It has become apparent that reduction in the dose of the constituents of oral contraceptives has markedly reduced mild and severe adverse effects, providing a relatively safe and convenient method of contraception for many young women. Treatment with oral contraceptives has also been shown to be associated with many benefits unrelated to contraception. These include a reduced risk of ovarian cysts, ovarian and endometrial cancer, and benign breast disease. There is a lower incidence of ectopic pregnancy. Iron deficiency and rheumatoid arthritis are less common, and
CHAPTER 40 The Gonadal Hormones & Inhibitors 737 of patients, and many other minor adverse effects are observed. Studies of patients treated with tamoxifen as adjuvant therapy for early breast cancer have shown a 35% decrease in contralateral breast cancer. However, adjuvant therapy extended beyond 5 years in patients with breast cancer has shown no further improvement in outcome. In fact, resistant lines of tumor cells may recognize tamoxifen as an agonist rather than an antagonist, perhaps due to changes in the coregulators that interact with the estrogen receptor. Toremifene is a structurally similar compound with very similar properties, indications, and toxicities.
contraceptives,
Ketoconazole, danazol
Anastrozole, others premenstrual symptoms, dysmenorrhea, endometriosis, acne, and hirsutism may be ameliorated with their use. ■ ESTROGEN & PROGESTERONE INHIBITORS & ANTAGONISTS TAMOXIFEN & RELATED PARTIAL AGONIST ESTROGENS Tamoxifen, a competitive partial agonist inhibitor of estradiol at the estrogen receptor (Figure 40–5), was the first selective estrogen receptor modulator (SERM) to be introduced. The mechanism of its mixed agonist/antagonist relations to the estrogen receptor has been intensively studied but is still not completely understood. Proposals include recruitment of differ-ent coregulators to the estrogen receptor when it binds tamoxi-fen rather than estrogen, differential activation of heterodimers (ERα-ERβ) versus homodimers, competition of ERα by ERβand others. Tamoxifen is extensively used in the palliative treat-ment of breast cancer in postmenopausal women and is approved for chemoprevention of breast cancer in high-risk women (see Chapter 54). It is a nonsteroidal agent (see structure below) that is given orally. Peak plasma levels are reached in a few hours. Tamoxifen has an initial half-life of 7–14 hours in the circulation and is predominantly excreted by the liver. One of its metabolites via CYP2D6 is 4-hydroxytamoxifen (endoxifen), a more potent SERM. Therefore, strong inhibitors of 2D6 should be avoided in patients receiving tamoxifen. It is used in doses of 10–20 mg twice daily. Hot flushes and nausea and vomiting occur in 25% CH3GnRH FSH, LH Estradiol Estrone Estriol Fulvestrant SERMs Estrogen response element Testosterone Progesterone Oral––(Luteal phase) Androstenedione –+danazol –––+/–+/AnteriorpituitaryOvary
FIGURE 40–5 Control of ovarian secretion and the actions of its hormones. In the follicular phase the ovary produces mainly estrogens; in the luteal phase it produces estrogens and progesterone. SERMs, selective estrogen receptor modulators. See text.
Prevention of the expected loss of lumbar spine bone density and plasma lipid changes consistent with a reduction in the risk for atherosclerosis have also been reported in tamoxifen-treated patients following spontaneous or surgical menopause. However, this agonist activity also affects the uterus and may increase the risk of endometrial cancer.