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Hepatic metabolism of tamoxifen produces N-desmethyltamoxifen, which has affinity for ER comparable to that of tamoxifen, and lesser amounts of the highly active metabolites 4-hydroxytamoxifen and endoxifen, which have 25-50 times higher affinity for both ERa and ERfi. Raloxifene is a nonsteroidal, polyhydroxylated compound. Clomiphene has two isomers: zuclomiphene (cis-clomiphene), a weak estrogen agonist, and enclomiphene (trans-clomiphene), a potent antagonist. Fulvestrant is a 7a-alkylamide derivative of estradiol.

Hepatic metabolism of tamoxifen produces N-desmethyltamoxifen, which has affinity for ER comparable to that of tamoxifen, and lesser amounts of the highly active metabolites 4-hydroxytamoxifen and endoxifen, which have 25-50 times higher affinity for both ERa and ERfi. Raloxifene is a nonsteroidal, polyhydroxylated compound. Clomiphene has two isomers: zuclomiphene (cis-clomiphene), a weak estrogen agonist, and enclomiphene (trans-clomiphene), a potent antagonist. Fulvestrant is a 7a-alkylamide derivative of estradiol.

Pharmacological Effects

All of these agents bind to the ligand-binding pockets of both ERa and ERfi and competitively block estradiol binding. However, the conformation of the ligand-bound ERs differs with different ligands. The distinct ER-ligand conformations recruit different coactivators and corepressors onto the promoter of a target gene. While 17fi-estradiol induces a conformation that recruits coactivators to the receptor, tamoxifen induces a conformation that recruits co-repressors to both

ERa and ER(3. The agonist activity of tamoxifen in tissues such as the endometrium is mediated by ERa.

Tamoxifen exhibits antiestrogenic, estrogenic, or mixed activity depending on the target gene measured. Tamoxifen inhibits the proliferation of cultured human breast cancer cells and reduces tumor size and number in women, yet it stimulates proliferation of endometrial cells. The drug has an antiresorptive effect on bone and decreases total cholesterol, LDL, and Lp(a) but does not increase HDL and triglycerides. Tamoxifen approximately doubles the relative risk of deep vein thrombosis and pulmonary embolism and endometrial carcinoma. Tamoxifen produces hot flashes and other adverse effects, including cataracts, nausea, and hepatic steatosis. Due to its agonist activity in bone, it does not increase the incidence of fractures.

Raloxifene is an estrogen agonist in bone and reduces the number of vertebral fractures by up to 50% in a dose-dependent manner. The drug also acts as an estrogen agonist in reducing total cholesterol and LDL but does not increase HDL or normalize plasminogen-activator inhibitor 1 in post-menopausal women. Raloxifene does not cause proliferation of the endometrium. Raloxifene has an antiproliferative effect on ER-positive breast tumors and on proliferation of ER-positive breast cancer cell lines and significantly reduces the risk of ER-positive but not ER-negative breast cancer. Ralox-ifene does not alleviate the vasomotor symptoms associated with menopause. Adverse effects include hot flashes and leg cramps and a threefold increase in deep vein thrombosis and pulmonary embolism.

In women with a functional hypothalamic-hypophyseal-ovarian system and adequate endogenous estrogen production, clomiphene is used to induce ovulation in conditions such as polycystic ovarian syndrome and dysfunctional bleeding with anovulatory cycles.

Fulvestrant binds to ERa and ER(3 with an affinity comparable to estradiol but represses trans-activation. Fulvestrant also stimulates the proteolytic degradation of ERa, which may explain its efficacy in tamoxifen-resistant breast cancer.

Absorption, Fate, and Excretion

Tamoxifen given orally reaches peak plasma levels after 4—7 hours; it has two elimination phases (half-lives of 7—14 hours and 4—11 days; thus, 3-4 weeks of treatment are required to reach steady-state plasma levels). Tamoxifen is metabolized by hepatic CYPs, some of which it also induces. In humans, the potent antiestrogens 4-hydroxytamoxifen and endoxifen are produced in the liver. The major route of elimination involves N-demethylation and deamination. The drug undergoes entero-hepatic circulation, and excretion is primarily in the feces as conjugates of the deaminated metabolite.

