Selective Estrogen Receptor Modulators. Antonio Cano

Chapter 11. Endometrial Effects of SERMs

• Santiago Palacios

11.1

Introduction

SERMs (Selective Estrogen Receptor Modulators) are compounds with a molecular structure different from that of steroids. They share with steroids their selective binding to estrogen receptors (ERs), which is followed by an agonistic or antagonistic effect, depending on the target cell and the hormonal environment. Initially known as antiestrogens, and developed for treatment of breast cancer, the two better known SERMs tamoxifen and raloxifene are being used currently in the prevention and treatment of breast cancer and osteoporosis, respectively. A recently published review of a total of 37,000 women in 55 trials confirmed that, when used as an additional treatment, tamoxifen significantly improved 10-year survival in women with breast cancer positive for ER (Early Breast Cancer Trialists’ Collaborative Group 1998). Nevertheless, the incidence of endometrial cancer appeared to double after 1 to 2 years of treatment, and nearly quadrupled when treatment lasted for 5 years (Early Breast Cancer Trialists’ Collaborative Group 1998).

These clinical observations demonstrate that the effect of tamoxifen and other SERMs on the endometrium needs to be studied in depth in order to offer objective evidence-based information on these compounds to our patients. This chapter provides a summary of the information available on the mechanism of action and on the clinical data of SERMs on the endometrium.

11.2

Mechanism of Action in the Endometrium

As has been widely commented in previous chapters, the agonist/antagonist profile of a given SERM is determined by the type of compound and the particular target tissue.

Members of the different SERM families bind to the ligand-binding domain (LBD) of the ER, whose particular crystal structure has been revealed for estradiol and for raloxifene (Brzozowski et al. 1997). Once inserted into the binding cavity, estradiol makes direct hydrogen bonds bewteen its A-ring and the carboxylate of Glu 353, the guanidinium group of Arg 394, and between a water molecule, and between its D-ring and His 524 (Brzozowski et al. 1997). As a consequence of the estradiol insertion within the LBD, the large helix 12 of the ER folds over and traps the steroid, thus exposing three specific amino acids, 540,543, and 547, critical within the activating function-2 (AF-2) region for binding coactivators (Tzukerman et al. 1994).

Raloxifene is also anchored to the same three amino acids as estradiol by direct hydrogen bonds, but it also interacts with Asp 351. The final orientation of raloxifene within the binding pocket determines that its side chain displaces helix 12. Then, helix 12 becomes reoriented and cannot seal the pocket containing the ligand (MacGregor et al. 1998). The repositioned AF-2 region impairs the formation of transcription complex by coactivators, and the signal transduction is blocked.

11.2.1

Tamoxifen

Together with other members of the triphenylethylene family, tamoxifen has been shown to act as an AF-2 antagonist, a trait shared with raloxifene. However, tamoxifen and other triphenylethylene derivatives act as partial agonists in the uterus, an effect that seems opposite to that of raloxifene. It may, therefore, be postulated that at the endometrial level (where both tamoxifen and raloxifene share the same tissue and promoter context), the contrasting action of those compounds may be due to particular details of the conformational change induced on the ligand-receptor complex, at either the AF-2 or other domain. Recent results obtained in mice further support the notion that tamoxifen acts in the endometrium as a classical impeded estrogen and that the AF-1 domain regulates its effects (Zhang et al. 2005).

The proliferative effects of tamoxifen on the endometrium have been supported by molecular data. The expression of both ER and progesterone receptors (PRs) was found to be consistently positive in endometria from women treated with tamoxifen for 1 month (Cano et al. 2000). That positivity has been reported to be even higher than that found in a control group of premenopausal women (Kommoss et al. 1998). Tamoxifen also mimicked estradiol treatment in up-regulating ERs, c-fos, and glyceraldehyde phosphate dehydrogenase mRNAs, together with other estrogen-induced genes (Rivera- Gonzalez et al. 1998; Robertson et al. 1998). The bromo-deoxyuridine index, an indicator of cell mitogenesis, has been shown to increase in endometrial cells from tamoxifen-treated uteri (Karlsson et al. 1998; Carthew et al. 1999). In this connection, the expression of markers of proliferation, e.g., Ki67, was potentiated by tamoxifen in human endometrium (Elkas et al. 1998). More recently, tamoxifen increased Ki67 expression in the human endometrial adenocarcinoma Ishikawa cell line (Koda et al. 2004). An increased susceptibility to genetic lesions associated with carcinogenesis linked to tamoxifen was suggested by a study on endometrium of surgically postmenopausal cynomolgus macaques, where the drug induced p53 positivity, although at a lower level than conjugated equine estrogens (CEE) (Isaksson et al. 1999).

The available experimental information is still of little help in clarifying whether tamoxifen is genotoxic and oncogenetic in human endometrium. There is, nonetheless, a great deal of debate about the actual relevance of minor concentrations of adducts (as detected by high-perfomance liquid chromatography and other modern technology), compared with the high concentrations induced in rat hepatic tumors, or the equally elevated concentrations formed in human DNA as a result of enviromental sources (Swen- berg et al. 1997). Accordingly, if tamoxifen is an endometrial carcinogen, as classified by the International Agency for Research on Cancer (IARC), its mechanism of action is possibly different from that reported in rat liver.

An alternative oncogenetic mode of action of tamoxifen on human endometrium may derive from its proliferative activity. It is possible that the increase in the rate of mitoses in a given tissue entails an augmented risk of mutation, the first step toward malignancy (Ames et al. 1990). Therefore, it is possible that the oncogenetic attributes of estrogens in tissues where they induce a proliferative effect (e.g., breast or endometrium) might be influenced by the mutagenic potential derived from a higher mitotic activity. This might also be the main pathway for the oncogenetic action of tamoxifen in the uterus, where one study showed that an increase in uterine weight by tamoxifen was accompanied by a doubled uterine expression of insulinlike growth factor-I (IGF-I), whereas the opposite occurred when the pure antiestrogen ICI 182780 was used instead of tamoxifen (Huynh et al. 1993). In a subsequent study, the same investigators showed that the expression of insulinlike growth factor-binding protein (IGFBP)-3, the principal quantitative binder of IGF-I, was similarly suppressed by estradiol and tamoxifen (Huynh et al. 1994).

