DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1180 increase the risk of ovarian cancer. The drug should not
be administered to pregnant women due to reports of
teratogenicity in animals, but there is no evidence of
this when the drug has been used to induce ovulation.
Clomiphene also may be used to evaluate the male
reproductive system because testosterone feedback on
the hypothalamus and pituitary is mediated to a large
degree by estrogens formed from aromatization of the
androgen.
Experimental SERM-Estrogen Combinations. There is
considerable interest in menopausal hormone therapy
using combinations of a pure estrogen agonist (e.g.,
estradiol) with a SERM that has predominantly antagonist
activity in the breast and endometrium but does
not distribute to the CNS. The strategy is to obtain the
beneficial actions of the agonist (e.g., prevention of hot
flashes and bone loss) while the SERM blocks
unwanted agonist action at peripheral sites (e.g., proliferative
effects in breast and endometrium) but does
not enter the brain to cause hot flashes. Animal studies
have been encouraging (Labrie et al., 2003), but clinical
efficacy and safety of this approach remain to be
established.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Estrogen-Synthesis Inhibitors
Several agents can be used to block estrogen biosynthesis.
Continual administration of GnRH agonists prevents
ovarian synthesis of estrogens but not their peripheral
synthesis from adrenal androgens (Chapter 38).
Aminoglutethimide inhibits aromatase activity, but its
use is limited by its lack of selectivity and its side effects
(sedation). It was discontinued in the U.S. in 2008.
The recognition that locally produced as well as circulating
estrogens may play a significant role in breast cancer has greatly stimulated
interest in the use of aromatase inhibitors to selectively block
production of estrogens (Chapter 63). Both steroidal (e.g., formestane
and exemestane [AROMASIN]) and nonsteroidal agents (e.g., anastrozole
[ARIMIDEX], letrozole [FEMARA], and vorozole) are available.
Steroidal, or type I, agents are substrate analogs that act as suicide
inhibitors to irreversibly inactivate aromatase, whereas the nonsteroidal,
or type II, agents interact reversibly with the heme groups of
CYPs (Haynes et al., 2003). Exemestane, letrozole, and anastrozole
are currently approved in the U.S. for the treatment of breast cancer.
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As discussed in Chapter 62, 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 adjuvant use for postmenopausal women (Coombes
et al., 2004), and are indicated either following tamoxifen for 2-5
years or as initial agents. They have the added advantage of not
increasing the risk of uterine cancer or venous thromboembolism.
Because they dramatically reduce circulating as well as local levels
of estrogens, they produce hot flashes. They lack the beneficial
effect of tamoxifen to maintain bone density and thus are usually
administered with bisphosphonates. Their effects on plasma lipids
remain to be established.
PROGESTINS
LETROZOLE
Compounds with biological activities similar to those of
progesterone have been variously referred to in the literature
as progestins, progestational agents, progestagens,
progestogens, gestagens, or gestogens. The progestins
(Figure 40–5) include the naturally occurring hormone
progesterone, 17α-acetoxyprogesterone derivatives in
the pregnane series, 19-nortestosterone derivatives in the
estrane series, and norgestrel and related compounds in
the gonane series. Medroxyprogesterone acetate (MPA)
and megestrol acetate are C21 steroids in the pregnane
family with selective activity very similar to that of progesterone
itself. MPA and oral micronized progesterone
are widely used with estrogens for MHT and other situations
in which a selective progestational effect is
desired. Furthermore, depot MPA is used as a long-acting
injectable contraceptive. The 19-nortestosterone derivatives
(estranes) were developed for use as progestins in
oral contraceptives, and although their predominant
activity is progestational, they exhibit androgenic and
other activities. The gonanes are another family of
“19-nor” compounds, containing an ethyl rather than a
methyl substituent in the 13-position. They have diminished
androgenic activity relative to the estranes. These
two classes of 19-nortestosterone derivatives are the
progestational components of most oral and some longacting
injectable contraceptives. The remaining oral
contraceptives contain a class of progestins derived from
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