Selective Estrogen Receptor Modulators. Antonio Cano

Chapter 2. Clinical Pharmacology of Selective Estrogen

Receptor Modulators (SERMs)

• Fernando Marin

• Ma Carmen Barbancho



Selective estrogen receptor modulators (SERMs) are a group of drugs with heterogeneous structural chemical characteristics that are characterized as high-affinity ligands (in the subnanomolar concentration range) to estrogenic receptors (ERs) but have the peculiarity of triggering estrogen-agonist or estrogen-antagonist actions, depending on the tissue in which they act. From a pharmacological perspective, SERMs should be differentiated from pure antiestrogens, such as fulvestrant (Chap. 6), which are molecules chemically related to estradiol and exclusively exhibit estrogenic antagonist activity. SERMs also should be differentiated from the so-called “gonadomimetic” drugs, such as tibolone, that act by means of nonselective binding to different types of sex steroid receptors.

The pharmacological development of these compounds has been closely connected, on one hand, to the vast experience that has been accumulated over decades in estrogen therapy (ET) and estrogen and progestin therapy (EPT) during menopause and, on the other hand, to the effects on nonbreast tissues of drugs traditionally classified as “antiestrogens”, tamoxifen being the principal example. ET and EPT have proven to be effective in the prevention and treatment of the signs and symptoms of early estrogen deficiency associated with perimenopause and accelerated bone mass loss occurring after ovarian function ceases. Numerous observational studies have demonstrated that postmenopausal women receiving long-term treatment with ET/EPT show a reduced risk of osteoporotic fractures, cardiovascular diseases, and even Alzheimer’s disease (Manson et al. 2001). However, the benefits suggested in the observational studies have not been confirmed in randomized, doubleblind, placebo-controlled clinical trials, the design of which eliminates the significant selection bias presented in naturalistic studies. Recent clinical trials clearly have shown the lack of benefit from EPT or ET alone in primary and secondary prevention of ischaemic heart disease and cerebrovascular disease (Hulley et al. 1998; Writing Group for the Women’s Health Initiative Investigators 2002; Women’s Health Initiative Steering Committee 2004) and cast serious doubts on its safety in the deterioration of higher cognitive functions (Shumaker et al. 2004). Furthermore, treatment compliance tends to be very low because of the poor acceptance by many women regarding the return of menstrual bleeding or spotting and the fear of an increased risk of breast or uterine cancer. On the other hand, WHI trials suggest a positive effect of ET and EPT in reducing the risk for hip fracture and colorectal cancer, although the overall risk-benefit balance is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases (Writing Group for the Women’s Health Initiative Investigators 2002; Women’s Health Initiative Steering Committee 2004).

Therefore, the primary objective for the pharmacological development of SERMs is to increase the benefit/risk ratio in comparison with ET and EPT in the prevention and treatment of several highly prevalent, chronic diseases in the postmenopausal period that are related to this physiological estrogen deficient state. As is often the case in medicine, the discovery of the pharmacological profile that gave grounds for hope in the development of this new drug class was the result of an unexpected paradox. Tamoxifen, a drug that was introduced over 35 years ago for hormone-dependent breast cancer treatment, has been considered an antiestrogen for decades because of its blocking action on the binding of endogenous estrogens to the estrogen receptor (ER) of neoplastic breast cells. However, several studies suggested that tamoxifen might have a protective action in bone tissue (estrogen agonist). For example, a study of postmenopausal women who previously had breast cancer but were clinically cancer free showed that tamoxifen increased lumbar spine bone mineral density compared to placebo (Love et al. 1992); that is, this study further suggested that tamoxifen was not purely antiestrogenic.

This drug class has an enormous potential in the primary and secondary prevention of several types of estrogen-dependent tumors, postmenopausal osteoporosis, and cardiovascular and neurodegenerative diseases.

In this chapter, a general review of SERMs will be given, highlighting some of the latest advances in the development of new SERMs and problems encountered during the clinical development of some of them. Details on the efficacy, safety, and clinical use of SERMs in which more clinical experience has been accumulated will be discussed in greater depth in other chapters.



