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

content of the bile. Transdermal estrogen appears to cause smaller
beneficial changes in LDL and HDL profiles (~50% of those seen
with the oral route) (Walsh et al., 1994) but may be preferred in
women with hypertriglyceridemia.
Tibolone (LIVIAL) is widely used in the E.U. for treatment of
vasomotor symptoms and prevention of osteoporosis but is not currently
approved in the U.S. The parent compound itself is devoid
of activity, but it is metabolized in a tissue-selective manner to
three metabolites that have predominantly estrogenic, progestogenic,
and androgenic activities. The drug appears to increase bone
mineral density and decrease vasomotor symptoms without stimulating
the endometrium, but its effects on fractures, breast cancer,
and long-term outcomes remain to be established (Modelska
and Cummings, 2002).
Regardless of the specific agent or regimen, menopausal hormone
therapy with estrogens should use the lowest dose and shortest
duration necessary to achieve an appropriate therapeutic goal.
Estrogen Treatment in the Failure of Ovarian Development. In
several conditions (e.g., Turner’s syndrome), the ovaries do not
develop and puberty does not occur. Therapy with estrogen at the
appropriate time replicates the events of puberty, and androgens
(Chapter 41) and/or growth hormone (Chapter 38) may be used concomitantly
to promote normal growth. Although estrogens and androgens
promote bone growth, they also accelerate epiphyseal fusion,
and their premature use can thus result in a shorter ultimate height.
SELECTIVE ESTROGEN RECEPTOR
MODULATORS AND ANTI-ESTROGENS
In the past, estrogen pharmacology was based on a simple
model of an agonist binding to a single ER that subsequently
affected transcription by the same molecular
mechanism in all target tissues and of antagonists that
acted by simple competition with agonists for binding.
This simple concept is no longer valid. By altering the
conformation of the two different ERs and thereby
changing interactions with co-activators and co-repressors
in a cell-specific and promoter-specific contexts, ligands
may have a broad spectrum of activities from
purely anti-estrogenic in all tissues, to partially estrogenic
in some tissues with anti-estrogenic or no activities
in others, to purely estrogenic activities in all
tissues. The elucidation of these concepts has been a
major breakthrough in estrogen pharmacology and
should permit the rational design of drugs with very
selective patterns of estrogenic activity (Smith and
O’Malley, 2004).
Selective Estrogen Receptor Modulators: Tamoxifen,
Raloxifene, and Toremifene. Selective estrogen receptor
modulators, or SERMs, are compounds with tissue-selective
actions. The pharmacological goal of
these drugs is to produce beneficial estrogenic actions
in certain tissues (e.g., bone, brain, and liver) during
postmenopausal hormone therapy but antagonist activity
in tissues such as breast and endometrium, where
estrogenic actions (e.g., carcinogenesis) might be deleterious.
Currently approved drugs in the U.S. in this
class are tamoxifen citrate, raloxifene hydrochloride
(EVISTA), and toremifene (FARESTON), which is chemically
related and has similar actions to tamoxifen.
Tamoxifen and toremifene are used for the treatment of
breast cancer, and raloxifene is used primarily for the
prevention and treatment of osteoporosis and to reduce
the risk of invasive breast cancer in high-risk postmenopausal
women. They are considered in detail in
Chapter 63.
Anti-Estrogens: Clomiphene and Fulvestrant. These
compounds are distinguished from the SERMs in that
they are pure antagonists in all tissues studied.
Clomiphene (CLOMID, SEROPHENE, others) is approved
for the treatment of infertility in anovulatory women,
and fulvestrant (FASLODEX) is used for the treatment of
breast cancer in women with disease progression after
tamoxifen.
Chemistry. The structures of the trans-isomer of tamoxifen, and of
raloxifene, trans-clomiphene (enclomiphene), and fulvestrant are:
1177
CHAPTER 40
ESTROGENS AND PROGESTINS