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

1184 Therapeutic Uses
The two most frequent uses of progestins are for contraception,
either alone or with an estrogen (Chapter 66;
see also later in this chapter), and in combination with
estrogen for hormone therapy of postmenopausal
women.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Progestins also are used diagnostically for secondary amenorrhea.
An oral progestin is given to an amenorrheic woman for 5-7 days. If
endogenous estrogens are present, withdrawal bleeding will occur.
Combinations of estrogens and progestins can also be given to test
for endometrial responsiveness in patients with amenorrhea.
In addition, progestins are highly efficacious in decreasing
the occurrence of endometrial hyperplasia and carcinoma caused by
unopposed estrogens; when used in this setting, there appears to be
less irregular uterine bleeding with sequential rather than continuous
administration. Local intrauterine application via a hormonereleasing
intrauterine device (IUD) containing levonorgestrel can be
used to decrease estrogen-induced endometrial hyperplasia while
reducing untoward effects (e.g., unfavorable lipid profiles and incidence
of breast cancer) of systemically administered progestins.
Finally, levonorgestrel is used as so-called emergency contraception
after known or suspected unprotected intercourse. The
medication is given orally within 72 hours after intercourse as either
a single 1.5-mg dose (PLAN B ONE STEP) or as two 0.75-mg doses
(PLAN B) separated by 12 hours. The mechanism of action may
involve several factors, including the prevention of ovulation, fertilization,
and implantation.
ANTI-PROGESTINS AND
PROGESTERONE-RECEPTOR
MODULATORS
The first report of an anti-progestin, RU 38486 (often
referred to as RU-486) or mifepristone, appeared in
1981; this drug is available for the termination of pregnancy
(Christin-Maitre et al., 2000). In 2010, the FDA
approved ulipristal acetate [ella (U.S.), ellaOne (E.U.)],
a partial agonist at the progsterone receptor, for emergency
contraception. Anti-progestins also have several
other potential applications, including to prevent conception,
to induce labor, and to treat uterine leiomyomas,
endometriosis, meningiomas, and breast cancer
(Spitz and Chwalisz, 2000).
O
N
MIFEPRISTONE
CH
OH 3
C CCH 3
O
O
N
N
Mifepristone
ONAPRISTONE
ULIPRISTAL ACETATE
CH
CH 2 CH 2 CH 2 OH
3
OH
Chemistry. Mifepristone is a derivative of the 19-norprogestin
norethindrone containing a dimethyl-aminophenol substituent at the
11β-position. It effectively competes with both progesterone and
glucocorticoids for binding to their respective receptors.
Mifepristone was initially thought to be a pure anti-progestin,
although it is now considered a progesterone-receptor modulator
(PRM) due to its context-dependent activity.
Other PRMs and pure progesterone antagonists now have
been synthesized, and most contain an 11β-aromatic group. Another
widely studied anti-progestin is onapristone (or ZK 98299), which is
similar in structure to mifepristone but contains a methyl substituent
in the 13α rather than 13β orientation. More selective progesteronereceptor
modulators, such as asoprisnil, are being studied experimentally
(DeManno et al., 2003).
Pharmacological Actions. Mifepristone acts primarily as
a competitive receptor antagonist for both progesterone
receptors, although it may have some agonist activity in
certain contexts. In contrast, onapristone appears to be a
pure progesterone antagonist. PR complexes of both
compounds antagonize the actions of progesterone-PR
complexes and also appear to preferentially recruit corepressors
(Leonhardt and Edwards, 2002).
When administered in the early stages of pregnancy, mifepristone
causes decidual breakdown by blockade of uterine progesterone
receptors. This leads to detachment of the blastocyst, which
decreases hCG production. This in turn causes a decrease in progesterone
secretion from the corpus luteum, which further accentuates
decidual breakdown. Decreased endogenous progesterone coupled
with blockade of progesterone receptors in the uterus increases uterine
prostaglandin levels and sensitizes the myometrium to their contractile
actions. Mifepristone also causes cervical softening, which
facilitates expulsion of the detached blastocyst.
Mifepristone can delay or prevent ovulation depending on the
timing and manner of administration. These effects are due largely
to actions on the hypothalamus and pituitary rather than the ovary,
although the mechanisms are unclear.
O
O
O