There is an extensive list of compounds that can be considered SERMs for which there are available results in either in vitro cellular models or in vivo animal and human experiments. Approximately 70 molecules with a SERM- like pharmacological profile were described in a recent review (Meegan et al. 2003). Table 2.1 provides a summary of the main SERM groups, classified according to chemical structure. Certain phytoestrogens, such as genistein and daidzein, also appear to have a SERM-type pharmacological profile. Currently there are two main chemical classes of SERMs approved for clinical use: triphenylethylene derivatives, such as tamoxifen and toremifene, used to treat and prevent breast cancer, and clomiphene for ovulation induction; and the benzothiophene derivative raloxifene, indicated for the treatment and prevention of osteoporosis.

Table 2.1. Classification of SERMs


Pharmacological Characteristics of SERMs



The primary objective of the initial clinical development of SERMs was the treatment of estrogen-dependent breast cancer, and it is in this disease in which the clinical benefit of these drugs has accumulated the largest amount of proof. Tamoxifen, a triphenylethylene derivative, has been used for over 35 years. The accumulated clinical experience in over 10 million women/year is proof of its beneficial effect in the treatment of disseminating breast cancer, in adjuvancy, and primary prevention of women at high risk of developing the disease (Fisher et al. 1998; Jordan et al. 1999; Wickherman 2002). It is important to emphasize that treatment with a first-generation SERM such as tamoxifen is efficient in all breast cancer subgroups except for ER-negative tumors in premenopausal women, which is not surprising considering its mechanism of action. The clinical problem of ER-positive breast cancer was the main driver for developing several new SERMs of the triphenylethylene family as toremifene (chlorotamoxifen), droloxifene (3-hydroxy-tamoxifen), idoxifene (4-iodo-pirrolidine-tamoxifen), ospemifene, fispemifene, miproxifene (TAT- 59), and GW5638 (Fig. 2.1). Clomiphene, which may be considered the first SERM for clinical use, is also a triphenylethylene derivative, but it has been used since 1967 exclusively for ovulation induction, and no investigation for its clinical use in postmenopausal women has been carried out. Of all these drugs, only toremifene has been commercialized for the treatment of disseminated breast cancer, and from a clinical point of view it has not shown any advantage over tamoxifen in the benefit/risk ratio (Buzdar et al. 1998). In fact, although both drugs lead to similar significant reductions in serum lipids, their effects on bone mineral density in postmenopausal women are different.

In a head-to-head trial, tamoxifen showed a more potent effect in the preservation of bone mass than toremifene, with the latter causing a small but significant reduction in bone mineral density (Marttunen et al. 1999). On the other hand, as toremifene is not susceptible to a-oxidation by the P450 enzymatic system, it has not been shown to lead to hepatocarcinogenesis in rodent preclinical models, unlike tamoxifen. Unfortunately, both compounds present an estrogen-agonist action in the endometrium. This has been well demonstrated both in animal models (O’Regan et al. 1998) and in clinical experience, where the risk of developing premalignant and malignant endometrial lesions increases significantly by two to seven times with both drugs (Shapiro et al. 2001). In fact, long-term uterine safety is one of the key aspects that have to be closely monitored during clinical trials in humans. Thus, the clinical development of idoxifene, miproxifene, and droloxifene (compounds of the triphenylethylene in endometrial thickness, evaluated by transvaginal ultrasound after only 12 weeks oftreatment in postmenopausal women. Furthermore, idoxifene was associated with an increased incidence of uterine prolapse (Hendrix et al. 2001), and this unexpected effect was unsuitable to evaluate in traditional preclinical models. Uterine prolapse has been a relatively frequent finding with other SERMs, as will be discused later.