The dysregulation of transforming growth factor-β (TGFβ) has also been suggested as an additional epigenetic (nongenotoxic) mechanism of tamoxifen carcinogenicity (Carmichael et al. 1998). It has been postulated that the tamoxifen-induced dysregulation of the TGFβ signalling pathway may create an environment that selects for the cells with genetic alterations in the signal system (Carmichael et al. 1998). Cells with mutations in this pathway become refractory to mitosis inhibitory signals, thus developing into end-stage tumors.

11.2.2

Raloxifene

Crystallographic studies have confirmed that a critical difference in the antiestrogenic action of raloxifene lies in the interaction of the alkylaminoethoxy side chain with the amino acid aspartate at position 351. The peculiar orientation of this side chain of the raloxifene molecule, an essential determinant of the antiestrogenic properties of the drug, is believed to account for its lack of endometrial activity (Clark et al. 1976; Grese et al. 1997; Bryant et al. 1998).

Biochemical data support the lack of agonistic activity of raloxifene on uterine tissue (Somjen et al. 1996). Raloxifene has exhibited little uterothropic activity in rodents (Black and Goode 1980, 1981; Black et al. 1983) and has not resulted in increases in uterine weight or in stimulation of epithelial cell height and eosinophilic infiltration (Bryant et al. 1998). In other experiments on ovariectomized rats, raloxifene was similar to the no-treatement controls with regard to uterine epithelial cell height myometrial thickness and stromal expansion (Black et al. 1994; Sato et al. 1996). There are, however, discrepant data showing increases in uterine weight and uterine epithelial thickness in ovariectomized (Sato et al. 1996) or immature (Ashby et al. 1997) rats. Interestingly, raloxifene has been shown to block the stimulating endometrial effects of estrogen and tamoxifen (Bryant et al. 1998; Black et al. 1994; Sato et al. 1996; Palacios et al. 2000), an effect confirmed on an endometrial carcinoma cell line grown in athymic mice (Kleinman et al. 1996).

Table 11.1. Actions of SERMs on uterus. Preclinical data (Gottardis et al. 1990)

A summary of preclinical data on the uterus is given in Table 11.1 (Gottardis et al. 1990).

11.3

Tamoxifen and Endometrium: Clinical Consideration

Descriptive as well as case-control and cohort studies have shown that tamoxifen may cause alterations, including cancer, in human endometrium. The findings have been observed in studies using ultrasound technology or histology data.

11.3.1

Ultrasonographic Findings

Studies carried out with transvaginal ultrasound (TVU) in postmenopausal women with breast cancer have shown that the endometrium is thickened more frequently in women receiving tamoxifen than in those not treated with the drug. For example, in a transversal study Cohen et al. observed that 94.6% of women treated with tamoxifen and nonsymptomatic from a gynecological point of view had an endometrial thickness ≥ 5 mm, an observation that was present in only 40% of women who did not receive this treatment (Cohen et al. 1994).

Further, postmenopausal women taking tamoxifen for secondary prevention of breast cancer for an average of 24 months seemed to have a uterus significantly larger and with a greater volume than those who did not take the drug. Their endometrium was also significantly thicker (average of 9.1 vs. 4.8 mm, respectively). Yet, although the normal appearance of the endometrium was more frequent in the untreated group, this difference was not significant. However, the image of thickened cystic endometrium was significantly more frequent in the tamoxifen group (Kedar et al. 1994).

11.3.2

Hystological Findings

The presence of an enlarged endometrium (≥ 5 mm) may be associated with endometrial abnormalities, principally polyps, hyperplasia, or even adenocarcinoma of the endometrium, in the postmenopausal woman (Dijkhuizen et al. 1996; Granberg et al. 1991; Holbert 1997). It seems that treatment with tamoxifen in postmenopausal women sustains this association. Thus, in the previously mentioned study by Cohen et al. (1994), the only endometrial abnormalities were found in those women whose endometrium had a thickness ≥ 5 mm. The endometrial pathology was seen more frequently in tamoxifen- treated women (35.5% vs. 20%). The histology of the endometrial biopsies obtained in women on tamoxifen was reported as proliferative endometrium (24.74%), polyps (5.38%), cancer of the endometrium (3.2%), and hyperplasia (2.15%). In the case of women not on tamoxifen, no material was obtained from biopsy in 80% of cases, and in the rest the diagnosis was proliferative endometrium. Although a clear relationship between length of treatment and the presence of pathological endometrium could not be demonstrated, all tamoxifen-treated women with abnormal endometrium had received treatment for approximately 1 year (Cohen et al. 1994). Healthy postmenopausal women were also associated with histological alterations of the endometrium when treated with tamoxifen.

A randomized placebo-controlled trial found that 39% of the tamoxifen- treated women had an endometrial abnormality, a percentage that was reduced to 10% of women on placebo (p < 0.0001) (Kedar et al. 1994), though no cases of endometrial cancer were diagnosed in this study. The histological abnormalities found in the tamoxifen group were atypical hyperplasia (16%), proliferative endometrium (13%), polyps (8%), or presence of mitosis (2%). The authors concluded that the predicative value of an endometrium thickness ≥ 8 mm was 100% for the presence of atypical hyperplasia or endometrial polyps. No correlation could be found between the presence of endometrial pathology and the length of treatment with tamoxifen (Kedar et al. 1994).

In contrast to the data from that study, other authors have suggested that the increased endometrial thickness found in postmenopausal women treated with tamoxifen is less frequently associated with endometrial abnormalities, even in the presence of a marked thickening and cystic appearance (Achiron et al. 1996; McGonigle et al. 1998). Those ultrasonographic findings often represent subendometrial processes such as cysts or stromal edema (Bese et al. 1996; Bornstein et al. 1994; Achiron et al. 1995).

In this respect McGonigle et al. (1998) have observed that after an average of 2.4 years the endometrial abnormalities associated with tamoxifen in a group of postmenopausal women were polyps (66%), found more frequently in women with vaginal bleeding previous to surgery, cysts covered with an atrophic endometrium, or cystic endometrial atrophy (29%). Although one of the polyps proved to be a leiomyoma, no cases of atypical hyperplasia or adenocarcinoma were found among the women studied, thus supporting the idea that endometrial thickening does not seem to reflect serious endometrial pathology in most cases. The authors suggest that the presence of cystic endometrial atrophy could explain the endometrial abnormalities detected by TVU and that do not correspond with polyps, hyperplasia, or adenocarcinoma. Given that TVU cannot differentiate between polyps, hyperplasia, and cysts, the authors recommended the use of sonohysterography in those cases where a taximofen-treated woman has a thickened endometrium and a benign histology after an endometrial biopsy. If sonohysterography does not reveal the presence of polyps, it is very possible that the patient will have a cystic endometrial atrophy (McGonigle et al. 1998).

