Page 751 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 40 The Gonadal Hormones & Inhibitors 737

contraceptive. When combined with a prostaglandin it is also an of patients, and many other minor adverse effects are observed.
effective abortifacient. Studies of patients treated with tamoxifen as adjuvant therapy for
early breast cancer have shown a 35% decrease in contralateral
Beneficial Effects of Oral Contraceptives breast cancer. However, adjuvant therapy extended beyond 5 years
in patients with breast cancer has shown no further improvement
It has become apparent that reduction in the dose of the constitu- in outcome. In fact, resistant lines of tumor cells may recognize
ents of oral contraceptives has markedly reduced mild and severe tamoxifen as an agonist rather than an antagonist, perhaps due to
adverse effects, providing a relatively safe and convenient method changes in the coregulators that interact with the estrogen recep-
of contraception for many young women. Treatment with oral tor. Toremifene is a structurally similar compound with very
contraceptives has also been shown to be associated with many similar properties, indications, and toxicities.
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 Hypothalamus
premenstrual symptoms, dysmenorrhea, endometriosis, acne, and
hirsutism may be ameliorated with their use.

■ ESTROGEN & PROGESTERONE
INHIBITORS & ANTAGONISTS – GnRH antagonists

GnRH
TAMOXIFEN & RELATED PARTIAL +/– GnRH agonists
AGONIST ESTROGENS
+ Clomiphene
Anterior
Tamoxifen, a competitive partial agonist inhibitor of estradiol pituitary – Oral
at the estrogen receptor (Figure 40–5), was the first selective contraceptives,
danazol
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 FSH, LH
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 Ovary
(ERα-ERβ) versus homodimers, competition of ERα by ERβ Progesterone
and others. Tamoxifen is extensively used in the palliative treat- (Luteal phase)
ment of breast cancer in postmenopausal women and is approved – Ketoconazole,
for chemoprevention of breast cancer in high-risk women (see danazol
Chapter 54). It is a nonsteroidal agent (see structure below) that
is given orally. Peak plasma levels are reached in a few hours. Testosterone
Tamoxifen has an initial half-life of 7–14 hours in the circulation
and is predominantly excreted by the liver. One of its metabolites Androstenedione
via CYP2D6 is 4-hydroxytamoxifen (endoxifen), a more potent – Anastrozole,
SERM. Therefore, strong inhibitors of 2D6 should be avoided others
in patients receiving tamoxifen. It is used in doses of 10–20 mg
twice daily. Hot flushes and nausea and vomiting occur in 25% Estradiol Estrone Estriol
– Fulvestrant
+/– SERMs
CH 3
OCH 2 CH 2 N
CH 3
Estrogen
response
element
C C
Expression in estrogen-responsive cells
CH 2 CH 3 FIGURE 40–5 Control of ovarian secretion and the actions of its
hormones. In the follicular phase the ovary produces mainly estro-
gens; in the luteal phase it produces estrogens and progesterone.
Tamoxifen SERMs, selective estrogen receptor modulators. See text.