Fig. 2.1. Chemical structure of several SERMs in triphenylethylene group. The estradiol molecule is also included as a comparative reference

family that were in Phase II-III clinical trials for the treatment of breast cancer and postmenopausal osteoporosis) has been recently cancelled due to uterine safety issues. The unexpected adverse events found in the clinical studies in humans suggest that preclinical toxicological studies, mainly in rodents, may not necessarily predict the endometrial response to certain types of SERMs in women. Thus, although idoxifene had shown a potent activity in breast cancer cell lines that were resistant to tamoxifen, and in preclinical models had not shown estrogen-agonist activity in the endometrium (Nuttall et al. 1998; Gutman et al. 2002), it was associated with a dose-dependent increase

Droloxifene (3-hydroxy-tamoxifen) behaves as an estrogen agonist in bone tissue and several lipid and coagulation markers in castrated rat models and does not show stimulation of the endometrial epithelium in preclinical studies (Ke et al. 1997). Endometrial stimulation has, however, been observed in clinical trials, which, together with the fact that as an estrogen agonist it is ten times less potent than tamoxifen in bone tissue and lipid metabolism (Hendrix et al. 2001) and that in a recent head-to-head comparison with tamoxifen droloxifene was demonstrated not to be superior in any parameter of breast cancer treatment efficacy (Buzdar et al. 2002), has resulted in cancellation of its clinical development.

Miproxifene (TAT-59) is a prodrug of 4-hydroxy-tamoxifen that has been developed for tamoxifen-resistant carcinoma, but relatively little information has been published on this drug. Compared with tamoxifen, miproxifene inhibits estradiol-stimulated proliferation of MCF-7 cells at a threefold lower dose than that of tamoxifen, and of dimethyl-benzanthracene (DMBA)-induced rat mammary tumors at a dose tenfold lower than tamoxifen (Toko et al. 1990). In any event, in preclinical castrated rat models, it shows an endometrial stimulation activity that is similar to that of tamoxifen, which means it has limited potential use in the prevention or treatment of osteoporosis or cardiovascular disease (Shibata et al. 2000). Similarly, considering the preclinical findings of endometrial stimulation reported on GW5638 (Willson et al. 1997), it is likely that this new SERM belonging to the triphenylethylene family will be limited in clinical use to the treatment of advanced tamoxifen-resistant breast cancer once its efficacy is demonstrated in human clinical trials.

More encouraging are the preliminary results of ospemifene (FC-1271a), a biologically active metabolite of toremifene (deamino-hydroxy-toremifene), which has shown a promising SERM-type pharmacological profile by preventing bone mass and bone strength loss in castrated rats and reducing cholesterol levels, without uterine wet weight gain (Qu et al. 2000). Also, it performs as a potent estrogen antagonist in ER-positive breast cancer cell lines (Taras et al. 2001), and it is now in Phase III clinical trials for the prevention and treatment of postmenopausal osteoporosis and urogenital atrophy (Gennari 2004). In Phase II trials, ospemifene had, unlike raloxifene, an estrogenic agonistic activity on the vaginal epithelium by improving symptoms of vaginal dryness (Rutanen et al. 2003). The compound also appeared to be neutral in its effects on climateric symptoms, including hot flashes and insomnia. Long-term studies will be needed to confirm the neutral effect of ospemifene on the uterus and its impact in the prevention of bone loss and osteoporotic fractures in postmenopausal women.

Fispemifene is a new triphenylethylene, closely related to ospemifene, currently going to Phase II clinical trials. It has antagonistic activity in breast tissue and acts as an estrogen agonist in bone and the vascular tissue repair response through the regulation of vascular smooth muscle cell function and reendothe- lialization, in a way that is very similar to that of tamoxifen, raloxifene, and ospemifene (Savolainen-Peltonen et al. 2004).

Finally, MDL 103,323 is a new SERM derived from clomiphene, originally developed as an antitumor drug for breast cancer, due to its potent inhibitor activity of breast cancer cell lines and its high affinity for ER (5- 6 times higher than tamoxifen) (Baumann et al. 1998). Subsequent preclinical studies in hy- pogonadal osteoporosis models have demonstrated that MDL 103,323 reduces bone turnover markers and increases bone mineral density and bone biomechanical properties in castrated rats and sheep (Chavassieux et al. 2001; Bourrin et al. 2002). There are few results on its effect on lipid metabolism, showing less efficacy than other SERMs in reducing high cholesterol levels induced by ovariectomy and with no modification in triglyceride levels (Ammann et al. 1999). Similarly, there are very little data published on its uterine effects. Published data are limited to the evaluation of uterine wet weight, a subrogate parameter of endometrial stimulation, with only partial predictive value in postmenopausal women.