An important criticism to most of the available information on tamoxifen- induced changes in endometrium has been that the initial status of the endometrium has not been assessed (Berlière et al. 1998). To establish a link between tamoxifen and endometrial changes, it has been said, the endometrium needs to be evaluated before and during treatment.

Three prospective studies have initially assessed the endometrium (Berlière et al. 1998; Neven et al. 2000; Gal et al. 1991). In two of them (Neven et al. 1990; Galet al. 1991), the low number of women studied, 16and 12, could be responsible for the lack of endometrial alterations detected prior to treatment and for their low incidence as a result of treatment. The third study (Berlière et al. 1998), however, which included 264 nonsymptomatic postmenopausal women with breast cancer, detected a high prevalence of endometrial abnormalities prior to treatment, 17.4%, polyps being the most frequent (77%). Note that one case of endometrial adenocarcinoma and another of atypical hyperplasia were detected in the pretreatment evaluation. Women with and without lesions were followed separately and, after 3 years of treatment (20 mg/d), the incidence of lesions with/without atypias was significantly greater in the group with lesions prior to treatment. The incidence of benign lesions was similar in both groups (9.8 vs. 11.1%), but atypic endometrial hyperplasia, and adenocarcinoma, had a significantly higher incidence in women with endometrial lesions before treatment with tamoxifen.

Interestingly, the authors observed that the severity of the lesions seemed to increase with the length ofexposure to tamoxifen. Women with previous alterations would be, they suggested, more sensitive to the carcinogenetic effects of tamoxifen, an indication favoring the concept that lesions would represent a risk factor (Berlière et al. 1998). However, contrary to what was observed by other researchers (Sasco et al. 1995; Magriples et al. 1993), the adenocarcinomas diagnosed during the study were well differentiated (Berlière et al. 1998). It was then postulated that, as observed for endometrial tumors associated with estrogen replacement therapy, tamoxifen would induce a high proportion of highly differentiated tumors with a better prognosis. Nevertheless, this hypothesis still lacks conclusive data.

11.3.3

Tamoxifen and Risk of Endometrial Cancer

The partial agonistic effect of tamoxifen on the uterus has caused concern not only regarding an increased incidence of endometrial pathology but also regarding a potential increase in endometrial cancer. The probability that a woman will develop endometrial cancer is low, varying from 12 cases per 100,000 women at 40 years to 84 cases per 100,000 women at 60 years (Rose 1996). Tamoxifen has been found to increase the risk for endometrial cancer in the majority of studies. The relative risks (RRs) seem to vary between 1,3 (van Leeuwen et al. 1994) and 6.4 (Early Breast Cancer Trialist’s Collaborative Group; Fornander et al. 1989; Andersson et al. 1991, 1992; Fisher et al. 1998) for dosages of 20-40 mg/d. However, some studies did not detect any increase in risk (Fisher et al. 1989; Stewart et al. 1989; Nayfield et al. 1991; Cook et al. 1995).

In a case-control study (van Leeuwen et al. 1994) in which 98 cases of invasive endometrial carcinoma were diagnosed at least 3 months after diagnosis of primary breast cancer, it was observed that the use of tamoxifen was associated with a RR of 1.3. The risk appeared to have a tendency to increase during treatment, from 0.6 for less than a year to 3.0 for more than 5 years of treatment. It should be noted that the accumulated dose of tamoxifen was significantly associated with risk of endometrial cancer. However, the average daily dose used (20-40 mg/d) did not seem to influence risk. Other authors have also observed that the increase in risk is only detected when a determined accumulated dose is attained (van Leeuwen et al. 1994; De Muylder et al. 1991).

The observation that women with breast cancer receiving tamoxifen had a reduced incidence of contralateral cancer was the basis for the NSABP- PI study, a randomized, double-blind, placebo-controlled trial that began in 1992. The main objective was to ascertain whether tamoxifen might effectively reduce the risk for breast cancer in women with a high risk of developing this disease. A total of 13,388 women ≥ 35 years old were randomized to either tamoxifen (20 mg/d) or placebo for 5 years. In 1998, the trial was prematurely interrupted as the hypothesis of the study was confirmed (Fisher et al. 1998). However, the reduction in breast cancer risk with tamoxifen was accompanied by an increase in the incidence of invasive endometrial cancer (mean RR = 2.53). The increased risk was seen principally among women ≥ 50 years old with a RR of 4.01, while among women ≤ 49 years old the RR was 1.21.

During the 66 months of the study the accumulated incidence of endometrial cancer was 5.4/1000 women in the placebo group and 13.0/1000 women in the treatment group. Fourteen out of the 15 cancers in the placebo group were diagnosed in stage 1 of the FIGO classification, and one cancer was diagnosed in stage IV. The 36 invasive endometrial tumors diagnosed in the tamoxifen- treated women were in stage I. Three out of the 4 cases of carcinomas in situ were detected in the placebo group. The only death due to endometrial cancer occurred in the placebo group. In light of these results, the authors commented that the concern about the excess of risk of endometrial cancer associated with tamoxifen could be somewhat exaggerated, in agreement with their and other studies (Fisher 1996; Fisher et al. 1994), the endometrial tumors associated with tamoxifen did not seem to be either more aggressive or to have a worse prognosis or mortality than those arising in women untreated or on estrogen therapy.

In a recent British case-control study, treatment information on 813 patients who had endometrial cancer after being diagnosed with breast cancer was compared to 1067 control patients with breast cancer but no subsequent endometrial cancer. The use of tamoxifen was associated with an increased risk of endometrial cancer (odds ratio = 2.4). Based on the concluding information, the majority of researchers recommended that women taking tamoxifen should be carefully evaluated from an endometrial point of view, both before starting treatment and periodically during its use, and that a physician be consulted in the case of abnormal vaginal bleeding. This risk should be considered for both premenopausal and postmenopausal women for at least 5 years after the last treatment (Swerdlow et al. 2005).

