which is much higher than the normal rate. Also, antiestrogen use is associated with
birth defects in 2–3% of live newborns.
Antiestrogens (e.g., tamoxifen (5.38)) are also active as antitumor agents in estrogen-
dependent mammary carcinoma (breast cancer), a neoplasm that has estrogen receptors.
Hormonally responsive estrogen receptors are found in about two-thirds of all breast
tumors. Paradoxically, the use of tamoxifen as an antiestrogen to treat breast cancer is
associated with an increased risk of endometrial cancer as a delayed side effect.
Alternatively, breast tumors can sometimes be treated with androgens, preferably the
nonvirilizing derivatives (see section 5.10), in addition to removal of the ovaries.
Both clomiphene (5.37) and tamoxifen (5.38) are aminoether derivatives of stilbene.
They are both structurally related to the nonsteroidal estrogens such as diethylstilbestrol
(DES) and chlorotrianisene. However, the latter two compounds are estrogen agonists,
whereas the former two are estrogen antagonists. When a nonsteroidal estrogen, such
as DES, enters a cell’s nucleus, it first binds to DNA and then triggers two activation
factors (TAF1, TAF2) which in turn displace a repressor molecule, allowing transcrip-
tion and protein synthesis; in this manner, DES functions as an estrogenic agonist. With
antiestrogens, on the other hand, the aromatic ring structure permits DNA binding, but
the dialkyl aminoethyl side-group precludes triggering of the TAF1 activation factor;
accordingly, these agents are antagonists.
5.9 STEROID HORMONES: SEX HORMONES—PROGESTINS
(GESTAGENS)
These hormones are essential for the maintenance of pregnancy. The only natural prog-
estin hormone, progesterone (3.38), is produced by the corpus luteum, an endocrine
tissue formed in the ovary by the ruptured ovarian follicle after the level of luteinizing
hormone peaks. If pregnancy occurs, the corpus luteum persists for the first three
months of the pregnancy; after that, its role is taken over by the placenta as the major
HORMONES AND THEIR RECEPTORS 325