The second group of SERMs includes drugs such as raloxifene (previously named keoxifene), arzoxifene (Fig. 2.2), and LY-117018. Raloxifene was initially designed as a drug to treat breast cancer, but its clinical development was later focused on prevention and treatment of postmenopausal osteoporosis, becoming the first SERM approved to prevent and treat this bone metabolic disorder. Raloxifene is also being investigated for the primary and secondary prevention of cardiovascular disease in postmenopausal women (Wenger et al. 2002) and in breast cancer prevention in high-risk women (Vogel et al. 2002). After tamoxifen, raloxifene is the SERM with the most information available on its pharmacological effects in postmenopausal women because of the size of its clinical program (over 40,000 women included in Phase III trials) and because of the fact that since its commercialization in 1998 it is estimated that approximately 2 million patients/year have been treated with the drug. Initial research on experimental osteoporosis models in castrated rats demonstrated raloxifene induces a bone antiresorptive effect similar to estrogens but without inducing endometrial proliferation (Black et al. 1994). In the same animal model, it has an effect on lipid metabolism very similar to estrogens (Black et al. 1994; Frolik et al. 1996). Furthermore, in vivo and in vitro studies on ER-positive breast cancer have shown raloxifene inhibits growth and tumor proliferation (Anzano et al. 1996), observations that have been confirmed in ER-positive breast cancer patients applying immunohistochemical markers of cell proliferation (Dowsett et al. 2001).

Fig. 2.2. Chemical structure of several SERMs in benzothiophene group

Clinical trials on postmenopausal women with osteoporosis have demonstrated that raloxifene reduces bone turnover markers by 25-35% after 1 year of treatment and reduces the relative risk of the occurrence of new vertebral fractures by 30-50% after 3 years of treatment (Ettinger et al. 1999). A post hoc analysis in women at high risk for cardiovascular diseases also showed a reduction of 40% in the rate of new cardiovascular events (Barrett-Connor et al. 2002), with no observed reduction in the overall study population after 4 years of treatment in the MORE trial.

The rate of invasive ER-positive breast cancer, a secondary objective in the MORE trial, showed an 84% reduction after 4 years of followup (Cauley et al.

2001); moreover, during the subsequent 4 years of followup in the so-called CORE trial (Continuous Outcomes Relevant to Evista), invasive ER-positive breast cancer, the primary objective of the study, was reduced by 66%. Over the 8 years of both trials, the incidences of invasive breast cancer and ER- positive invasive breast cancer were reduced by 66% and 76%, respectively, in the raloxifene group compared with the placebo group (Martino et al. 2004). These effects have not been associated with harmful effects on the endometrium (Cohen et al. 2000) or the pelvic floor (Goldstein et al. 2001).

Other drugs in this group are arzoxifene (LY353381-HCl), a potent benzothiophene similar to raloxifene that has demonstrated an antagonist potency 10 times greater that raloxifene in MCF-7 breast cancer and endometrial cancer cell lines (Sato et al. 1998). It is currently under research for treatment and prevention of postmenopausal osteoporosis given its favorable effects on cholesterol lowering, bone mineral density, and uterine weight in ovariec-tomized rats (Ma et al. 2002). LY-117018 has shown similar skeletal effects to raloxifene in osteoporotic experimental models (Li et al. 1998; Di'az Curiel et al. 1998). Phase II trials with different doses of arzoxifene in tamoxifen-sensitive and tamoxifen-resistant women with advanced or metastatic breast cancer showed positive results with reductions on the time to progression of disease (Buzdar et al. 2003) and response rates (Baselga et al. 2003).



