Estrogen Agonists/Antagonists in Combination With Estrogen for Prevention and Treatment of Menopause-associated Signs and Symptoms

Dale W Stovall; JoAnn V Pinkerton


Women's Health. 2008;4(3):257-268. 

In This Article

Estrogen Agonists/Antagonists

Estrogen agonists/antagonists are compounds with tissue-selective actions. The pharmacological goal of these compounds is to produce beneficial estrogenic actions in certain tissues (e.g., bone and brain), but antagonistic activity in tissues such as the breast and endometrium where long-term estrogen actions might be deleterious. Currently approved drugs in the USA in this class include tamoxifen citrate (e.g., Nolvadex®), raloxifene hydrochloride (Evista®) and toremifene (Fareston®), which is chemically related to and has similar actions to tamoxifen. Recently, clinical trials involving bazedoxifene, studied specifically for use in menopausal women, have been completed. However, this compound is not currently approved by the FDA. Tamoxifen and toremifene are approved for the treatment of breast cancer; tamoxifen is also approved for breast cancer prevention. Raloxifene is currently approved for the prevention and treatment of osteoporosis, and for the prevention of invasive breast cancer.

Tamoxifen is a triphenylethylene with the same stilbene nucleus as diethylstilbesterol, it is administered orally and peak plasma levels are reached in 4 to 6 h. It displays two elimination phases with half-lives of 7 to 14 h and 4 to 11 days. Tamoxifen has an antiresorptive effect in bone and stimulates proliferation of endometrial cells. It causes a two- to three-fold increase in deep venous thrombosis and pulmonary embolism and a twofold increase in endometrial cancer.[12] Tamoxifen also produces hot flashes, cataracts and nausea. It has been shown to induce ovulation and to be similarly effective as compared to clomiphene citrate.

Raloxifene is a second-generation estrogen agonist/antagonist. It is a polyhydroxylated nonsteroidal compound with a benzothiophene core. It is rapidly absorbed after oral administration and has an absolute bioavailablity of approximately 2%. The drug has a half-life of approximately 28 h. Raloxifene is an estrogen agonist in bone, where it exerts an antiresorption effect. The drug does not cause endometrial stimulation and significantly reduces the risk of ER-positive breast cancer. Adverse effects include hot flashes and leg cramps.

Bazedoxifene is an investigational nonsteroidal indole-based estrogen agonist/antagonist that is being developed as a daily oral drug for the prevention and treatment of postmenopausal osteoporosis. In Phase I clinical trials, the maximum plasma concentration was 1-2 h after dosing with serum, the half-life was approximately 28 h and there was greater than 99% protein binding. Steady-state plasma concentrations are reached by day 7 to 14.[13,14] Bazedoxifene has shown affinity for both ERα and ERß, with slightly more affinity for ERα and serves as a competitive inhibitor of 17ß-estradiol at either receptor. Bazedoxifene does not promote the proliferation of breast cells, and in the presence of 17ß-estradiol-treated cells, inhibits proliferation. This inhibition is dose-dependent, thus bazedoxifene is likely antagonistic in breast tissue, similar to raloxifene.[13] Clinical studies have shown prevention of bone loss in postmenopausal women without osteoporosis and reduction in vertebral fracture risk in postmenopausal women, without stimulation of endometrium or breast. Bazedoxifene combined with conjugated estrogens (CE) is being investigated as a tissue-selective estrogen complex, pairing a selective ER modulator with estrogens. Clinical trials with bazedoxifene/CE in postmenopausal women have shown skeletal benefit with improvement in menopausal vasomotor symptoms and little or no stimulation of endometrial or breast tissue.


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