are in various stages of clinical development. The effects of many of these compounds on the breast, the uterus, and the skeletal, cardiovascular, and central nervous systems have not yet been reported.

Tamoxifen Derivatives (Triphenylethylenes)

Droloxifene. Droloxifene (3-hydroxytamoxifen) has been clinically evaluated for the treatment of breast cancer. A phase II study showed antitumor activity in postmenopausal women with advanced breast cancer, but clinical development of the drug for breast cancer therapy was subsequently halted because of lack of sufficient efficacy. (74) Droloxifene is reported to exert a greater antiestrogenic effect on the rat uterus than tamoxifen (75) and has shown prevention of ovariectomy-induced bone loss in rats, as well as lowering of total serum cholesterol. (76) In a recent study, 24 women were randomized to receive droloxifene or estrogen in a crossover trial comparing the effects of droloxifene and estrogen on plasma lipids. Droloxifene use led to a 16% reduction in LDL cholesterol compared with a 12% reduction for estrogen. Estrogen, but not droloxifene, raised HDL cholesterol levels. (77)

Idoxifene. Idoxifene (pyrollidino-4-iodotamoxifen) is in clinical testing for osteoporosis prevention and breast cancer treatment. Preliminary results in 331 osteopenic women indicated that the daily use of 5 or 10 mg of idoxifene, for 3 months, reduced biochemical markers of bone resorption and reduced LDL cholesterol. (78) Adverse effects of idoxifene included hot flashes, vaginal discharge, and increased endometrial thickness. (79)

Miproxifene. Miproxifene (TAT 59) is in phase III clinical trials for treatment of advanced breast cancer. In vitro, TAT 59 exerts a greater antiestrogenic effect than tamoxifen against tumors exhibiting low levels of estrogen receptor activity. (80) The estrogenic activity of TAT 59 has been evaluated in ovariectomized rats. TAT 59 suppresses the ovariectomy-induced decrease in bone density and reduces cholesterol levels. (81)

FC1271A. This new triphenylethylene compound appears to have an estrogen agonist/antagonist profile similar to that of tamoxifen. In ovariectomized rats, FC1271A prevents ovariectomy-induced bone loss and decreases cholesterol. At higher doses, there is an increase in uterine weight (in rats) but less than the increase seen with tamoxifen or toremefine. (82)

Raloxifene Derivatives (Benzothiophenes)

LY353381. LY35338 1 is currently being clinically evaluated. It seems to be more potent than raloxifene as an estrogen antagonist in the rat endometrium and more potent than raloxifene as an estrogen agonist on bone and serum lipids. (83) In a recently completed Phase I trial (84) ofLY35338l for treatment of metastatic breast cancer, 32 patients with recurrent or metastatic breast cancer were treated with oral daily doses of LY353381. It was found to be safe and well tolerated and of possible clinical benefit for patients with extensively pretreated metastatic breast cancer. Further studies to evaluate its efficacy are under way.

Conclusions

Because women live for an average of 30 years past menopause, they and their physicians inevitably face questions about the risks and benefits of HRT and alternative treatment with SERMs. Pharmaceutical companies are striving to produce the SERM with the ideal profile of estrogen agonist and antagonist properties for the treatment and prevention of breast cancer, osteoporosis, and cardiovascular disease. These compounds provide a rich new category of drug therapy that is only beginning to be understood and clinically evaluated. Tamoxifen and raloxifene have already proved to be safe and effective for the treatment of breast cancer and osteoporosis, respectively. New SERMs in development may be of even greater benefit, but much more research and clinical experience are necessary before the full risks and potential benefits of these drugs are understood.

Table 1

Selective estrogen receptor modulators currently available and in
development


The Triphenylethylenes
 Clomiphene citrate
 Tamoxifen
 Toremifene
 Droloxifene (in development)
 Idoxifene (in development)
 Miproxifene (in development)
 FC1271A (in development)
The Benzothiophenes
 Raloxifene
 LY353381 (in development)

Table 2

Estrogenic agonist/antagonist effects of tamoxifen, toremifine, and
raloxifene

Drug        Breast      Bone     Lipids   Uterus

Tamoxifen   Antagonist  Agonist  Agonist  Agonist
Toremifine  Antagonist  Agonist  Agonist  Agonist
Raloxifene  Antagonist  Agonist  Agonist  Antagonist

Table 3

Tamoxifen and raloxifene: Indications for use


Tamoxifen
  Treatment of metastatic breast cancer in men and women
  Treatment of node-positive breast cancer in postmenopausal women
    after total mastectomy or segmental mastectomy, axillary
    dissection, and breast irradiation
  Treatment of node-negative breast cancer in women after total
    mastectomy or segmental mastectomy, axillary dissection,
    and breast irradiation
  Reduction in breast cancer risk in high-risk women
Raloxifene
  Prevention of osteoporosis in postmenopausal women

Accepted April 23, 2002.

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From the Section of General Internal Medicine, Yale University School of Medicine, New Haven, and the VA Women's Health Center, VA Connecticut, West Haven, CT.

Reprint requests to Sally 0. Haskell, MD, VA Connecticut, 950 Campbell Avenue, West Haven, CT 06516. Email: [e-mail]

Copyright [c] 2003 by The Southern Medical Association 0038-4348/03/9605-0469