The principal representative of this group of SERMs is lasofoxifene (CP-336,156) (Fig. 2.3), which is currently at Phase III of clinical research for the prevention and treatment of osteoporosis in postmenopausal women. Lasofoxifene shows excellent SERM-type properties in in vivo animal models, showing a binding affinity to ERa similar to estradiol, and approximately 10 times higher than other SERMs, including tamoxifen, raloxifene, and droloxifene (Ke et al. 1998). In ovariectomized rats treated with several doses of lasofoxifene for 52 weeks, there was no observation of stimulation of the endometrial epithelium, although a slight, but significant, increase in uterine weight was detected. It also was observed that bone mineral density loss and ultimate bone strength associated with ovariectomy was prevented at the lumbar spine level (Ke et al. 2004). Previous shorter studies had shown that in ovariectomized rats, lasofoxifene reduced serum cholesterol levels and fat body mass (Ke at al. 1998). Bone marrow cell cultures suggest that this bone effect may be mediated by a 15-25% increase in the number of apoptotic osteoclasts. Unlike other SERMs, lasofoxifene also has been studied in aging and orchidectomized male rat models. It has been shown that this drug prevents bone mass loss and reduction of bone biomechanical properties in these rats, which may be indicative of its potential role in the treatment of male osteoporosis secondary to hypogonadism or simply associated with old age (Ke et al. 2000,2001).

Recently, 1-year Phase II results in postmenopausal women have been reported. Lasofoxifene significantly decreased LDL-cholesterol and biochemical markers of bone turnover and significantly increased lumbar spine bone mineral density in early postmenopausal women, with no adverse effects on the reproductive tract and no clinically meaningful effect on the endometrium (Moffett et al. 2004). Head-to-head studies versus raloxifene have also been reported (McClung et al. 2004a,b). After 2 years of therapy, lasofoxifene 0.25 mg and 1 mg/day was associated with greater reductions in biochemical markers of bone turnover, fibrinogen, Lp(a), and LDL-cholesterol than raloxifene 60 mg/day. Lumbar spine BMD, but not hip BMD, was higher with lasofox- ifene therapy. The safety profile was relatively similar with the two SERMs having statistically significant differences versus placebo in the incidence of hot flashes and leg cramps and a significant increase in leukorrhea in the lasofoxifene arms (7%-11% versus 2% with raloxifene and 4% with placebo). No endometrial safety data were included in this preliminary report (McClung et al. 2004b).

Fig. 2.3. Chemical structure of several SERMs in naphthylene group

Trioxifene is an older SERM with low estrogenic properties and a higher affinity for ER than tamoxifen. It has shown an unfavorable safety profile in clinical studies of women with breast cancer (leukopenia in 41% of patients, nausea in 31%) (Witte et al. 1986), which is why, in addition to its response rates being no better than in tamoxifen (Lee et al. 1986), its clinical development has been cancelled.



The two principal representatives of this group of SERMs are pipendoxifene (ERA-923) and bazedoxifene (TSE-424, WAY-140424) (Fig. 2.4). Pipendoxifene is a potent SERM that is currently undergoing Phase II trials in women with hormone-dependent metastatic breast cancer (Sorbera et al. 2002). In preclinical studies, pipendoxifene inhibits estrogen-stimulated growth of the cell line MCF-7, at a similar rate to tamoxifen, but, unlike the latter, it also inhibits proliferation of endometrial and ovarian cancer cell lines. The most interesting aspect of pipendoxifene is that it has been shown to inhibit growth of breast cancer tumor lines that are resistant to tamoxifen, without stimulating the endometrium (Greenberger et al. 2001). Phase I trials on 50 healthy female volunteers treated for a 28-day period have not demonstrated significant effects on different bone turnover markers, on total cholesterol, HDL-cholesterol, or LDL-cholesterol, or on triglycerides (Cotreau et al. 2002); thus, its long-term effects on bone and cardiovascular disease are uncertain. About 20% of the study subjects reported hot flashes.