11.4

Raloxifene

None of the clinical trials carried out to evaluate the effects of raloxifene, extending from 8 weeks to 4 years, detected stimulating effects of the drug on endometrium. Consequently, an antiestrogenic, or neutral, profile of raloxifene on endometrium has been vindicated.

11.4.1

Data Obtained from Biopsy

The clarification of whether raloxifene has any potential agonistic effect on the endometrium has been investigated through quantification of the ratio of estrogenicity. This effect has been assessed by studying endometrial tissue samples obtained though biopsy. In one clinical trial by Draper et al. (1996) on 251 healthy postmenopausal women, the treatment with raloxifene at a dose of 200 or 600 mg/d for 8 weeks did not produce changes in the degree of estrogenicity of the endometria when compared with biopsies taken before initiating treatment. In contrast, a group of women randomly assigned to CEE (0.625 mg/d) in the same study exhibited a significant increase in the aforementioned ratio after 8 weeks of treatment. Even the placebo-treated women had a estrogenicity significantly superior to that of women receiving raloxifene (Draper et al. 1996).

In a subsequent study, Boss et al. (1997) confirmed that raloxifene (200 or 600 mg/d) did not produce significant morphological changes in the glandular epithelium or in the stroma when compared with placebo. As expected, treatment with CEE (0.625 mg/d) induced changes clearly proliferative. Curiously, treatment with raloxifene produced, similarly to estrogens, an improved quality in the sample obtained from biopsy, that is to say, the percentage of samples obtained with intact glands and with stromal tissue increased with respect to samples obtained prior to treatment. The authors suggested that raloxifene could produce a lighter edematous endometrium, which in turn would enlarge the cervical orifice, facilitating its entrance and increasing the surface of the sample (Boss et al. 1997).

11.4.2

Ultrasonographic Data and Symptomatology

Delmas et al. (1997) carried out a clinical trial on 601 healthy postmenopausal women to evaluate the antiosteoporotic effect of 2 years of raloxifene treatment at a dose of 30, 60, or 150 mg/d vs. placebo. In this study TVU was used to evaluate the effect of raloxifene on the thickness of the endometrium. No change was observed in endometrial thickness in the 4 groups during the whole study. Vaginal bleeding was observed in 3.0% of women on 60 mg/d raloxifene, which was not significantly different from the 2.2% observed in the control group. Endometrial thickness in these women who bled was in all cases ≤ 5 mm, an indication favoring the hypothesis that the bleeding came from atrophic endometrium.

Another clinical trial on women treated with raloxifene at dosages of 60 or 120 mg/d for 6 months confirmed a low incidence in vaginal bleeding, 5 and 3%, respectively. This incidence was similar to that observed in the placebo group (5%) and significantly less than in the group on hormonal treatment (0.625 mg/d of CEE + 2.5 mg/d of MPA), where bleeding attained 45%. No dropouts were produced as a result of bleeding in either of the raloxifene- treated groups or in the placebo group, whereas 9% of women treated with hormones dropped out of the study for this reason (Walsh et al. 1998).

Cohen et al. (2000) presented integrated data from two identically designed, randomized, double-blind, placebo-controlled trials, including 969 healthy women less than 60 years old who were followed for a period of 3 years. Dosages of 30, 60, and 150 mg of raloxifene were used. Endometrial thickness was measured by TVU at the initial stage and then regularly at 6-month intervals for 2 years and again at 3 years. There was no statistical difference between the groups in terms of the endometrial thickness at the initial stage. None of the raloxifene dosages increased vaginal bleeding, affected endometrial thickness, or was associated with uterine pathologies. These findings were confirmed in studies comparing raloxifene with hormone therapy (Christodoulacos et al. 2002; Neven et al. 2000) (Fig. 11.1).

Fig. 11.1. Effects of raloxifene on endometrial thickness compared to combined continuous Hormones: 2 mgr of 17 B-estradioland 1 mgr of noretisterone acetate for 6 months. (Palacios et al. 2000)

As concluded from the above-mentioned data, the presence of bleeding or spotting is rare during treatment with raloxifene, the incidence being similar to that of placebo. In another study (Christodoulacos et al. 2002), only 7.7% of patients who took raloxifene presented sporadic spotting during the first 6 months of treatment. The incidence of bleeding-spotting was similar in the placebo group and significantly lower than in a group receiving a continuous combined hormonal formulation (estradiol plus norethisterone acetate [NETA]). These results are similar to those of the Euralox study (Neven et al. 2000) and those of Fugere et al. (2000), who reported an incidence of 6.8 and 9%, respectively. All these results further reinforce the notion that raloxifene does not stimulate the endometrium.

Recently Neven et al. (2003) published data of the Euralox study in which the use of raloxifene was not associated with an increase in vaginal bleeding or spotting or in uterine volume after 6 and 12 months of treatment (Fig. 11.2). In this trial, where raloxifene was compared with a formulation containing continuous combined estrogen plus progestin therapy, women using hormones had a higher incidence of benign endometrial pathology, which required more frequent protocol-specific gynecological assessment and followup (Table 11.2) (Neven et al. 2004).

In another study where raloxifene (60 mg/d) was compared with placebo in postmenopausal women for up to 5 years, a similar incidence of vaginal bleeding or a mean endometrial thickness of more than 5 mm was found. No diagnosis of endometrial hyperplasia or endometrial cancer was made in either group (Jolly et al. 2003).

Fig. 11.2. Percentage of women who referred to vaginal bleeding or spotting previous to treatment and after 6 months oftreatment with Raloxifene or continuous combined therapy with 2 mgr of 17B-estradiol and 1 mgr of noretisterone acetate (Neven et al. 2003)

Additionally it has been observed that raloxifene reduces the risk of breast cancer by 58-66%, without producing an increased risk of endometrial cancer in postmenopausal women (Cummings et al. 1999; Jordan et al. 1998). The Multiple Outcomes of Raloxifene Evaluation (MORE) clinical trial is particularly eloquent in this regard (Cummings et al. 1999). A total of 7704 postmenopausal women(average age 66.5 years)with osteoporosis and with out history of breast or endometrial cancer were included. The trial, which was randomized and double-blind, used two doses of raloxifene (60 or 120 mg/d) or placebo to assess whether raloxifene reduced the number of fractures more effectively than placebo. Apart from the successful effect against fractures, raloxifene significantly reduced the risk of breast cancer (RR = 0.26) with respect to placebo after an average of 28.9 months of followup. Moreover, raloxifene did not significantly change the incidence of endometrial cancer (Cummings et al. 1999). This neutral effect was subsequently confirmed after 48-month followup in the MORE study (Cauley et al. 2001).

