Figure 25.15 • Selective estrogen receptor modulators (SERMs) and antiestrogens.

of the increased risk of endometrial cancer with tamoxifen therapy, tamoxifen should be used to prevent breast cancer only in women at high risk. Women without a family history of breast cancer or other risks should not use tamoxifen in this manner.

Raloxifene is another SERM, but its profile of activity differs from that of tamoxifen. Raloxifene is an ER antagonist in both breast and endometrial tissue, but has agonist action on bone and acts as an estrogen agonist in lowering total cholesterol and low-density lipoprotein (LDL). The subtle structural differences between the two drugs underlie the distinct activity profiles.55 The agonist action on bone tissue is the basis for the use of this drug for treating osteoporosis.

A key question is why do compounds like tamoxifen and raloxifene exhibit antagonist action in some tissues, but agonist action in other tissues? Major developments in the past few years are beginning to provide the answer to this ques-tion.15,56-58 Tamoxifen,59 raloxifene, and estradiol18 all bind to the ER at the same site, but their binding modes are different. In addition, each induces a distinct conformation in the transactivation region of the ligand-binding domain.18 These unique conformations dictate how the receptor-ligand complex will interact with coregulator proteins (coactivators or corepressors).56 In all tissues, the estradiol-ER complex recruits coactivators, so gene transcription is stimulated.

In breast tissue, both raloxifene- and tamoxifen-bound receptors prevent the association with coactivators, but rather recruit corepressors, so antagonist action is observed. In uterine tissue, however, the raloxifene-ER complex recruits corepressors, whereas the tamoxifen-ER complex recruits a coactivator, SRC-1, which leads to agonist action.57 An additional factor involved in this agonist action of tamoxifen is the context in which the liganded receptor interacts with the target gene. The liganded ER can interact directly with DNA or can interact indirectly by being tethered to other transcription factors. When the tamoxifen-bound receptor interacts in a tethered manner with the target genes in uterine tissue, the SRC-1 coactivator is recruited, and gene transcription is promoted.56,57 A deeper understanding of how the liganded receptors interact with target genes and the mechanisms for recruitment of coregulators may help explain the phenomenon of tamoxifen resistance, which results from increased tamoxifen agonism in breast tissue.56

Bazedoxifene is a new SERM that should soon be marketed for the treatment of osteoporosis. Bazedoxifene incorporates an indole ring system in place of the benzothiophene of raloxifene. Bazedoxifene was the result of a screening program that selected for compounds that did not stimulate breast or uterine tissue.60 Lasofoxifene, arzoxifene, and ospemifene are the other newer SERMs that are in the late stage of development (Fig. 25.15).61 Lasofoxifene can be viewed as a constrained, saturated analog of 4-hydroxytamoxifen. A new drug application (NDA) was filed with the Food and Drug Administration (FDA) in late 2007 and the review is still in progress. Structurally, arzoxifene is most similar to ralox-ifene, with an ether bridge, rather than a carbonyl bridge, attached to the benzothiophene core. Arzoxifene is being investigated (phase III) for treating osteoporosis and for preventing breast cancer. Ospemifene is an analog of toremifene, which has an OH in place of the A,A-dimethyl amino substituent. It is in phase III clinical trials for the treatment of vaginal atrophy in postmenopausal women.

Clomiphene is another drug that exhibits antiestrogen actions, but it is not used for treating breast cancer or osteoporosis; rather, it is used for increasing the odds of a successful pregnancy. Clomiphene's therapeutic application as an ovulation stimulant results from its ability to increase GnRH production by the hypothalamus. The mechanism is presumably a blocking of feedback inhibition of ovary-produced estrogens (via ER antagonism). The hypothalamus and pituitary interpret the false signal that estrogen levels are low and respond by increasing the production of GnRH. The increased GnRH, in turn, leads to increased secretion of LH and FSH, maturation of the ovarian follicle, and ovulation (as described previously in this chapter; see Fig. 25.9). Support for the feedback inhibition mechanism is provided by tests with experimental animals in which clomiphene has no effect in the absence of a functioning pituitary gland.

Multiple births occur about 10% of the time with patients taking clomiphene, and birth defects in 2% to 3% of live newborns. Vasomotor "hot flashes" occur about 10% of the time, and abnormal enlargement of the ovaries about 14%. Abdominal discomfort should be discussed immediately with the physician.

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