In addition to lasofoxifene and arzoxifene, bazedoxifene (TSE-424, WAY- 140424) is one of the newer SERMs in advanced Phase III clinical development for the prevention and treatment of postmenopausal osteoporosis. In pre-

Fig. 2.4. Chemical structure of several SERMs in indole group

clinical models, bazedoxifene has shown to fulfill the profile of a SERM: it binds with high and similar affinity to ERα and ERβ, inhibits proliferation of MCF-7 cells induced by estradiol, prevents bone mass loss in castrated rats, reduces serum cholesterol, and does not have a stimulant effect on the uterine epithelium of intact and ovariectomized rats (Miller et al. 2001). The selection of bazedoxifene in the molecular screening process to improve the SERM profile has incorporated new preclinical animal experiments especially designed to evaluate its potential secondary effects on the uterus, with the objective of avoiding problems previously encountered in the clinical development of other SERMs. Thus, bazedoxifene has not shown any agonist activity on in vitro models in an experiment to test the transcriptional activation of the promoter of the component of complement 3 (C3), which is a gene that requires estrogen stimulation to be expressed in the endometrial cells of rodents and has proven to be fairly reliable as a predictor of the in vivo endometrial response. In this model, other SERMs such as tamoxifen, idoxifene, and droloxifene do act as agonists of the C3 promoter (tamoxifen > idoxifene > droloxifene), while raloxifene stimulates it to a minimal extent (Komm et al. 2001).

Other interesting aspects that have been included in the bazedoxifene preclinical program is the evaluation of the vasomotor response in an experimental model of hot flashes, consisting of intact adult rats addicted to morphine, which develop a very marked vasomotor response when they receive a naloxone injection. This response, observed through a temperature increase of 4-5 °C in the rat’s tail, may be inhibited if the animal has been treated with estrogens. However, bazedoxifene and raloxifene do not act as estrogen agonist in this model (Komm et al. 2001). The antagonist effect of bazedoxifene and raloxifene on estrogen effects, in the prevention of vasomotor crises, occurs at a dose of ≥ 1.0mg/kg. Considering that the necessary dose of bazedoxifene to protect bone is 0.3 mg/kg, it appears that there is a certain therapeutic “window” to prevent the vasomotor response in these rats, and this would not be observed with raloxifene, which requires a dose of 3 mg/kg to produce beneficial effects on the bone in the castrated rat model. Published clinical data on this compound are limited. After 3 months therapy in 494 postmenopausal women, bazedoxifene (doses as low as 5 mg/d) had effects on bone turnover markers and LDL-cholesterol comparable to those seen with raloxifene. No increases in hot flashes or endometrial thickness were reported (Ronkin et al. 2001; Komm et al. 2001).



The SERMs that belong to the benzopyrans group form a large group of drugs (Fig. 2.5), several of which are at early stages of clinical development for the treatment of hormone-dependent breast cancer and endometrial cancer.

Ormeloxifene (centchroman) has been used since 1980 as an oral contraceptive in India using a weekly dose (Singh 2001), while its L-enantiomer (levormeloxifene) recently had its clinical program cancelled in the prevention and treatment of postmenopausal osteoporosis following the detection of uterine safety problems during Phase III clinical trials. This is probably the chemical group of SERMs that is undergoing more activity in the development of new target molecules. There has been a recent report on results in experimental models of postmenopausal osteoporosis using SP-500263 (Sutherland et al. 2003) in which has been shown a profile similar to raloxifene in the same model, also acting as an antiestrogen in in vitro breast cancer models.

EM-800 (SCH-57050) and its active metabolite EM-652 (acolbifene, SCH- 57068), are highly potent antiestrogens in human breast and uterine cancer cells in vitro as well as in vivo in nude mice and are currently undergoing clinical trials in the treatment of hormone-dependent breast cancer and endometrial cancer (Labrie et al 1999). Acolbifene shows a higher capacity of binding to the estrogenic receptor than the majority of pure estrogens and SERMs, and, in fact, its affinity for ERs is 2.9 times higher than estradiol itself. It shows a 200-fold greater potency than tamoxifen in displacing [3H]estradiol from ERs. In in vitro preclinical models on hormone-dependent breast tumors (cell lines ZR-75-1, MCF-7, and T-47D), endometrial adenocarcinoma cell lines, and also in in vivo tumor models (breast cancer induced by DBMA, xenografts of human breast cancer in athymic mice), acolbifene and EM-800 have been shown to inhibit tumor growth to a greater extent than pure anti estrogens such as fulvestrant (ICI 182,780) and ICI 164,384, and than 4-hydroxy-tamoxifen, toremifene, idoxifene, GW5638, droloxifene, and raloxifene (Labrie et al. 1999; Gutman et al. 2002).