Table 11.2. Uterine effects of estrogen plus progestin therapy and raloxifene (Euralox study) (Neven et al. 2004)

Estrogen/progestin therapy vs. raloxifene Average values in %

Benign endometrial proliferation

8.8 vs. 1.2

p < 0.001

Endometrial polyps

4.3 vs. 2

p = 0.048

Cystic atrophy

5.5 vs. 1.2

p < 0.001

11.5

Others SERMs

11.5.1

Arzoxifene

Arzoxifene is an orally active third-generation selective ER modulator. Arzox- ifene has been shown to induce apoptosis in an ER-positive cell line through a mechanism that includes induction of TGFβ (Colletta et al. 1990). The capacity to induce TGF-β expression may contribute to the potential antiproliferative effects of arzoxifene in hormonally responsive uterine.

In preclinical models, arzoxifene exerts an estrogen agonistic effect on bone and on the lipid profile and an estrogen antagonistic effect in breast and endometrium (Sato et al. 1998; Russo et al. 1990; Ma et al. 1998). Thus, in both the ovariectomized rat and the ovary-intact rat arzoxifene did not stimulate uterine weight gain (Russo et al. 1990).

Clinical phase I and II data reveal arzoxifene to be safe, well tolerated, and efficacious. Two multi-institutional phase II trials including 100 women with metastatic or recurrent endometrial cancer have demonstrated significant activity of arzoxifene at 20 mg/d in patients with metastatic or recurrent endometrial cancer. The observed clinical response rates were 25 and 31%, with a mean response duration of 19.3 and 13.9 months, respectively. Progression of the disease was stabilised in a substantial number of women. Toxicity was mild, except for two cases of pulmonary embolism that might have been drug related (Burke et al. 2003).

Phase III trials on treatment and prevention of postmenopausal osteoporosis are in progress.

11.5.2

Bazedoxifene Acetate

Bazedoxifene acetate is a third-generation SERM. In in vitro studies bazedox- ifene competitively inhibited 17β-estradiol binding to both ERa (Ki = 0.1 nM) and ERβ (Ki = 0.03 nM). Bazedoxifene’s ability to competitively bind to ERs while exhibiting estrogenlike activity in a promoter and cell-type selective manner is the hallmark of SERM-type action and a prominent characteristic of this drug (Miller et al. 2002).

Bazedoxifene’s primary indication is the treatment and prevention of postmenopausal osteoporosis (Miller et al. 2002). In animal models bazedoxifene displays estrogenlike agonistic activity on bone loss and significantly reduces total cholesterol levels with doses as low as 0.1 mg/kg (Miller et al. 2002). Also in these models, there is no evidence of an estrogenic stimulatory effect on the endometrial epithelial cell (Miller et al. 2001).

Clinical phase I and II data reveal bazedoxifene to be safe, very well tolerated, and efficacious. Phase III trials are currently in progress.

11.5.3

Lasofoxifene

This is a third-generation SERM. It binds with high affinity to human estrogen receptors and acts as a tissue-selective estrogen antagonist or agonist.

In preclinical models of postmenopausal osteoporosis, lasofoxifene inhibited bone turnover and prevented bone loss throughout the skeleton (Maeda et al. 2004). The primary indication of lasofoxifene is the treatment and prevention of postmenopausal osteoporosis. In preclinical models, lasofox- ifene inhibited breast tumor formation and reduced serum cholesterol (Maeda et al. 2004). Lasofoxifene-treated animals did not differ from ovariectomized controls with respect to endometrial thickness and superficial and basal endometrial gladular epithelial luminal area (Maeda et al. 2004; Ke et al. 2004).

The clinical phase I and II trials correlate well with the preclinical pharmacology. Phase III trials are currently in progress.

11.5.4

Ospemifene

Ospemifene is a novel third-generation SERM that in animal models has been shown to have agonistic effects on bone and the cardiovascular system and antagonistic effects in uterus and breast.

In a double-blind, placebo-controlled phase I study, ospemifene exerted a very weak estrogenic effect on endometrial histology, and no clinically significant changes were seen in endometrial thickness at any dose level (Voipio et al. 2002). In another double-blind study, ospemifene at daily doses of 30 to 90 mg did not stimulate growth of endometrial thickness (Rutanen et al. 2003).

11.6

Conclusions

The preclinical data indicate that SERMs exert a specific action depending not only on the tissue on which they act but also on the hormonal enviroment. Tamoxifen, through its partial estrogenic agonism on the uterus, seems to produce a trophic effect in the endometrium and myometrium in ovariectomized rats. Raloxifene behaves as an estrogenic antagonist at this level, producing a minimum effect on the uterus. However, both raloxifene and tamoxifen produced a decrease in the weight of the uterus in intact rats, although to a lesser degree than that produced by surgical castration.

According to results from clinical trials, the agonistic effects of tamoxifen detected in animals were also observed in the human uterus as it produces a trophic effect and an increase in the incidence of endometrial pathology, which is related to endometrial thickening (≥ 4 mm). Its use seems to be associated with an increase in endometrial cancer, which is related to the length of treatment and the accumulated dose of tamoxifen. Nevertheless, these tumors do not seem to be more aggressive or to have a worse prognosis than those found in women who do not follow this treatment or who receive hormone therapy.

Clinical evidence indicates that the use of tamoxifen increases survival up to 10 years in women with breast cancer. Tamoxifen also seems to diminish the incidence of breast cancer in healthy women with a high risk of suffering from the tumor. Its use as a therapy in breast cancer should be accompanied by careful periodic vigilance of the endometrium. In healthy women, a careful evaluation of the risk/benefit for each and every woman should be imposed.

Unlike tamoxifen, raloxifene seems to have a minimum effect on the uterus in postmenopausal women. It does not seem to produce any estrogenic effect on the endometrium or the myometrium from a histological or ultrasonographic point of view. The low incidence of vaginal bleeding is similar to that observed in untreated women, and these data should be taken into consideration as they will facilitate adherence to treatment. An important strength of raloxifene is its efficacy in the prevention and treatment of osteoporosis without increasing the risk of endometrial cancer, at least during 4 years of treatment.

