Selective Estrogen Receptor Modulators (SERMs)

SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

Selective ER modulators (SERMs) are nonhormonal pharmacological agents that bind to ERs. A characteris-tic feature of the SERMs is that a given agent will act as an estrogen agonist in one or more tissues and as an es-trogen antagonist in one or more other estrogen target organs. Tamoxifen citrate (Nolvadex), clomiphene cit-rate (Clomid, Serophene) and raloxifene (Evista) are examples of nonsteroidal SERMs. The best studied SERM is tamoxifen citrate, a drug formerly character-ized as an antiestrogen.

Tamoxifen is a partial estrogen agonist in breast and thus is used as a treatment and chemopreventative for breast cancer. Tamoxifen is a full agonist in bone and endometrium, and prolonged use of tamoxifen leads to a fourfold to fivefold increase in the incidence of en-dometrial cancer.

Raloxifene (Evista) is a new SERM approved for use in the treatment and prevention of osteoporosis be-cause it has estrogenic activity in bone. Raloxifene is an estrogen antagonist in both breast and endometrial tis-sues. The estrogenlike properties of raloxifene result in the maintenance of a favorable serum lipid profile (de-creased low-density lipoprotein levels with no change in either high-density lipoproteins or triglycerides). Raloxifene is 95% bound to plasma proteins. Absorp-tion of raloxifene is impaired by cholestyramine.

Tamoxifen, clomiphene, and raloxifene are orally ac-tive. The primary route of excretion of all three drugs is in the feces. The undesirable effects common to all three of these SERMs are increased frequency of hot flashes and increased risk of thromboembolism. Both effects are attributable to their estrogenic activity.

Faslodex (Fulvestrant) is a SERM with no known agonist activity on the ER. It is administered as a monthly injection. In phase III clinical trials faslodex showed good activity against advanced breast cancer.