Fig. 2.5. Chemical structure of several SERMs in benzopyrans group

Both EM-800 and acolbifene have been studied in the ovariectomized rat model, and their initial pharmacological profile (described as pure antiestrogens) has been ruled out because they also prevent bone mass loss and reduce cholesterol and triglycerides in a similar magnitude to raloxifene (Labrie et al.

1999). In a recent Phase II clinical trial in 42 patients with advanced-stage, tamoxifen-resistant breast carcinoma, EM-800 produced responses in a significant proportion of patients, results that previously had not been achieved with other SERMs, such as toremifene or raloxifene, when used as salvage therapy in tamoxifen-resistant patients (Labrie et al. 2004). The response observed was similar to fulvestrant, a pure antiestrogen, but, given the possible advantages of EM-800 and acolbifene regarding its oral bioavailability and its protective effect on bone loss, they can be considered potential alternatives once their efficacy and safety are confirmed in larger trials.

The preclinical and clinical development of levormeloxifene, a benzopyran SERM, and its final outcome present a paradigmatic experience in SERM pharmacological development because, for the first time, the data that indicated a SERM profile in animal studies were not confirmed in clinical research when the drug was subjected to Phase II—III clinical trial conditions. Thus, although levormeloxifene did not induce proliferation of the endometrial epithelium in castrated rats, postmenopausal women treated with this drug showed an increased endometrial thickness (approximately 6 mm versus placebo) after 1 year of treatment. Biopsies did not show any cellular proliferative findings (Alexandersen et al. 2001). These negative results were balanced with positive outcomes at the bone, with lumbar spine bone mineral density increases of 2.9% versus placebo, and in the lipid metabolism with 15% and 25% decreases in serum cholesterol and LDL-cholesterol in the levormeloxifene group (Alexandersen et al. 2001), respectively.

The second study, which included 2924 postmenopausal women with osteoporosis, had to be cancelled after 10 months due to a marked increase in adverse uterine effects induced by the two doses of levormeloxifene under study in comparison with the placebo arm: leukorrhea (30% versus 3%), increased endometrial thickness (19% versus 1%), increased uterine volume (17% versus 3%), uterovaginal prolapse (7% versus 2%), urinary incontinence (17% versus 4%), increased micturition frequency (9% versus 4%), and pelvic pain (17% versus 6%) (Goldstein et al. 2002). Similar findings were observed in clinical trials with idoxifene in which 1.5% of the women treated with this drug developed a uterine prolapse versus none in the placebo group (Hendrix et al. 2001). The mechanism behind these SERM-caused uterine effects is not clear, although there are several hypotheses that suggest greater elasticity of pelvic floor tissues secondary to collagen alterations, edema, or an increased uterine weight. A very recent report suggests that differences in the expression of matrix metalloproteinase 2 (MMP2) activity induced by estrogen and different SERMs in the uterus of ovariectomized rats may be relevant to collagen turnover and degradation and, hence, uterine prolapse and urinary incontinence. While estrogen, lasofoxifene, and levormeloxifene increased MMP2 activity in this model, which may result in increased proteolytic cleavage of type I and IV collagen, raloxifene did not (Helvering et al. 2004).

As a result of these findings, a scheduled standard pelvic exploration is now an obligatory procedure in clinical trials with new SERMs. It is important to note that this adverse effect has not been associated with tamoxifen or toremifene therapy (Maenpaa et al. 1997; Fisher et al. 1998), and in the case of raloxifene, a post hoc metaanalysis of 6926 nonhysterectomized postmenopausal women participating in clinical trials for 3 years or more showed a significant 50% reduction in the incidence of surgery for repairing pelvic floor relaxation, reported as an adverse event, compared with placebo (Goldstein et al. 2001).