References

1. Achiron R, Lipitz S, Sivan E, Goldenberg M, Mashiach S (1995) Sonohysterography for ultrasonographic evaluation of tamoxifen-associated cystic thickened endometrium. J Ultrasound Med 14:685-688

2. Achiron R, Grisaru D, Golan-Porat, Lipitz S (1996) Tamoxifen and the uterus: an old drug tested by new modalities. Ultrasound Obstet Gynecol 7:374-378

3. Ames BN, Gold LS (1990) Too many rodent carcinogens: mitogenesis increases mutagenesis. Science 249(4972):970-971

4. Andersson M, Storm HH, Mouridsen HT (1991) Incidence of new primary cancers after adjuvant tamoxifen therapy and radiotherapy for early breast cancer. J Natl Cancer Inst 83:1013-1017

5. Andersson M, Storm HH, Mouridsen HT (1992) Carcinogenic effects of adjuvant tamoxifen treatment and radiotherapy for early breast cancer. Acta Oncol 31:259-263

6. Ashby J, Odum J, Foster JR (1997) Activity of raloxifene in immature and ovariectomized rat uterotrophic assays. Regul Toxicol Pharmacol 25(3):226-231

7. Berlière M, Charles A, Galant C, Donnez J (1998) Uterine side effects of tamoxifen: a need for systematic pretreatment screening. Obstet Gynecol 91:40-44

8. Bese T, Kosebay D, Demirkiran F, Arvas M, Bese N, Mandel N (1996) Ultrasonographic appearence of endometrium in postmenopausal breast cancer patients receiving tamoxifen. Eur J Obstet Gynecol Reprod Biol 67:157-162

9. Black LJ, Goode RL (1980) Uterine bioassay of tamoxifen, trioxifene and a new estrogen antagonist (LY117018) in rats and mice. Life Sci 26(17):1453-1458

10. Black LJ, Goode RL (1981) Evidence for biological action of the antiestrogens LY117018 and tamoxifen by different mechanisms. Endocrinology 109(3):987-989

11. Black LJ, Jones CD, Falcone JF (1983) Antagonism of estrogen action with a new ben- zothiophene derived antiestrogen. Life Sci 32(9):1031-1036

12. Black LJ, Sato M, Rowley ER, Magee DE, Bekele A, Williams DC, Cullinan GJ, Bendele R, Kauffman RF, Bensch WR, et al. (1994) Raloxifene (LY139481 HCI) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J Clin Invest 93(1):63-69

13. Bornstein J, Auslender R, Pascal B, Gutterman E, Isakov D, Abramovici H (1994) Diagnostic pitfalls of ultrasonographic uterine screening in women treated with tamoxifen. J Reprod Med 39:674-678

14. Boss SM, Huster WJ, Neild JA, Glant MD, Eisenhut CC, Draper MW (1997) Effects of raloxifene hydrochloride on the endometrium of postmenopausal women. Am J Obstet Gynecol 177:1458-1464

15. Bryant HU, Dere WH (1998) Selective estrogen receptor modulators: an alternative to hormone replacement therapy. Proc Soc Exp Biol Med 217(1):45-52

16. Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L, Greene GL, Gustafsson JA, Carlquist M (1997) Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389(6652):753-758

17. Burke TW, Walker CL (2003) Arzoxifene as therapy for endometrial cancer. Gynecol Oncol 90(2 Pt 2):S40-46

18. Cano A, Hermenegildo C (2000) The endometrial effects of SERMs. Hum Reprod Update 6(3):244-254

19. Carmichael PL, Mills JJ, Neven P (1998) An epigenetic mechanism for tamoxifen- associated uterine carcinogenesis? Eur J Cancer 34(Suppl 4):S10-S11

20. Carthew P, Edwards RE, Nolan BM (1999) Uterotrophic effects of tamoxifen, toremifene, and raloxifene do not predict endometrial cell proliferation in the ovariectomized CD1 mouse. Toxicol Appl Pharmacol 158(1):24-32

21. Cauley JA, Norton L Lippman ME, Eckert S, Krueger KA, Purdie DW, et al. (2001) Continued breast cancer risk reduction in postmenopasusal women treated with raloxifene: 4 year results from the MORE trial. Breast Cancer Res Treatment 65:125-134

22. Christodoulacos G, Panoulis C, Botsis D, Rizoz D, Kassanos D, Creatsas G (2002) Transvaginal sonographic monitoring of the uterine effects of raloxifene and a continuous combined replacement therapy in postmenopausal women. Maturitas 42:77-84

23. Clark ER, Jordan VC (1976) Oestrogenic, anti-oestrogenic and fertility effects of some triphenylethanes and triphenylethylenes related to ethamoxytriphetol (MER 25). Br J Pharmacol 57(4):487-493

24. Cohen I, Rosen DJ, Shapira J, Cordoba M, Gilboa S, Altaras MM, et al. (1994) Endometrial changes with tamoxifen: comparison between tamoxifen-treated and nontreated asymptomatic, postmenopausal breast cancer patients. Gynecol Oncol 52:185-190

25. Cohen FJ, Watts S, Shah A, Akers S, Plouffe L (2000) Uterine effects of 3-years raloxifene therapy in postmenopausal women younger than age 60. Obstet Gynecol 95(1):104-111

26. Colletta AA, Wakefield LM, Howell FV, van Roozendaal KE, Danielpour D, Ebbs SR, Sporn MB, Baum M (1990) Anti-oestrogens induce the secretion of active transforming growth factor beta from human fetal fibroblasts. Br J Cancer 62(3):405-409

27. Cook LS, Weiss NS, Schwartz SM, White E, McKnight B, Moore DE, et al. (1995) Population-based study of tamoxifen therapy and subsequent ovarian, endometrial, and breast cancers. J Natl Cancer Inst 87:1359-1364

28. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, et al. (1999) The effect of raloxzifene on risk of breast cancer in postmenopausal women:results from MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. J Am Med Assoc 281:2189-2197

29. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, et al. (1997) Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337:1641-1647

30. De Muylder X, Neven P, De Somer M, Van Belle Y, Vanderick G, De Muylder E (1991) Endometrial lesions in patients undergoing tamoxifen therapy. Int J Gynaecol Obstet 36:127-130