Raloxifene has an oral bioavailability of about 2%. The drug has a t/2 of about 28 hours and is eliminated primarily in the feces after hepatic glucuronidation.

Clomiphene is well absorbed following oral administration, and the drug and its metabolites are eliminated primarily in the feces. The long plasma t122 (5-7 days) is due largely to plasma-protein binding, enterohepatic circulation, and accumulation in fatty tissues.

Fulvestrant is administered monthly by intramuscular depot injections. Plasma concentrations peak in 7 days and then are maintained for a month. The drug is eliminated primarily via the feces.

Therapeutic Uses breast cancer Tamoxifen is highly efficacious in the palliation of advanced breast cancer in women with ER-positive tumors and for hormonal treatment of both early and advanced breast cancer in women of all ages. Response rates are ~50% in women with ER-positive tumors and 70% for ER-positive, PR-positive tumors. Tamoxifen increases disease-free and overall survival; a 5-year treatment period is more efficacious than shorter treatments. Tamoxifen reduces by 50% the risk of developing contralateral breast cancer in women at high risk and is approved for primary prevention in this setting. Prophylactic treatment should be limited to 5 years. The most frequent side effect is hot flashes. Tamoxifen increases the risk of endometrial cancer and throm-boembolic disease by two- to threefold.

Toremifene has therapeutic actions similar to tamoxifen. Fulvestrant may be efficacious in women who become resistant to tamoxifen, perhaps by downregulating ERa. Untoward effects of fulvestrant include hot flashes, GI symptoms, headache, back pain, and pharyngitis.

osteoporosis Raloxifene reduces the rate of bone loss and may increase bone mass at certain sites. Raloxifene increased lumbar bone mineral density by more than 2% and reduced the rate of vertebral fractures by 30-50%, but did not significantly reduce nonvertebral fractures. Raloxifene does not appear to increase the risk of endometrial cancer. The drug has beneficial actions on lipoprotein metabolism, reducing both total cholesterol and LDL; HDL is not increased. Adverse effects include hot flashes, deep vein thrombosis, and leg cramps.

infertility Clomiphene is used primarily for treatment of female infertility due to anovulation. By increasing FSH levels, clomiphene enhances follicular recruitment. The drug is relatively inexpensive, orally active, and requires less extensive monitoring than do other fertility protocols. Untoward effects include ovarian hyperstimulation, increased incidence of multiple births, ovarian cysts, hot flashes, and blurred vision. Prolonged use (e.g., 12 or more cycles) may increase the risk of ovarian cancer. Clomiphene should not be administered to pregnant women due to reports of teratogenicity in animals, although there is no evidence of this in humans.

Estrogen-Synthesis Inhibitors

Continual administration of GnRH agonists prevents ovarian synthesis of estrogens but not their synthesis from adrenal androgens (see Chapter 55). The recognition that locally produced estrogens may play a significant role in breast cancer has greatly stimulated interest in the use of aromatase inhibitors to selectively block estrogen production. Both steroidal (e.g., formestane and exemestane [aromasin]) and nonsteroidal agents (e.g., anastrozole [arimidex], letrozole [femara], and voro-zole) are available. Steroidal (type 1) agents are substrate analogs that act as suicide inhibitors to irreversibly inactivate aromatase, while the nonsteroidal (type 2) agents interact reversibly with the heme groups of CYPs. Exemestane, letrozole, and anastrozole are approved in the U.S. for the treatment of breast cancer. The structures of exemestane and anastrozole are shown in the 11th edition of the parent text:

These agents may be used as first-line treatment of breast cancer or as second-line drugs after tamoxifen. They are highly efficacious and actually superior to tamoxifen in some adjuvant settings; unlike tamoxifen, they do not increase the risk of uterine cancer or venous thromboembolism. Because they dramatically reduce circulating and local levels of estrogens, they produce hot flashes. The marked decreases in estrogen levels are likely to be associated with significant bone loss, but long-term studies are needed.

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  • demsas
    Does raloxifene raise blood pressure?
    5 months ago

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