The main pharmacodynamic characteristics of the SERMs that are currently available reflect their antineoplastic activity in estrogen-dependent breast cancer (tamoxifen and toremifene) and the beneficial effects on bone remodeling, bone mineral density, and reduction of osteoporotic fractures in postmenopausal women observed with raloxifene. However, one major consequence of the Women’s Health Initiative findings has been an increased interest in the full therapeutic potential of SERMs - still to be explored - because of their potential to retain some of the beneficial effects of estrogen while avoiding most of its adverse effects. Given the extraordinary complexity of the different diseases that SERMs can impact, this exploration is contemplated as a major, long-term, costly task. In this respect, clinical trials that are close to being finalized with raloxifene will clarify within the next few years the potential role of this SERM in primary prevention of breast cancer and cardiovascular disease in postmenopausal women. Likewise, the encouraging preliminary results on new SERMs such as lasofoxifene, bazedoxifene, arzox- ifene, ospemifene, etc. are still to be confirmed in large-scale clinical trials currently under way.

With regard to our current knowledge of these drugs, it is tempting to speculate on the ideal pharmacological characteristics of a selective estrogen receptor modulator (Fig. 2.6). Obviously, any new SERM that is intended for the treatment of breast cancer must, at a minimum, exceed tamoxifen’s efficacy regarding its rates of tumor remission and relapse, without having negative effects on uterine safety in terms of hyperplasia and endometrial neoplasia or uterine prolapse. Ideally, these new SERMs must be effective against tamoxifen-resistant breast cancer, and preliminary results with some of them are encouraging (Labrie et al. 2004), although a likely shift in the gold standard endocrine therapy of hormone-responsive breast cancer is on the horizon with the introduction of aromatase inhibitors (Smith et al. 2003). New SERMs that are planned to be developed for the prevention and treatment of osteoporosis and cardiovascular disease in postmenopausal women, in addition to showing a nonstimulant effect on the uterus and on the development of breast neoplasms, must ideally present a profile of neutral side effects with regard to the onset of hot flashes or venous thromboembolic disease, which are the principal side effects of raloxifene and tamoxifen.

Fig. 2.6. Illustration of pharmacological characteristics of a SERM with an ideal pharmaco logical profile

It is important to note that the reported increased risk, by a factor of 1.5 to 3, observed in venous thromboembolic disease with SERMs in wide use, namely tamoxifen and raloxifene, is very similar to that reported with the use of ET/EPT and oral contraceptives. Although the in-depth molecular mechanism of this procoagulatory activity in the venous territory is as yet unknown, it would appear that it is an estrogen-agonist effect in the SERMs that should be minimized or eliminated in the development of new molecules indicated for long-term use. Considering the present uncertainty regarding the role of ET/EPT in the prevention and treatment of senile dementia, it would be risky to suggest that SERMs may play a beneficial role in this pathology, but what is considered a must is that in no way can they become harmful. Therefore, it is necessary to carry out meticulous evaluations in preclinical models and during clinical trials of the effects of these drugs on higher cognitive functions. In this respect, clinical findings with raloxifene are encouraging (Yaffe et al. 2001; Neele et al. 2001).

Finally, a major question in SERM development is whether the new compounds will behave like estrogens with respect to cardiovascular events, which would be a worthless property given the results of the WHI trial (Writing Group for the Women’s Health Initiative Investigators 2002; Women’s Health Initiative Steering Committee 2004). This is a complex issue that will depend on the unique profile of action of the new SERM on the different components of the atherosclerosis process and the patient population and study design and conduct that is implemented.

Is it feasible to find a single drug with all these ideal characteristics? In the short term it does not appear to be realistic that one SERM alone will be able to fulfill all these requirements. However, the great speed at which progress is being made in the molecular biology of the ER activation cascade, together with progress in genomics and combinatorial and proteomic chemistry, there is room to be optimistic that if, for example, we can identify the coactivator proteins of a certain cell, we may be able to design ligands to ERs with a selective activity to recruit these coactivators, or we may be able to design molecules with an exclusive affinity for one ER subtype. All these advances will also benefit the development and extension of the pharmacological concept of executable modulation to other members of the nuclear receptor superfamily, like selective glucocorticoid receptor modulators, selective androgen receptor modulators, selective progesterone receptor modulators, and selective peroxisome proliferator-activated receptor modulators, among others.


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