31. Dijkhuizen FP, Brolmann HA, Potters AE, Bongers MY, Heintz AP (1996) The accuracy of transvaginal ultrasonography in the diagnosis of endometrial abnormalities. Obstet Gynecol 87:345-349

32. Draper MW, Flowers DE, Huster WJ, Neild JA, Harper KD, Arnaud C (1996) A controlled trial of raloxifene (LY139481) HCl: impact on bone turnover and serum lipid profile in healthy postmenopausal women. J Bone Miner Res 11:835-842

33. Early Breast Cancer Trialists’ Collaborative Group (1998) Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 351(9114):1451-1467

34. Elkas J, Gray K, Howard L, Petit N, Pohl J, Armstrong A (1998) The effects of tamoxifen on endometrial insulin-like growth factor-1 expression. Obstet Gynecol 91(1):45-50

35. Fisher B (1996) A commentary on endometrial cancer deaths in tamoxifen-treated breast cancer patients. J Clin Oncol 14:1027-1039

36. Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J, et al. (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(8):479-484

37. 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

38. Fisher B, Costantino JP, Wickerham L, Redmond CK, Kavanah M, Cronin WM, et al. (1998) Tamoxifen for prevention of brest cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-1388

39. Fornander T, Rutqvist LE, Cedermark B, Glas U, Mattsson A, Silfversward C, et al. (1989) Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1(8630):117-120

40. Fugere P, Scheele WH, Shah A, et al. (2000) Uterine effects of raloxifene in comparison with continuous-combined hormone replacement therapy in postmenopausal women. Am J Obstet Gynecol 182:568-574

41. Gal D, Kopel S, Basheukin M, Lebowicz J, Lev R, Tancer L (1991) Oncogenic potential of tamoxifen on endometria of postmenopausal women with breast cancer. Preliminary report. Gynecol Oncol 42:120-123

42. Gottardis MM, Ricchio ME, Satyaswaroop PG, Jordan VC (1990) Effect of steroidal and nonsteroidal antiestrogens on the growth of a tamoxifen-stimulated human endometrial carcinoma (EnCa101) in athymic mice. Cancer Res 50(11):3189-3192

43. Granberg S, Wikland M, Karlsson B, Norstrom A, Friberg L (1991) Endometrial thickness as measured by endovaginal ultrasonography for identifying endometrial abnormality. Am J Obstet Gynecol 164:47-52

44. Grese TA, Sluka JP, Bryant HU, Cullinan GJ, Glasebrook AL, Jones CD, Matsumoto K, Palkowitz AD, Sato M, Termine JD, Winter MA, Yang NN, Dodge JA (1997) Molecular determinants of tissue selectivity in estrogen receptor modulators. Proc Natl Acad Sci USA 94(25):14105-14110

45. Holbert TR (1997) Transvaginal ultrasonographic measurement of endometrial thickness in postmenopausal women receiving estrogen replacement therapy. Am J Obstet Gynecol 176:1334-1339

46. Huynh HT, Pollak M (1993) Insulin-like growth factor I gene expression in the uterus is stimulated by tamoxifen and inhibited by the pure antiestrogen ICI 182780. Cancer Res 53(23):5585-5588

47. Huynh H, Pollak M (1994) Uterotrophic actions of estradiol and tamoxifen are associated with inhibition of uterine insulin-like growth factor binding protein 3 gene expression. Cancer Res 54(12):3115-3119

48. Isaksson E, Cline JM, Skoog L, Soderqvist G, Wilking N, von Schoultz E, von Schoultz B (1999) p53 expression in breast and endometrium during estrogen and tamoxifen treatment of surgically postmenopausal cynomolgus macaques. Breast Cancer Res Treat 53(1):61-67

49. Jolly EE, Bjarnason NH, Neven P, Plouffe L Jr, Johnston CC Jr, Watts SD, Arnaud CD, Mason TM, Crans G, Akers R, Draper MW (2003) Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years. Menopause 10(4):337-344

50. Jordan VC, Glusman JE, Eckert S, Lippman M, Powles T, Costa A, et al. (1998) Incident primary breast cancer are reduced by raloxifen: integrated data from multicenter, double-blind, randomized trial in ~ 12,000 postmenopausal women. Proc Am Soc Clin Oncol 17:122a (abstract)

51. Karlsson S, Iatropoulos MJ, Williams GM, Kangas L, Nieminen L (1998) The proliferation in uterine compartments of intact rats of two different strains exposed to high doses of tamoxifen or toremifene. Toxicol Pathol 26(6):759-768

52. Ke HZ, Foley GL, Simmons HA, Shen V, Thompson DD (2004) Long-term treatment of lasofoxifene preserves bone mass and bone strength and does not adversely affect the uterus in ovariectomized rats. Endocrinology 145(4):1996-2005

53. Kedar RP, Bourne TH, Powles TJ, Collins WP, Ashley SE, Cosgrove DO, et al. (1994) Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet 343:1318-1321

54. Kleinman D, Karas M, Danilenko M, Arbell A, Roberts CT, LeRoith D, Levy J, Sharoni Y (1996) Stimulation of endometrial cancer cell growth by tamoxifen is associated with increased insulin-like growth factor (IGF)-I induced tyrosine phosphorylation and reduction in IGF binding proteins. Endocrinology 137(3):1089-1095

55. Koda M, Jarzabek K, Haczynski J, Knapp P, Sulkowski S, Wolczynski S (2004) Differential effects of raloxifene and tamoxifen on the expression of estrogen receptors and antigen Ki-67 in human endometrial adenocarcinoma cell line. Oncol Rep 12(3):517-521

56. Kommoss F, Karck U, Prompeler H, Pfisterer J, Kirkpatrick CJ (1998) Steroid receptor expression in endometria from women treated with tamoxifen. Gynecol Oncol 70(2):188-191

57. Ma L, Palkowitz A, Bryant HU, Rowley E, Adian MD, Cole HW, Shetler P, Smith S, Turner CH, Yao W, et al. (1998) Long-term dosing of LY353381HC1 preserves bone quality, reduces turnover and lowers cholesterol levels in ovariectomized rats. Bone 23(Suppl 5):S609

58. MacGregor JI, Jordan VC (1998) Basic guide to the mechanisms of antiestrogen action. Pharmacol Rev 50(2):151-196

59. Maeda T, Ke HZ, Simmons H, Thompson D (2004) Lasofoxifene, a next generation estrogen receptor modulator: preclinical studies. Clin Calcium 14(10):85-93

60. Magriples U, Naftolin F, Schartz PC, Carcangiu ML (1993) High-grade endometrial carcinoma in tamoxifen-treated breast cancer patients. J Clin Oncol 11:485-490

61. McGonigle KF, Shaw SL, Vasilev SA, Odom-Maryon T, Roy S, Simpson JF (1998) Abnormalities detected on transvaginal ultrasonography in tamoxifen-treated postmenopausal breast cancer patients may represent endometrial cystic atrophy. Am J Obstet Gynecol 178:1145-1150

62. Miller CP, Collini MD, Tran BD (2001) Design, synthesis, and preclinical characterization of novel, highly selective indole estrogens. J Med Chem. 44:1654-1657

63. Miller CP, Harris HA, Konmin BS (2002) Bezedoxifene Acetate. Drugs Future 27(2):117- 121

64. Nayfield SG, Karp JE, Ford LG, Dorr FA, Kramer BS (1991) Potential role of tamoxifen in prevention of breast cancer. J Natl Cancer Inst 83:1450-1459

65. Neven P, De Muylder X, Van Belle Y, Vanderick G, De Muylder E (1990) Hysteroscopic follow-up during tamoxifen treatment. Eur J Obstet Gynecol Reprod Biol 35:235-238

66. Neven P, Lunde T, Benedetti-Panicini P, et al. (2000) A multicentre randomized trial to compare the uterine effects of raloxifene(evista) with a continuous combined hormone replacement therapy (kliogest); results from Euralox I. Gynecol Endocrinol 14(2):77

67. Neven P, Lunde T, Benedetti-Panici P, Tiitinen A, Marinescu B, Villiers T, Hillard T, Cano A, Peer E, Quail D, Nickelsen T (2003) A multicentre randomised trial to compare uterine safety of raloxifene with a continuous combined hormone replacement therapy containing oestradiol and norethisterone acetate. Br J Obstet Gynaecol 110:157-167

68. Neven P, Quail D, Levrier M, Aguas F, The HS, De Geyter C, Glant MD, Beck H, Bosio- LeGoux B, Schmitt H, Hottgenroth A, Nickelsen T (2004) Uterine effects of estrogen plus progestin therapy and raloxifene: adjudicated results from the EURALOX study. Obstet Gynecol 103(5 Pt 1):881-891

69. Palacios S, Cifuentes I, Menendez C, von Helde S (2000) Los SERMs y el utero. In: Cano A, Calaf J (eds) Moduladores selectivos de los receptores de estrogenos (SERM). Ediciones Doyma, Barcelona

70. Rivera-Gonzalez R, Petersen DN, Tkalcevic G, Thompson DD, Brown TA (1998) Estrogen-induced genes in the uterus of ovariectomized rats and their regulation by droloxifene and tamoxifen. J Steroid Biochem Mol Biol 64(1-2):13-24

71. Robertson JA, Bhattacharyya S, Ing NH (1998) Tamoxifen up-regulates oestrogen receptor-alpha, c-fos and glyceraldehyde 3-phosphate-dehydrogenase mRNAs in ovine endometrium. J Steroid Biochem Mol Biol 67(4):285-292

72. Rose PG (1996) Endometrial carcinoma. N Engl J Med 335:640-649

73. Russo J, Gusterson BA, Rogers AE, Russo IH, Wellings SR, van Zwieten MJ (1990) Comparative study of human and rat mammary tumorigenesis. Lab Invest 62(3):244- 278

74. Rutanen EM, Heikkinen J, Halonen K, Komi J, Lammintausta R, Ylikorkala O (2003) Effects of ospemifene, a novel SERM, on hormones, genital tract, climacteric symptoms, and quality of life in postmenopausal women: a double-blind, randomized trial. Menopause 10(5):433-439

75. Sasco AJ, Raffi F, Satge D, Goburdhun J, Fallou HB, Leduc B (1995) Endometrial müllerian carcinosarcoma after cessation of tamoxifen therapy for breast cancer. Int J Gynaecol Obstet 48:307-310

76. Sato M, Rippy MK, Bryant HU (1996) Raloxifene, tamoxifen, nafoxidine, or estrogen effects on reproductive and nonreproductive tissues in ovariectomized rats. FASEB J 10(8):905-912

77. Sato M, Zeng GQ, Rowley E, Turner CH (1998) LY353381 x HCl: an improved benzoth- iophene analog with bone efficacy complementary to parathyroid hormone-(1-34). Endocrinology 139(11):4642-4651

78. Somjen D, Waisman A, Kaye AM (1996) Tissue selective action oftamoxifen methiodide, raloxifene and tamoxifen on creatine kinase B activity in vitro and in vivo. J Steroid Biochem Mol Biol 59(5-6):389-396

79. Stewart HJ, Knigth GM (1989) Tamoxifen and the uterus and endometrium. Lancet 1:375-376

80. Swenberg JA (1997) Clinical relevance of laboratory and animal data on tamoxifen. Oncology (Huntingt) 11(2 Suppl 1):39-44

81. Swerdlow AJ, Jones ME, British Tamoxifen Second Cancer Study Group (2005) Tamoxifen treatment for breast cancer and risk of endometrial cancer: a case-control study. J Natl Cancer Inst 97(5):375-384

82. Tzukerman MT, Esty A, Santiso-Mere D, Danielian P, Parker MG, Stein RB, Pike JW, McDonnell DP (1994) Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions. Mol Endocrinol 8(1):21-30

83. van Leeuwen FE, Benraadt J, Coebergh JW, Kiemeney LA, Gimbrère CH, Otter R, et al. (1994) Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet 343:448-452

84. Voipio SK, Komi J, Kangas L, Halonen K, DeGregorio MW, Erkkola RU (2002) Effects of ospemifene (FC-1271a) on uterine endometrium, vaginal maturation index, and hormonal status in healthy postmenopausal women. Maturitas 43(3):207-214

85. Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JB, et al. (1998) Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. J Am Med Assoc 279:1445-1451

86. Zhang H, McElrath T, Tong W, Pollard JW (2005) The molecular basis of tamoxifen induction of mouse uterine epithelial cell proliferation. J Endocrinol 184(1):129-140



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